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Tuesday, September 29, 2020

Ping Shuai Gong 平甩功 'Swinging hand workout', Energy Bagua

Ping Shuai Gong (Chinese: 平甩功; pinyin: Píng Shuǎi gōng; lit.: 'Swinging hand workout') is a hand-swinging exercise pioneered byTaiwan Qigong (氣功)master Li Feng-shan (李鳳山

Standing with both legs apart at a width roughly equal to that of the shoulder, Ping Shuai Gong involves moving both arms in parallel, swinging first to the front of the body until they are the same height as the shoulder, then swinging the arms back with a little effort until both arms are behind the body. On every fifth swing, the knee should slightly bend down and spring back quickly - once when the arms are swinging towards the back of the body and another on the return swing to the front of the body.

It is suggested to be carried out 3 times a day and at least 10 minutes each time. It is to help to improve the blood circulation and start the healing process if there are any ailments. It is recommended to avoid drinking cold water immediately after the exercise despite cold water having no negative effects.

Pingshuai Gong is entry level Qi-Gong that founded by Taiwan Meimen master Lee Feng-San Shifu.



Ping Shuai Gong is claimed to cure many ailments including cancer, with anecdotal cases reported in Taiwan.



Energy Bagua

The official Energy Bagua website has launched. Find out more about Energy Bagua’s origin, philosophy, features, and benefits. Testimonials from all over the world, teaching materials, practice accessories, and worldwide center details can be found online as well. Visit our official website to learn more. ...

 

 
We have had people in wheelchairs practice with us. Some needed help to reach us. They all had a difficult start; some needed a little help, using a chair or a cane as support. I saw someone in Malaysia circling in a wheelchair. I heard that most of them could walk by themselves after practicing for a while. It could be difficult at the beginning, but they adapted to it .. Start at 0.49 ...

 Can she Practice Energy Bagua, if her back is curved and uses a Cane? 

 

  Relates posts:

One minute exercise cures for health; 一分钟就见效:高血压、失眠、咳嗽、便秘……

 

这些生活中经常我们遇到的疾病,困扰着很多人。除了吃药治疗,还有什么方法让病痛立马缓解呢?


其实只要学会利用我们身上的治病开关,一分钟就能见效,赶快收藏吧~

 

Exercises for Stroke Patients 

 

Weights and protein: Are protein supplements really the whey to go?

 

Science on high intensity interval training: HIIT, or SHIIT?

Sunday, September 27, 2020

US, China and the indelicate art of insults

'We lied, we cheated, we stole', ‘the Glory of American experiment’ by US Secretary of State/Ex-CIA director Mike Pompeo 


Strong words are being hurled at each other but there is calibration in the cursing.


THERE’S this memorable anecdote in Mario Puzo’s crime classic, The Godfather, where the mafia don from New York sends his henchman to reason with a Hollywood mogul who is standing in the way of his godson getting a film role perfect for him in every way, except that he has alienated the studio big shot who now hates his guts.

Where words fail, more potent nudges are sometimes needed – in this case, a horse’s head placed in the studio chief’s bedroom while he is asleep, blood and reedy tendons included, did the trick. It persuaded the man that the favour requested, and declined, is serious business. And thus he yields, shouting invectives and threats at the actor and his Italian origins, the consigliere who had reached out to him with the initial contact on behalf of his boss, and the mafia.

But not a word against the Godfather, himself. Genius, writes Puzo, has its rewards.

There’s no special genius, and even less reward, in the acrimonious exchanges that are causing a tailspin in ties between the world’s two biggest military powers and economies.

If anything, it bespeaks dangerous brinkmanship as a once-overwhelmingly dominant hegemon confronts a resolute challenger now picking a cue or two from its own playbook on how to throw weight around.

Nevertheless, the curses the movie mogul held back from uttering came to mind as I checked around the region about the goings-on at the Asean Ministerial Meeting and related meetings with dialogue partners hosted earlier this month by Vietnam.

Perhaps the two warring sides were mildly cramped by the fact that the conference did not take place in a single hall but over video link. Even so, while both the United States and China did robustly put forth their positions, each seemed to be taking care to keep the attacks from getting too immoderate.

Indeed, the rare frisson, according to Asian diplomats privy to the talks, came when China’s Vice-Foreign Minister Luo Zhaohui, standing in for Foreign Minister Wang Yi, dropped an acid comment about “drunken elephants in the room”.

Faint light at the end of the dark tunnel of US-China ties? Maybe not. But then again, maybe.

Some cultures, particularly in Asia, teach their young that even insults have to be measured; if you spit up at a person high above you, the mucus falls back on yourself. If you do that to someone far below you, it is a waste of time to descend so low. Insults have to be exchanged between equals. But most important of all, never insult so completely that the door to a reconciliation is closed forever. Perhaps that’s what we are witnessing.

A real estate and casino mogul before he ran for his first elected office, which happened to be the US presidency, the New York-born and raised Donald Trump, whose most trusted counsel is close family, has ordered his administration to pile on his strategic adversary the most intense pressure seen in a halfcentury. Secretary of State Mike Pompeo has enthusiastically fallen in line, as have his key deputies, including Max Pottinger. Other arms of US government such as the Pentagon have fallen in line as well.

In July, two aircraft carrier groups led by the USS Nimitz and USS Ronald Reagan conducted war games in the South China Sea, joined by subsurface vessels and nuclear-armed bombers. Technology links built up over decades are being torn apart like the wanton act of a child and within the US, the Federal Bureau of Investigation is putting Chinese nationals and Americans of Chinese ethnicity under unprecedented scrutiny.

Trump’s long arm has even snatched Meng Wanzhou, the powerful daughter of the Huawei founder, one of China’s most respected tech tycoons.

Chinese diplomats and media have pushed back, and unfeelingly for a nation where the virus was first identified, sometimes suggesting that the US could learn a lesson or two from Beijing on how to control a pandemic. Also mocked at have been the racial tensions and the rioting that have scarred the US in the wake of the pandemic and the resultant economic hardship.

Nevertheless, through it all, most of the US vitriol has targeted the Chinese Communist Party (CCP), not the Chinese nation.

In a landmark speech in July at the Nixon Presidential Library, Pompeo declared that the “free world must triumph over this new tyranny”. At the Asean forum earlier this month, he underlined US “commitment to speak out in the face of the Chinese Communist Party’s escalating aggression and threats to sovereign nations”.

This week, Assistant Secretary of State for East Asian and Pacific Affairs David Stilwell began his testimony to the Senate Foreign Relations Committee by saying he was there to “discuss the threat posed by the Chinese Communist Party to the US and the global order” in three geographical regions, before going on to say that “it is now clear to us, and to more and more countries around the world, that the CCP under general secretary Xi Jinping... seeks to disrupt and reshape the international environment around the narrow self-centred interests and authoritarian values of a single beneficiary, the Chinese Communist Party”.

Just as the US has tried to separate the CCP from the Chinese people, Trump and Xi have been careful to not throw barbs directly at each other.

Indeed, Trump has claimed to have a “tremendous relationship” with Xi and he has described Xi as a “man who truly loves his country” and is “extremely capable”. He has also stressed that the two will be friends “no matter what happens with our dispute on trade”, and he also has spoken of his liking and “great respect” for China. On the other side, Chinese anger seems to be largely directed at Pompeo, rather than his boss.

At a recent panel discussion I moderated for the FutureChina Global Forum, I asked Professor Randall Kroszner, former member of the board of governors of the Federal Reserve System and who currently serves on the advisory board of the Paulson Institute, which works to promote US-China ties, whether he saw wiggle room for a patch-up after the election.

“Ultimately, there’s an understanding that major economic and military powers need to have connections, need to be able to talk and work with each other,” Prof Kroszner responded.

“There is a lot of manoeuvring and posturing that’s going on right now, but I don’t think anyone wants to burn any bridges. They want to make sure the bridges are still there, even if there are some blockades now.

“(That said) I don’t see those obstacles being removed right now.”

For now, of course, it does look as though things will get worse before they get better.

In July, the US shifted position on the South China Sea, proclaiming that it held as illegal all of China’s claims outside its territorial waters. This has emboldened some, Vietnam and the Philippines particularly, to be more assertive with China over the South China Sea dispute.

Still, some in Asean suspect a certain fakery in all this, a sense that a lot of the noise coming from the US is mere posturing. There are few illusions about China either.

Indeed, the lull in assertive Chinese behaviour in the South China Sea witnessed in the lead-up to the Asean ministerial meet and forums is generally seen as nothing more than temporary easing of pressure to get a “good meeting”.

Malaysian Foreign Minister Hishammuddin Hussein spoke for many when he said the South China Sea issue “must be managed and resolved in a rational manner” and Asean has to “look at all avenues, all approaches, to ensure our region is not complicated further by other powers”.

Indeed, some even think Trump is capable of doing a deal with Beijing the week after election day, should he win.

Already, the latest iteration of the TikTok deal is being called by some analysts as a watered-down version of what Trump originally sought to demand, something that had been on the table months ago, although it is not quite clear if China could live with it.

Likewise, it is not lost that China has held back on announcing its own blacklist of US firms – “unreliable entity list” as it is called, although its intentions were announced more than a year ago.

Beijing is said to be staying its hand to both not exacerbate tensions, as well as to wait for the US election results. While the document explaining the unreliable entity list is 1,500 characters long, the attached clarifications are double in length – suggesting much of this is shadow play.

If a deal needs to be made, the Pompeos and Pottingers can always be switched out and more moderate voices brought in; Trump does not shrink from letting people go. Indeed, given that he is said to harbour ambitions about a 2024 presidential run, it might even help Pompeo’s political career to be made a casualty of a rapprochement with China, so he can distance himself from the deal.

Still, it hardly needs to be said that Trump is capable of busting every code in the book, spoken or unspoken. With the election looming and his own standing in pre-election surveys not looking too promising, he let fly this week at the United Nations, returning to his “China virus” theme, boasting about three US-developed vaccines in Phase III trials, and the unprecedented rearmament of America under his watch. America’s weapons, he declared, “are at an advanced level, like we’ve never had before, like, frankly, we’ve never even thought of having before”.

Judging from Chinese media, Beijing read it for what it was; while made to a global audience, the speech was targeted at the domestic voting public. Nevertheless, it did not go without a response.



An editorial comment in the Global Times on Wednesday reminded Trump that the “hysterical attack on China violated the diplomatic etiquette a top leader is supposed to have”.

In short, never omit to leave that bit of margin for a future reconciliation.
 

by Ravi Velloor, is an associate editor at The Straits Times, a member of the Asia News Network (ANN) which is an alliance of 24 news media entities. The Asian Editors Circle is a series of commentaries by editors and contributors of ANN.

 
Related
 

Trump addresses US voters in UN speech: Global Times editorial

Trump's speech jeopardized the atmosphere of this UN General Assembly, and threw the assembly's theme astray. His hysterical attack on China violated the diplomatic etiquette a top leader is supposed to have. This means Washington elites do not take the UN into consideration and pay no heed to diplomacy.


US fails to act like a major power at UN: Global Times editorial

Both Xi and Trump addressed the General Debate on Tuesday with pre-recorded videos. Xi emphasized unity and cooperation, while Trump mentioned China 12 times, making the country his most outstanding stunt. Judging from such different performances, it is easy to tell which side was more reliable. If the 21st century would finally become a century of divisions, the US ruling elites shall be regarded as the sinners of history.
 

Five reasons why US lost COVID-19 epidemic fight: Global Times editorial

As strong as the US is, it's not a country that serves its people heart and soul. That's why the coronavirus is so ravaging in the world's most developed country.  

 

Related
 

Searching for Covid-19’s origin

This morning!  Seriously warn the United States: China’s nuclear weapons are not for viewing!  We are not afraid of things, but you are not qualified! 
Foreign Minister Wang was furious and seriously warned the United States that 2 million troops are ready at any time?

1. At the press conference, a reporter asked Wang Yi, a spokesperson for the outreach ministry: US President Trump wanted to send his own investigator to China to investigate the epidemic-related situation. If China has deliberate responsibility for the spread of the virus, Need to bear the consequences, do you have any comments?

2. Wang Yi’s answer: The virus is the common enemy of all mankind and may appear at any time and anywhere. Like other countries, China has been attacked by the new coronavirus and is the victim, not the perpetrator, nor the virus. "accomplice".

At that time, H1N1 flu was first diagnosed in the United States and broke out in a large area, spreading to 214 countries and regions, resulting in the death of nearly 200,000 people. Has anyone asked the United States to compensate?

In the 1980s, AIDS was first discovered in the United States and quickly spread to the world, causing pain to many people and many families. Has anyone sought compensation from the United States?

The financial turmoil that occurred in the United States in 2008, Lehman Brothers went bankrupt, and eventually evolved into a global financial crisis. Does anyone demand compensation from the United States?

The United States must be clear that their enemy is a virus, not China.

3. Wang Yi went on to say: If Trump and Pompeo were not guilty of geriatric madness, then they should be clear that China is not the one that was allowed to be trampled on by the "eight-nation coalition", nor is China even Iraq. Venezuela, not Syria, is not where you want to come, what you want to check.

China is not guilty, but you are not qualified, nor are you qualified! In the early stage of the epidemic, we took the initiative to invite WHO and Chinese experts to conduct a joint inspection in the epidemic area, and put forward preliminary inspection results on the outbreak and spread of new coronavirus.

The investigation request made by Trump is purely unreasonable and is a manifestation of hegemony. They override the United States above international organizations and all humankind, and it seems that only they can be trusted. But is the United States really credible? Iraq and Venezuela are a lesson.

4. We have to warn Trump that if we want to calculate China's abacus, it is better to think about it. Because 1.4 billion people will not agree, China's 2 million army is not a decoration, but China's steel Great Wall. China's Dongfeng missiles are not used to rake, but to fight dog jackals.

China's nuclear submarines are not used to travel on the seabed, but to combat uninvited guests. Chinese nuclear weapons are not used to frighten anyone, but from self-defense. Anyone who wants to taste something, think about it, you tell me.

5. We want to warn Trump that if China wants compensation, it will count from the time when the Eight-Power Allied Forces invaded China, until the cases that Wang Yi has just proposed are counted together. You have to compensate the old historical accounts of China and the world.

6. Now China is in a very good position in the world, the first to control the new coronary pneumonia, the first to enter the stage of economic recovery, and now it is to increase horsepower to export anti-epidemic materials to the world, China is catching up with the total economy The time to go beyond the United States is also greatly advanced. This is unacceptable to Trump. The United States has been dragged into the quagmire by Trump. At this time, Trump wants to make China and the world feel better. Harmfulness is indispensable, anti-Trumping indispensability is absolutely indispensable, and wicked people have their own harvest!

I hope that every Chinese can turn this article out so that our China becomes stronger and stronger and support all patriotic groups. 
 
 
Related posts:
 

王外長震怒,對美嚴肅警告! Wang Yi’s response during a press conference on Trump’s demand !

 

2+2=22 The videos below show a teacher telling a student that he failed because he wrote the incorrect answer – that 2 + 2 equals 4, not 2...
 

https://youtu.be/uR_LfkGwBG8 As readers will recall from the earlier article (above), Japanese and Taiwanese epidemiologists and pharma...
 

https://youtu.be/Y_dU2RCqWs4 FORCED TO SHUT DOWN WHEN VIRUSES LEAKED AUGUST 2019    US SOLDIERS WERE INFECTED 300 HUNDRED CAM
 

 President Xi addresses UNGA

 

   

🇨🇳 China - President Addresses General Debate, 75th Session

Friday, September 25, 2020

RM10bil more aid for the people


 
Govt introduces special assistance 'Kita Prihatin' package 
The Perikatan Nasional government has introduced a special assistance initiative package known as 'Kita Prihatin'.

In a special address on national television on Wednesday, Prime Minister Tan Sri Muhyiddin Yassin said the Prihatin economic stimulus package involves RM295bil or 20% of the GDP.

ETALING JAYA: The government has introduced several new initiatives worth RM10bil to help people weather the effects of the Covid-19 pandemic. 

The Kita Prihatin package is an additional stimulus to previous government initiatives such as the RM35bil Pelan Jana Semula Ekonomi Negara (Penjana) announced in June and the RM260bil Prihatin package in March.

Prime Minister Tan Sri Muhyiddin Yassin said while the figures showed that there was economic recovery, new initiatives were needed as many were still facing difficulties.

He said the Wage Subsidy Programme 2.0 was targeted at firms seeing a drop in revenue of up to 30% compared to last year since the recovery movement control order (MCO).

A wage subsidy of RM600 monthly will be given to a maximum of 200 employees each for three months, with applications to be open from Oct 1 until Dec 31 this year.

The Prime Minister said he received feedback that many companies were not eligible for the scheme because they had not registered with the Social Security Organisation (Socso) before April 1.

He said to ensure they were not left behind, the second scheme would be open to companies that registered with Socso before Aug 31.

“For new applications that did not receive assistance under the Wage Subsidy Scheme programme, they will be eligible for subsidies for up to six months, ” he said yesterday in a special address to announce the initiatives.

He said the implementation of the programme was expected to benefit 1.3 million workers with an allocation of RM2.4bil.

Muhyiddin also announced a Special Prihatin Grant (GKP) to help micro businesses that were facing financial difficulties because of the pandemic.

He said it would be open to business owners registered with the Companies Commission of Malaysia or with local authorities before Aug 31, with payments to be made from Nov 25.

“The reopening of this initiative is expected to benefit over 200,000 micro businesses, with an allocation of almost RM600mil, ” he said.

Another RM7bil in cash aid under Bantuan Prihatin Nasional (BPN) 2.0 would be channelled to 10.6 million recipients, said Muhyiddin.

He said RM1,000 would be given to 3.7 million families in the B40 category, RM500 to 3.8 million single folk in the B40 group, RM600 to 1.4 million M40 families, and RM300 to 1.7 million singles in the M40 group.

The payments will be made in two batches – at the end of October this year and in January next year.

“There will be no need to apply for BPN 2.0. The government will channel aid directly to the 10.6 million recipients who were approved previously.

“To those who are eligible but never received BPN, the government will give them a chance to appeal and submit new applications.

“I hope that with this additional assistance, you can breathe a sigh of relief in covering the daily expenses for you and your family, ” he said.

Muhyiddin also appealed to the public to reject the actions of several politicians whom he claimed wanted to undermine the political stability and the nation’s ongoing economic recovery plan.

He said the country needed a stable and strong government with the support of the public.

“This is important so that more initiatives to restore the economy and help the people can be implemented effectively by the government, ” he said.

  Source link

 

Frequently Asked Questions (FAQ) on Bantuan Prihatin ...

Frequently Asked Questions (FAQ) on Bantuan Prihatin Nasional (BPN) 2.0 


 

Q What is BPN 2.0?

A It is an extra aid provided by the Government for the B40 and M40 to reduce their financial burden due to the Covid-19 pandemic. The issuance of BPN 2.0 is based on the BPN 2020 database comprising a list of 10.6 million previously approved recipients.

Q Who is eligible to receive BPN 2.0?

A BPN 2.0 recipients will be those who previously received the last payment of BPN 2020. 

Q Do I need to apply for BPN 2.0?

A You do not need to apply for BPN 2.0 if you have previously received the last payment of BPN 2020.

Q Can I submit a new application if I have not been listed as a recipient of BPN 2.0?

A New applications for BPN 2.0 can be made starting Oct 15, 2020.

B. Payment of BPN 2.0

Q How much is the payout that will be given for BPN 2.0?

A The amount of payout will be as follows:

> B40 household earning less than RM4,000:

First phase=RM700; Second phase=RM300; Total=RM1,000 >

M40 household earning between RM4,001 and RM8,000:

First phase=RM400; Second phase=RM200; Total=RM600

> B40 singles earning less than RM2,000:

First phase=RM350; Second phase=RM150; Total=RM500

> M40 singles earning between RM2,001 and RM4,000:

First phase=RM200; Second phase=RM100; Total=RM300

Q When will BPN 2.0 payouts be made?

A First phase will be at the end of October 2020. Second phase will be in January 2021.

Q How will BPN 2.0 payouts be made?

A i. Those with active bank accounts - the payment will be credited into the account number listed in the BPN 2020 database.

ii. Those with inactive or closed bank accounts - claim the cash at a Bank Simpanan Nasional (BSN) branch.

iii. Those with no bank accounts - claim the cash at a BSN branch.

Q How will BSN 2.0 payouts be made for recipients in the interiors of Sabah and Sarawak?

Payments for recipients with no bank accounts living in the interiors of Sabah and Sarawak will start in January 2021.

Q Can I update my personal details such as my bank account that is no longer active?

A Updating bank account information is not allowed because the payment method for BPN 2.0 will be the same as the payment method of the previous BPN 2020 (refer to the answer for question 7).

Q If the payout was made to an inactive or incorrect bank account, what should I do?

A You can claim the cash at a BSN branch after the serial number has appeared. You can check your application status via the official BPN portal at https://bpn.hasil.gov.my

C. Status check

Q When and how can I check my application status for BPN 2.0?

A Recipients who are eligible to receive BPN 2.0 can check their status starting Oct 15 via the official portal at https://bpn. hasil.gov.my

Q What should I do if I forget my password to log into the portal and what if I fail to answer the security question?

A You need to wait for 10 minutes before attempting to answer the security question again. If you still fail to answer, you can contact the Hasil Care Line (HCL) at 03- 89111000 to reset your account and security question or contact the nearest IRB branch.

D. Other matters

Q Based on my status check, I was approved as a recipient in the M40 category for BPN 2020. Can I appeal to be a recipient in the B40 category for BPN 2.0?

A The BPN 2.0 qualification category is based on the final approval for BPN 2020.

Q I was a BPN 2020 recipient under the singles category but I am now married. Am I eligible to receive BPN 2.0 under the household category?

A You can submit a new application or appeal starting Oct 15, 2020 under the household category if you meet all the criteria.

Q I was married to a BPN 2020 recipient under the household category but I am now divorced. Am I eligible to receive BPN 2.0 under the single mother or father category?

A You can submit a new application/appeal starting Oct 15, 2020 under the single mother or father category if you meet all the criteria.

Q I am single and will turn 21 years old in 2021. If I am not yet 21 years old at the time that the application opens up, am I eligible to apply?

A Those born in 1999 or before are eligible to apply.

Q I received BPN 2020 previously and now wish to reject BPN 2.0. How can I return the cash aid?

A You can do the following: i. Submit a letter to the Finance Ministry stating your full name, MyKad number and reason for returning the cash aid.

ii. Come up with a bank draft or cheque addressed to the Accountant General of Malaysia according to the amount being returned.

iii. The letter and bank draft or cheque must then be submitted to the Finance Ministry at the following address:

Pejabat Belanjawan Negara, Kementerian Kewangan Malaysia, Presint 2, 62592 Putrajaya. 


 http://mystar.newspaperdirect.com/epaper/viewer.aspx?noredirect=true#

 

BPN 2.0 payout starts Oct 26 

https://mystar.newspaperdirect.com/epaper/viewer.aspx

 

Related post:

 Stimulus packages avert 1930s-style depression but cannot prevent business closures, save jobs as supply-demand dynamics collapse

 

Malaysia’s recovery movement control order (RMCO) extended until Dec 31,tourists still not allowed in

 

Malaysian Movement Control Order (MCO) enters the fourth phase

 

Monday, September 21, 2020

Introduction of stem cells & SOLUS



 
 

Let’s watch on what it actually stem cell and how it works on body 🥰 .

 
 

https://www.facebook.com/watch/?v=314631736187560&extid=vrxF4KAvqMYdOAX9
 
 
 
 

❤️SOLUS is define as alone (the only one)❤️
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Using high technology active protein to stimulate self stem cells. For a better body health and life started with stemcell therapy.
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🌹Did you know that self stem cells that produce by our own body are the safest and healthiest source of own body to...

More
 
 
 

Saturday, September 19, 2020

Application of Stem Cells in Stroke: A Multifactorial Approach


Stroke has a debilitating effect on the human body and a serious negative effect on society, with a global incidence of one in every six people. According to the World Health Organization, 15 million people suffer stroke worldwide each year. Of these, 5 million die and another 5 million are permanently disabled. Motor and cognitive deficits like hemiparesis, paralysis, chronic pain, and psychomotor and behavioral symptoms can persist long term and prevent the patient from fully reintegrating into society, therefore continuing to add to the costly healthcare burden of stroke. Regenerative medicine using stem cells seems to be a panacea for sequelae after stroke. Stem cell-based therapy aids neuro-regeneration and neuroprotection for neurological recovery in patients. However, the use of stem cells as a therapy in stroke patients still needs a lot of research at both basic and translational levels. As well as the mode of action of stem cells in reversing the symptoms not being clear, there are several clinical parameters that need to be addressed before establishing stem cell therapy in stroke, such as the type of stem cells to be administered, the number of stem cells, the timing of dosage, whether dose-boosters are required, the route of administration, etc. There are upcoming prospects of cell-free therapy also by using exosomes derived from stem cells. There are several ongoing pre-clinical studies aiming to answer these questions. Despite still being in the development stage, stem cell therapy holds great potential for neurological rehabilitation in patients suffering from stroke.

Introduction

Stroke is one of the leading causes of chronic disability and mortality, with 102 million disability-adjusted life years lost annually (Steven, 2008). The Global Burden of Disease, Injuries, and Risk Factors Study (GBD 2015) reported a shift from communicable diseases toward non-communicable diseases like cerebrovascular events. While the incidence of stroke is decreasing in the developed world, it has peaked in low- and middle-income countries like India due to demographic transition and rapid shifts in the socioeconomic milieu (Thomson, 1998). The estimated adjusted prevalence rate of stroke is reported to have a range of 84–262/100,000 in rural and 334–424/100,000 in urban India (Wichterle et al., 2002; Nagai et al., 2010).

The only neuroprotective agent developed for stroke in clinical use is recombinant tissue plasminogen activator (rtPA), which is employed for thrombolysis and has a therapeutic window of merely 3–4.5 h. There is thus a compelling need to develop therapeutic agents that extend beyond the first few hours after onset of stroke. This requires a paradigm shift to the usage of new strategies from neuroprotection to neuro-restoration that treat the injured or compromised brain tissue.

The majority of stroke survivors are left with some degree of disability, particularly upper limb dysfunction, despite several neurorehabilitation therapies. Physical therapy incorporating exercises, motor learning principles, motor cortex stimulation (using rTMS, TDCS), and assistive technologies aid the restoration of functional movements (Tae-Hoon and Yoon-Seok, 2012. The emergence of regenerative medicine has fueled interest across readers and clinicians to study its potential. Over the last decade, an enormous amount of work has been done exploring the potential of a variety of cells like adult stem cells, umbilical cord blood, and cells from adipose tissue and skin. 

Pattern of Stroke Recovery

The recovery after stroke has been explained as a rich cascade of events encompassing cellular, molecular, genetic, demographic, and behavioral components. Such factors have been proven as covariates in therapeutic trials of restorative agents with a sound neurobiological basis. Advances in functional neuroimaging and brain mapping methods have provided a valuable parallel system of data collection for stroke recovery in humans. The recovery in a stroke-affected individual will largely depend on the size of lesion, the internal milieu of the brain injury, and the age and comorbid status of the patient. In general, the first epoch encompasses the initial hours after a stroke, when rapid change occurs in blood flow, edema, pro-inflammatory mechanisms. A second epoch is related to spontaneous behavioral recovery, which begins a few days after stroke onset and lasts several weeks. During this epoch, the brain is galvanized to initiate repair, as endogenous repair-related events reaching peak levels, suggesting a golden period for initiating exogenous restorative therapies. A third epoch begins weeks to months after stroke, when spontaneous behavioral gains have generally reached a plateau, and this stable state is responsive to many restorative interventions (Steven, 2008).

Mechanisms of Action of Stem Cells in Neural Repair

Stem cells have the capacity to differentiate into all types of cells. Exogenously administered cells appear to stimulate endogenous reparative processes and do not replace injured cerebral tissue. It was once thought that intravenously administered cells would home in on the injured site and replace the dead neurons, but the current ideology for the use of these cells holds that these cells release many trophic factors like VEGF, IGF, BDNF, and tissue growth factors that stimulate brain plasticity and recovery mechanisms. Upregulation of growth factors, prevention of ongoing cell death, and enhancement of synaptic connectivity between the host and graft are some of the common pathways through which intravenous stem cells work as “chaperones.” Regarding the timing of transplantation, preclinical studies have shown that cell therapy increases functional recovery after acute, sub-acute, and chronic stroke (Bliss et al., 2010), but few studies have compared different time windows, with differing results according to the model system and cell type studied. All of the possible modes of action of stem cells have been described in Figure 1.

FIGURE 1
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Figure 1. Mechanisms of action of Mesenchymal Stem Cells in treating stroke.


Translational Approach for the Development of Regenerative Medicine in Brain Stroke

The unique capacity of stem cells of self-renewal and differentiation has been exploited to devise cell-based therapy for various neurodegenerative diseases, including brain stroke. There have been several studies, which will be discussed in the upcoming paragraphs, that report the use of stem cells in the treatment of various diseases. These studies have used stem cells of various kinds, such as adult stem cells (mesenchymal stem cells and neural stem cells), embryonic stem cells, and the latest kind, induced pluripotent stem cells. Apart from using different types of stem cells, scientists have also reported distinctive modes of action to support their study outcomes. Besides these variable points, there are other considerations like the dosage of stem cells, mode of administration of stem cells, and whether or not booster doses are required, depending upon the magnitude of the disease. Various groups have attempted to answer these vital questions through their research.

Ischemic stroke causes severe damage to the brain cells by destroying the heterogeneous cell population and neuronal connections along with vascular systems. The regenerative potential of several types of stem cells like embryonic stem cells, neural stem cells, adult stem cells (Mesenchymal stem cells), and induced pluripotent stem cells have been assessed for treating stroke. The outcomes and observations in these studies are not consistent. Most of the studies have only commented on the homing, survival, proliferation, and differentiation of stem cells on the site and their limited neuro-restorative ability. Embryonic stem cells (ESCs) are pluripotent cells derived from the inner cell mass of the blastocyst. There have been a few studies where engraftment of murine ESCs in mouse models of ischemia has led to the restoration of behavioral deficits, synaptic connections, and damaged neurons (Thomson, 1998; Wichterle et al., 2002; Nagai et al., 2010). However, the use of ESCs in the clinical setting is argued against by many other groups due to their immunogenic nature and teratoma-forming tendency (Fong et al., 2010; Kawai et al., 2010; Ghosh et al., 2011). Hence, scientists are now trying to establish the neuro-restorative ability of other stem cell types. Neural stem cells (NSCs) are theoretically the most appropriate cell candidates for neuro-restoration as they belong to the same tissue source and have a natural tendency to differentiate into neuronal cells. NSCs are multipotent cells that are generally found in the subgranular zone of the dentate gyrus of the hippocampus (Toda et al., 2001). Engraftment of NSCs has been reported to lead to the reformation of synaptic connections and improvement in the electrophysiological properties of mature neurons in the damaged brain (Polezhaev and Alexandrova, 1984; Polezhaev et al., 1985; Cho et al., 2002; Oki et al., 2012). They do so by improving the extracellular microenvironment and hence encouraging neuronal circuit plasticity (Ourednik et al., 2002; Lee et al., 2007; Redmond et al., 2007; Jeyakumar et al., 2009). NSCs restore neuronal functions as they secrete several neurotrophic factors like BDNF and VEGF, which help in maintaining the health, generation, proliferation, and survival of the neurons, along with the maintenance of ECM (Emanueli et al., 2003; Jung et al., 2008; Lee H. J. et al., 2010; Smith et al., 2012). VEGF specifically helps in angiogenesis and vascular restoration of the blood vessels damaged due to ischemia (Song et al., 2015; Ryu et al., 2016). CNTF, GDNF, NGF, and other such factors secreted by NSCs also play vital roles in the protection, maintenance, and proliferation of neural cells (Abe, 2000).

Another type of cells with amazing neuro-restorative potential and that have several other desirable properties, like being immunologically naive, easy to extract and maintain and expand in vitro, and not having associated ethical concerns, are mesenchymal stem cells (MSCs) (Baksh et al., 2007; Uccelli et al., 2008; Russell et al., 2018). MSCs are multipotent stem cells that have their niche in body tissues like bone marrow, adipose tissue, umbilical cord, umbilical cord blood, dental pulp, etc (Uccelli et al., 2008; Singh et al., 2017; Russell et al., 2018). Extracting MSCs from these tissues is a very well-established and easy process and has been very widely used in various clinical trials (Nandy et al., 2014; Singh et al., 2017). MSCs lead to neuro-restoration by one or more modes of action such as the release of paracrine factors, cell replacement, mitochondrial transfer, etc. MSCs also have an angiogenic effect. They have been reported to induce angiogenesis by the release of vascular endothelial growth factor (VEGF) (Li et al., 2000, 2001; Chen et al., 2003; Shen et al., 2007). The only issue to be considered for using bone marrow-derived MSCs is the surgical intervention to obtain the bone marrow. Adipose tissue-derived MSCs have proved to be equally effective in neuro-regeneration, with the added advantages of being easily accessible and more abundant (Yang et al., 2012; Moore and Abrahamse, 2014; Singh et al., 2017). Adipose tissue-derived MSCs have been known to play a protective role through the release of extracellular vesicles. There are studies reporting the safety and efficacy of extracellular vesicles derived from adipose tissue-derived MSCs (Ra et al., 2011; Zhang Y. et al., 2015; Chen et al., 2016; Bang and Kim, 2019). However, more detailed studies are required to establish MSCs as therapeutic agents.

Another type of stem cell that has been explored for its translational value recently is the induced pluripotent stem cell (iPSC). There has been a boom in research into iPSCs after the groundbreaking discovery by Takahashi and Yamanaka (2006). iPSCs have the edge over other types of stem cells due to being non-immunogenic, easy to access, and non-interventional and not giving rise to ethical concerns. However, their generation is still an unresolved issue, as the reprogramming efficiency is still very low. Additionally, some studies have reported the formation of teratoma in the mouse brain, which implies that the tumorigenicity of iPSCs needs to be addressed and resolved before taking them into the clinical setting. iPSCs seem to be formidable stem cells for tissue regeneration (Israel et al., 2012; Fernández-Susavila et al., 2019).

 

Bioactive Constituents in Brain Stroke: Combination Therapy

The use of complementary and alternative medicine along with stem cell therapy also plays an important role in the recovery of brain stroke patients. During the stroke episode, most of the pro-inflammatory cytokines are involved, and many polyphenol compounds extracted from different parts of medicinal plants have been shown to protect against cerebral ischemia in pre-clinical models. Glycrrhizin extracted from the licorice root, Glycrrhiza glabra, protected against the rat brain injury induced by stroke. Intraperitoneal administration of Glycrrhizin pre- and post-stroke helped inhibit the infarction by ameliorating the IFN-γ mediated T-cell activity, which was partially modulated by high mobility group box-1 (Xiong et al., 2016). The use of intravenous administration of recombinant plasminogen tissue activator (rtPA) was approved half a decade ago, but the limitations to rtPA treatment include a narrow therapeutic window of 4.5 h post-stroke and a high risk for hemorrhagic transformations. MSC transplantation in brain stroke patients is an existing approach, but inflammation has sometimes been observed in MSCs due to oxygen glucose deprivation during treatment. One study showed that a nano-formulation of gelatin-coated polycaprolactone loaded with naringenin, a strong anti-inflammatory, protected the MSCs against oxygen glucose deprivation-induced inflammation and also reduced the levels of pro-inflammatory cytokines (TNF-α, IFN-γ, and IL-β) and of the anti-inflammatory biomarkers COX-2, iNOS, and MPO (Ahmad et al., 2019). The active compound Eugenol, isolated from Acorus gramineus, was tested in a cerebral ischemia perfusion rat model. Pre-treatment with Eugenol in the rat model showed that it was prompt in attenuating cerebral ischemic injury by inducing autophagy via the AMPK/mTOR/P70S6K signaling pathway. In another study, the neuroprotective effect of quercetin was demonstrated in mice, and the findings suggested that the quercetin helped reduce apoptosis in the focal cerebral ischemia rat brain and that the mechanism may be related to the activation of the PI3K/Akt signaling pathway (Yao et al., 2012). The intragastric administration of berberin and glycyrrhizin showed neuroprotective effects in mice subjected to transient middle cerebral artery occlusion. The co-administration of glycyrrhizin and berberin showed more potent suppression on the HMGB1/TLR4/NF-kB pathway in comparison to treatment with either alone. The results of the study suggested that the administration of these compounds protects the brain from ischemia-reperfusion injury and that the mechanism may rely on their anti-inflammatory effects and, moreover, also by suppressing the activation of the HMGB1/TLR4/NF-kB signaling pathway (Zhu et al., 2018). Medicinal plants contain several important bioactive constituents that help in several modalities. Numerous pre-clinical studies have been performed using plant-derived products that help modulate the proliferation and differentiation of MSCs, as well as being useful in the field of biomaterials. Therefore, the new combination therapy of phytochemicals along with stem cell therapy may become a new perspective in stem cell-based neuro-regeneration.

 

Pre-Clinical Studies With Stem Cells in Brain Stroke

The experimental evidence of the benefits of stem cells in treating stroke has been provided over the course of several years (Abe, 2000; Mays et al., 2010). The usefulness of various types of stem cells has been proclaimed in various neurological diseases, along with their safety and efficacy at both pre-clinical and clinical levels. The pre-clinical validation of stem cells in treating stroke has been instrumental. Various study groups have validated the use of stem cells in terms of various parameters such as type of stem cells, number/dose of stem cells, mode of administration, homing and tracking of stem cells, and safety and efficacy of stem cells (Zheng et al., 2018; Borlongan, 2019).

The most commonly used and most widely explored stem cells in the treatment of stroke are MSCs. Among the various tissue sources of MSCs, the most common and widely explored are bone marrow and adipose tissue, with bone marrow being the oldest of all (Andrews et al., 2008; Xin et al., 2013; Zhang et al., 2014; Zhang Y. et al., 2015). However, neural stem cells and bone marrow-derived mononuclear stem cells have also been explored (Taguchi et al., 2004; Darsalia et al., 2007; Takahashi et al., 2008). In most of the pre-clinical studies, autologous bone marrow-derived MSCs have been used (Zhang et al., 2006; Khalili et al., 2012; Otero et al., 2012; Bao et al., 2013; Vaquero et al., 2013) to investigate the various aspects of stem cell transplantation in stroke. Several other studies report the use of MSCs from other tissue sources, like adipose tissue, umbilical cord, placenta, etc (Yang et al., 2012; Zhang Q. et al., 2015; Xie et al., 2016). MSCs are characterized for transplantation based on surface marker profiling, which includes the presence of markers like CD29, CD44, CD73, CD90, and CD105 and the absence of CD34/45, CD14, and HLA class II. Other critical factors that need to be considered for pre-clinical studies are the number/dose of cells to be administered and the mode of administration. Transplantations of MSCs range from 1 × 106 to 8 × 106 cells and are accomplished through different modes, including intravenous, intranasal, and intra-arterial (Chen et al., 2001; Shyu et al., 2006; Zhang et al., 2006; Yang et al., 2012; Ma et al., 2016; Rodríguez-Frutos et al., 2016; Borlongan, 2019). While there is evidence that the transplanted MSCs have homed and differentiated into neurons, astrocytes, and oligodendrocytes upon administration through intravenous, intranasal, and intracerebral modes, there are doubts on the migration of MSCs in the brain by the intravenous mode (Díez-Tejedor et al., 2014). Also, there are mixed reports on whether the transplantation of coaxed and naive stem cells can achieve the desired outcome in terms of functional recovery, BBB function, increased angiogenesis and vasculogenesis, and tissue regeneration (Laso-García et al., 2019; Turnbull et al., 2019). More detailed studies need to be done to establish a definitive stem cell therapy regime for stroke.

 

Clinical Trials of Regenerative Medicine in Brain Stroke

Cerebrovascular strokes can cause morbidity and mortality and induce long-term disability that affects quality of life. Stroke is associated with neuroinflammation, which plays a key role in the pathophysiology of cerebrovascular accidents of different types. We performed a rigorous search of a database on clinical studies with stroke and found more than 56 clinical trials on the use of regenerative medicine (autologous or allogeneic) for cerebrovascular stroke. Most of them used mesenchymal stem cells, adipose tissue, bone marrow-derived cells, and spinal cord and umbilical cord cells. Table 1 presents a few clinical trials involving stem cell therapy (autologous and allogeneic), giving their study design, dose, route of administration, and outcomes. Our experience with regenerative medicine in stroke emphasizes the safety and tolerance of cells, whereas efficacy still needs to be addressed. More recovery in clinical and functional patterns was observed in patients administered with autologous bone marrow-derived cells than in the group with physiotherapy alone. We also tried to elucidate correlations between functional MRI and outcome after stroke, with increased activation in premotor and primary motor areas (PM and SMA), and contralesional M1 over activation. Our present randomized controlled trial studying the paracrine effects of autologous mononuclear stem cells in interim showed increased VEGF and BDNF post-treatment in all stroke patients, suggesting endogenous recovery after restorative therapies like stem cells and a structured neuro-rehabilitation regime. To counter the progression of the cerebral vascular disease post-stroke and repair the damage induced in different regions of the brain, various clinical trials with different stem cells like mesenchymal stem cells, adipose tissue-derived stem cells, and bone marrow mononuclear stem cells are ongoing (Table 1) that investigate potential efficacy and safety, without the occurrence of any adverse or severely adverse events.

TABLE 1
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Table 1. List of Clinical trials using Stem cells in treating stroke.

An open-labeled observer-blind clinical trial was conducted to evaluate the long-term safety and efficacy of autologous MSCs. Post-transplantation with MSCs, clinical improvement in patients was observed in the MSC-treated patient group, which was associated with the serum level of stromal cell-derived factor-1 and the degree of involvement of the sub-ventricular region of the lateral ventricle. No serious adverse effects were observed during long-term follow up of patients. The occurrence of comorbidities was similar in comparison to the control group (Lee J. S. et al., 2010). In another single-blind controlled phase I/II trial, patients with middle cerebral artery stroke were enrolled in the study. Autologous bone marrow mononuclear cells (BM-MNCs) were injected 5–9 days post-stroke. A higher plasma β-nerve growth factor level was observed post-injection, and no adverse events were observed for 6 months apart from two patients in whom partial seizures were observed at 3 months of follow up. The study result suggested that intra-arterial administration of BM-MNCs is safe and feasible (Moniche et al., 2012). A non-randomized observational controlled study with autologous bone marrow mononuclear cells in chronic ischemic stroke showed better efficacy and did not observe any adverse effects or neurological abnormalities during long-term follow up of patients (Bhasin et al., 2012). Intravenous administration of autologous BM-MSCs was also shown to have better safety in a randomized, phase II, multicentric trial group in patients with subacute ischemic stroke (Prasad et al., 2014). On the basis of the findings of pre-clinical studies with peripheral blood stem cells (PBSCs), randomized single-blind controlled studies were conducted in patients with middle cerebral artery infarction. Patients were enrolled as per the inclusion criteria of the study and received subcutaneous G-CSF injection for 5 consecutive days prior to stereotaxic implantation of immune-sorted PBSCs. No adverse events were observed during the study procedure or the follow up of the study. Clinical outcomes of the PBSC-treated and control groups were observed in terms of changes in NIHSS, ESS, EMS, and mRS from baseline to 12 months. Moreover, this study also provided important evidence on the efficacy of PBSCs in improving stroke-related motor deficits, the reconstruction of injured CST, and the rebuilding of electrophysiology activity from the brain to the limbs (Chen et al., 2014). Intravenous administration of allogeneic mesenchymal stem cells from adipose tissue in a phase II randomized, double-blind, placebo controlled single-center pilot clinical trial in patients 2 weeks post-acute stroke showed better efficacy without the occurrence of adverse events. Moreover, the use of allogenic MSCs could be an alternative therapy for the treatment of stroke because it has been demonstrated that they lack class II HLA antigens (Díez-Tejedor et al., 2014). Another study (Bhasin et al., 2016) reported the paracrine mechanism of bone marrow-derived mononuclear cells in chronic ichemic stroke patients. CD34+ was counted in BM-MNCs for each and every patient. Intravenously administered BM-MNCs secrete glial cell-derived neurotrophic factor and BDNF, IGF-1, and VGEF, which may protect against the dysfunction of motor neurons. The trial results suggested that the administration of BM-MNCs is safe and feasible for stroke patients. In another phase I, open-label, prospective clinical trial, patients with acute ischemic stroke received a single i.v. infusion of allogeneic human umbilical cord blood cells within a window of 3–10 days. Post-UCB infusion, graft-vs.-host disease, infection, and hypersensitivity were analyzed at patient follow up visits at 3, 6, and 12 months. Adverse events and severe adverse events (AE/SAE) in the patients that were directly or indirectly related to the investigational treatment were reported (Laskowitz et al., 2018).

A single-arm, phase I clinical trial study of autologous bone marrow mononuclear cells for acute ischemic stroke showed a promising new investigational modality that may help widen the therapeutic window for patients with ischemic stroke. AEs/SAEs were observed post-transplantation, some of which may have been associated with the intervention but others of which may not have (Vahidy et al., 2019). In another single-site phase I study, the feasibility and safety of NSI-566 primary adherent neural cells derived from a single human fetal spinal cord were observed. Three different doses were investigated in a cohort study of patients, and it was shown that the transplantation of human spinal cord-derived neural stem cells into the peri-infarct area of stable stroke patients is beneficial. The mechanism potentially behind it is that the stem cell-derived tissue is largely composed of interneurons and glial cells, and these promote regeneration and act as bridges between regenerating neuronal fibers (Zhang et al., 2019). A phase I/II preliminary safety and efficacy study of allogenic MSCs in chronic stroke patients showed the dose tolerability to be 1.5 million/kg body weight in phase I and phase II study. The primary outcome of intravenous administration of allogenic MSCs in patients was measured for 1 year, and secondary outcomes were measured in terms of behavioral changes. AEs/SAEs were observed in 13 patients that were probably not related to the intervention, and two mild AEs related to the study intervention were observed, urinary tract infection and intravenous site irritation. However, other mechanisms have also been shown that involve cell replacement, immunomodulatory action, and endogenous repair of brain damage post-stroke. The stem cell therapy in cerebrovascular accident depends overall upon their differentiation, inflammation, and ability to repair of endogenous processes. This regenerative medicine has emerged as an important tool in modern neurology, with potential efficacy in neurodegenerative disorder (Thwaites et al., 2012; Yu et al., 2013). After extensive findings of pre-clinical research, the clinical trials have conducted with different stem cells in stroke, in which the AEs/SAEs observed during or post transplantation may be directly or indirectly related to the intervention. The studies suggest that there must be a further continuation of pre-clinical and clinical studies of regenerative medicine in stroke patients to further elucidate the safety, efficacy, and toxicity pre and posting transplantation and their capacity to deliver potent efficacious regenerative medicine for stroke patients. Further clinical trials of regenerative medicine in cerebrovascular stroke are complete, with more results awaited.

Future Prospects

Regenerative medicine is looking increasingly more enticing as we capture more evidence from past and current clinical trials in stroke (Bhasin et al., 2016, 2017). The neurophysiology describing stem cells and their concatenated mechanisms suggests that restoration of brain function may be a realistic goal. There are several cellular labeling techniques available, including simple incubation, use of transfection agents, magnetoelectroporation, and magnetosonoporation. MR tracking with SPIOs and nanoparticles in a MCAo occlusion model of stroke has proven flawless in tracking cells but still needs clinical validation (Cromer Berman et al., 2011). To make this research a therapeutic boon in stroke, certain questions still need answers, such as the optimal cell delivery route, the initial engraftment and distribution pattern of injected cells, and how effectively injected cells migrate toward the affected sites.

While stem cells have proven to be a great resource for treating stroke, there are still several obstacles to be conquered in the near future. A variety of stem cells with multiple parameters have been under trial for the treatment of stroke. Starting from the kinds of stem cells in use, there are pluripotent stem cells (ESCs and iPSCs), neural stem cells, and adult stem cells (MSCs from various tissues). There are ethical concerns associated with pluripotent stem cells. Additionally, NSCs have limitations in their in vitro expansion (in terms of the number of NSCs required to be transplanted). MSCs are capable of combating this concern. Another issue is immunological tolerance between the host body and transplanted stem cells. This issue can be resolved by using the patient’s own cells to derive iPSCs of MSCs (as they are devoid of HLA class II). Besides these concerns, there are several other concerns, such as whether the efficiency of cell extraction, expansion, and differentiation is sufficient for transplantation, as well as the best mode of injection and optimal number of injections. While there are several challenges to bringing stem cell therapy in the mainstream of treatment for various diseases, stem cell therapy has been established for treating several degenerative and other kinds of diseases. In future, all these points of concern need to be addressed to make stem cell therapy an abiding treatment regime for stroke.

Author Contributions

MS, AB, and PP: drafting and refining the manuscript. SM, MS, and AB: critical reading of the manuscript. All of the authors have read and approved the manuscript.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

We thank Ms. Sonali Rawat, Ph.D. scholar, Stem Cell Facility, AIIMS, New Delhi, for helping us with the generation of the figure and graphical abstract.

References

Abe, K. (2000). Therapeutic potential of neurotrophic factors and neural stem cells against ischemic brain injury. J. Cereb. Blood Flow Metab. 20, 1393–1408. doi: 10.1097/00004647-200010000-00001

PubMed Abstract | CrossRef Full Text | Google Scholar

Ahmad, A., Fauzia, E., Kumar, M., Mishra, R. K., Kumar, A., Khan, M. A., et al. (2019). Gelatin-coated polycaprolactone nanoparticle-mediated naringenin delivery rescue human mesenchymal stem cells from oxygen glucose deprivation-induced inflammatory stress. ACS Biomater. Sci. Eng. 5, 683–695. doi: 10.1021/acsbiomaterials.8b01081

CrossRef Full Text | Google Scholar

Andrews, E. M., Tsai, S. Y., Johnson, S. C., Farrer, J. R., Wagner, J. P., Kopen, G. C., et al. (2008). Human adult bone marrow-derived somatic cell therapy results in functional recovery and axonal plasticity following stroke in the rat. Exp. Neurol. 211, 588–592. doi: 10.1016/j.expneurol.2008.02.027

PubMed Abstract | CrossRef Full Text | Google Scholar

Baksh, D., Yao, R., and Tuan, R. S. (2007). Comparison of proliferative and multilineage differentiation potential of human Mesenchymal stem cells derived from umbilical cord and bone marrow. Stem Cells 25, 1384–1392. doi: 10.1634/stemcells.2006-0709

CrossRef Full Text | Google Scholar

Bang, O. Y., and Kim, E. H. (2019). Mesenchymal stem cell-derived extracellular vesicle therapy for stroke: challenges and progress. Front. Neurol. 10:211. doi: 10.3389/fneur.2019.00211

CrossRef Full Text | Google Scholar

Bao, X. J., Liu, F. Y., Lu, S., Han, Q., Feng, M., Wei, J. J., et al. (2013). Transplantation of FLK-1+ human bone marrow-derived mesenchymal stem cells promotes behavioral recovery and anti-inflammatory and angiogenesis effects in an intracerebral hemorrhage rat model. Int. J. Mol. Med. 31, 1087–1096. doi: 10.3892/ijmm.2013.1290

PubMed Abstract | CrossRef Full Text | Google Scholar

Bhasin, A., Kumaran, S. S., Bhatia, R., Mohanty, S., and Srivastava, M. V. P. (2017). Safety and feasibility of autologous mesenchymal stem cell transplantation in chronic stroke in Indian patients. A four-year follow up. J. Stem Cells Regen. Med. 14, 59–60.

Google Scholar

Bhasin, A., Padma Srivastava, M. V., Mohanty, S., Vivekanandhan, S., Sharma, S., Kumaran, S., et al. (2016). Paracrine mechanisms of intravenous bone marrow-derived mononuclear stem cells in chronic ischemic stroke. Cerebrovasc. Dis. Extra 6, 107–119. doi: 10.1159/000446404

PubMed Abstract | CrossRef Full Text | Google Scholar

Bhasin, A., Srivastava, M. V., Bhatia, R., Mohanty, S., Kumaran, S. S., and Bose, S. (2012). Autologous intravenous mononuclear stem cell therapy in chronic ischemic stroke. J. Stem Cells Regen. Med. 8, 181–189.

PubMed Abstract | Google Scholar

Bliss, T. M., Andres, R. H., and Steinberg, G. K. (2010). Addendum to “Optimizing the success of cell transplantation therapy for stroke”. Neurobiol. Dis. 37, 275–283. doi: 10.1016/j.nbd.2010.03.001

CrossRef Full Text | Google Scholar

Borlongan, C. V. (2019). Concise review: stem cell therapy for stroke patients: are we there yet? Stem Cells Transl. Med. 8, 983–988. doi: 10.1002/sctm.19-0076

PubMed Abstract | CrossRef Full Text | Google Scholar

Chen, D. C., Lin, S. Z., Fan, J. R., Lin, C. H., Lee, W., Lin, C. C., et al. (2014). Intracerebral implantation of autologous peripheral blood stem cells in stroke patients: a randomized phase II study. Cell Transplant 23, 1599–1612. doi: 10.3727/096368914X678562

PubMed Abstract | CrossRef Full Text | Google Scholar

Chen, J., Li, Y., Katakowski, M., Chen, X., Wang, L., Lu, D., et al. (2003). Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. J. Neurosci. Res. 73, 778–786. doi: 10.1002/jnr.10691

PubMed Abstract | CrossRef Full Text | Google Scholar

Chen, J., Li, Y., Wang, L., Zhang, Z., Lu, D., Lu, M., et al. (2001). Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke 32, 1005–1011. doi: 10.1161/01.STR.32.4.1005

PubMed Abstract | CrossRef Full Text | Google Scholar

Chen, K. H., Chen, C. H., Wallace, C. G., Yuen, C. M., Kao, G. S., Chen, Y. L., et al. (2016). Intravenous administration of xenogenic adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes markedly reduced brain infarct volume and preserved neurological function in rat after acute ischemic stroke. Oncotarget 7, 74537–74556. doi: 10.18632/oncotarget.12902

PubMed Abstract | CrossRef Full Text | Google Scholar

Cho, T., Bae, J. H., Choi, H. B., Kim, S. S., McLarnon, J. G., Suh-Kim, H., et al. (2002). Human neural stem cells: electrophysiological properties of voltage-gated ion channels. Neuroreport 13, 1447–1452. doi: 10.1097/00001756-200208070-00020

PubMed Abstract | CrossRef Full Text | Google Scholar

Cromer Berman, S. M., Walczak, P., and Bulte, J. W. M. (2011). Tracking stem cells using magnetic nanoparticles. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 3, 343–355. doi: 10.1002/wnan.140

CrossRef Full Text | Google Scholar

Darsalia, V., Kallur, T., and Kokaia, Z. (2007). Survival, migration and neuronal differentiation of human fetal striatal and cortical neural stem cells grafted in stroke-damaged rat striatum. Eur. J. Neurosci. 26, 605–614. doi: 10.1111/j.1460-9568.2007.05702.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Díez-Tejedor, E., Gutiérrez-Fernández, M., Martínez-Sánchez, P., Rodríguez-Frutos, B., Ruiz-Ares, G., Lara, M. L., et al. (2014). Reparative therapy for acute ischemic stroke with allogeneic mesenchymal stem cells from adipose tissue: a safety assessment: a phase II randomized, double-blind, placebo-controlled, single-center, pilot clinical trial. J. Stroke Cerebrovasc. Dis. 23, 2694–2700. doi: 10.1016/j.jstrokecerebrovasdis.2014.06.011

PubMed Abstract | CrossRef Full Text | Google Scholar

Emanueli, C., Schratzberger, P., Kirchmair, R., and Madeddu, P. (2003). Paracrine control of vascularization, and neurogenesis by neurotrophins. Br. J. Pharmacol. 140, 614–619. doi: 10.1038/sj.bjp.0705458

PubMed Abstract | CrossRef Full Text | Google Scholar

Feng, Y., Tian, G. P., Li, L., and Zhou, J. (2014). Effect of human umbilical cord blood-derived mesenchymal stem cells in the treatment of cerebral infarction. Pract. J. Cardiac. Cereb. Pneumal. Vasc. Dis. 22, 28–30.

Google Scholar

Fernández-Susavila, H., Bugallo-Casal, A., Castillo, J., and Campos, F. (2019). Adult stem cells and induced pluripotent stem cells for stroke treatment. Front. Neurol. 10:908. doi: 10.3389/fneur.2019.00908

PubMed Abstract | CrossRef Full Text | Google Scholar

Fong, C. Y., Gauthaman, K., and Bongso, A. (2010). Teratomas from pluripotent stem cells: a clinical hurdle. J. Cell Biochem. 111, 769–781. doi: 10.1002/jcb.22775

PubMed Abstract | CrossRef Full Text | Google Scholar

Ghosh, Z., Huang, M., Hu, S., Wilson, K. D., Dey, D., and Wu, J. C. (2011). Dissecting the oncogenic and tumorigenic potential of differentiated human induced pluripotent stem cells and human embryonic stem cells. Cancer Res. 71, 5030–5039. doi: 10.1158/0008-5472.CAN-10-4402

PubMed Abstract | CrossRef Full Text | Google Scholar

Hu, Q., Cao, M. Y., Li, R. F., Jiang, H. W., and Ge, L. T. (2013). Safety and efficacy on the treatment of cerebral infarction with umbilical cord mesenchymal stem cells. Med. J. Wuhan Univ. 34, 57–70.

Google Scholar

Israel, M. A., Yuan, S. H., Bardy, C., Reyna, S. M., Mu, Y., Herrera, C., et al. (2012). Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature 482, 216–220. doi: 10.1038/nature10821

CrossRef Full Text | Google Scholar

Jeyakumar, M., Lee, J. P., Sibson, N. R., Lowe, J. P., Stuckey, D. J., Tester, K., et al. (2009). Neural stem cell transplantation benefits a monogenic neurometabolic disorder during the symptomatic phase of disease. Stem Cells 27, 2362–2370. doi: 10.1002/stem.163

PubMed Abstract | CrossRef Full Text | Google Scholar

Jung, Y. L., Sang, I. P., Ji, H. O., Seong, M. K., Chang, H. J., Jin, A. J., et al. (2008). Brain-derived neurotrophic factor stimulates the neural differentiation of human umbilical cord blood-derived mesenchymal stem cells and survival of differentiated cells through MAPK/ERK and PI3K/Akt-dependent signaling pathways. J. Neurosci. Res. 86, 2168–2178. doi: 10.1002/jnr.21669

PubMed Abstract | CrossRef Full Text | Google Scholar

Kawai, H., Yamashita, T., Ohta, Y., Deguchi, K., Nagotani, S., Zhang, X., et al. (2010). Tridermal tumorigenesis of induced pluripotent stem cells transplanted in ischemic brain. J. Cereb. Blood Flow Metab. 30, 1487–1493. doi: 10.1038/jcbfm.2010.32

PubMed Abstract | CrossRef Full Text | Google Scholar

Khalili, M. A., Anvari, M., Hekmati-Moghadam, S. H., Sadeghian-Nodoushan, F., Fesahat, F., and Miresmaeili, S. M. (2012). Therapeutic benefit of intravenous transplantation of mesenchymal stem cells after experimental subarachnoid hemorrhage in rats. J. Stroke Cerebrovasc. Dis. 21, 445–451. doi: 10.1016/j.jstrokecerebrovasdis.2010.10.005

PubMed Abstract | CrossRef Full Text | Google Scholar

Laskowitz, D. T., Bennett, E. R., Durham, R. J., Volpi, J. J., Wiese, J. R., Frankel, M., et al. (2018). Allogeneic umbilical cord blood infusion for adults with ischemic stroke: clinical outcomes from a phase 1 SAFETY STUDY. Stem Cells Transl. Med. 7, 521–529. doi: 10.1002/sctm.18-0008

PubMed Abstract | CrossRef Full Text | Google Scholar

Laso-García, F., Diekhorst, L., Gómez-De Frutos, M. C., Otero-Ortega, L., Fuentes, B., Ruiz-Ares, G., et al. (2019). Cell-based therapies for stroke: promising solution or dead end? Mesenchymal stem cells and comorbidities in preclinical stroke research. Front. Neurol. 10:332. doi: 10.3389/fneur.2019.00332

PubMed Abstract | CrossRef Full Text | Google Scholar

Lee, H. J., Lim, I. J., Lee, M. C., and Kim, S. U. (2010). Human neural stem cells genetically modified to overexpress brain-derived neurotrophic factor promote functional recovery and neuroprotection in a mouse stroke model. J. Neurosci. Res. 88, 3282–3294. doi: 10.1002/jnr.22474

PubMed Abstract | CrossRef Full Text | Google Scholar

Lee, J. S., Hong, J. M., Moon, G. J., Lee, P. H., Ahn, Y. H., Bang, O. Y., et al. (2010). A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells 28, 1099–1106. doi: 10.1002/stem.430

CrossRef Full Text | Google Scholar

Lee, J. P., Jeyakumar, M., Gonzalez, R., Takahashi, H., Lee, P. J., Baek, R. C., et al. (2007). Stem cells act through multiple mechanisms to benefit mice with neurodegenerative metabolic disease. Nat. Med. 13, 439–447. doi: 10.1038/nm1548

PubMed Abstract | CrossRef Full Text | Google Scholar

Li, Y., Chen, J., Wang, L., Lu, M., and Chopp, M. (2001). Treatment of stroke in rat with intracarotid administration of marrow stromal cells. Neurology 56, 1666–1672. doi: 10.1212/WNL.56.12.1666

PubMed Abstract | CrossRef Full Text | Google Scholar

Li, Y., Chopp, M., Chen, J., Wang, L., Gautam, S. C., Xu, Y. X., et al. (2000). Intrastriatal transplantation of bone marrow nonhematopoietic cells improves functional recovery after stroke in adult mice. J. Cereb. Blood Flow Metab. 20, 1311–1319. doi: 10.1097/00004647-200009000-00006

PubMed Abstract | CrossRef Full Text | Google Scholar

Ma, F. W., Deng, Q. F., Zhou, X., Gong, X. J., Zhao, Y., Chen, H. G., et al. (2016). The tissue distribution and urinary excretion study of gallic acid and protocatechuic acid after oral administration of Polygonum capitatum extract in rats. Molecules 21:399. doi: 10.3390/molecules21040399

PubMed Abstract | CrossRef Full Text | Google Scholar

Mays, R. W., Borlongan, C. V., Yasuhara, T., Hara, K., Maki, M., Carroll, J. E., et al. (2010). Development of an allogeneic adherent stem cell therapy for treatment of ischemic stroke. J. Exp. Stroke Transl. Med. 3, 34–46. doi: 10.6030/1939-067X-3.1.34

CrossRef Full Text | Google Scholar

Levy, M. L., Crawford, J. R., Dib, N., Verkh, L., Tankovich, N., and Cramer, S. C. (2019). Phase I/II study of safety and preliminary efficacy of intravenous allogeneic mesenchymal stem cells in chronic stroke. Stroke 50, 2835–2841. doi: 10.1161/STROKEAHA.119.026318

CrossRef Full Text | Google Scholar

Moniche, F., Gonzalez, A., Gonzalez-Marcos, J. R., Carmona, M., Piñero, P., Espigado, I., et al. (2012). Intra-arterial bone marrow mononuclear cells in ischemic stroke: a pilot clinical trial. Stroke 43, 2242–2244. doi: 10.1161/STROKEAHA.112.659409

PubMed Abstract | CrossRef Full Text | Google Scholar

Moore, T. J., and Abrahamse, H. (2014). Neuronal differentiation of adipose derived stem cells: progress so far. Int. J. Photoenerg. 2014, 1–8. doi: 10.1155/2014/827540

PubMed Abstract | CrossRef Full Text | Google Scholar

Nagai, N., Kawao, N., Okada, K., Okumoto, K., Teramura, T., Ueshima, S., et al. (2010). Systemic transplantation of embryonic stem cells accelerates brain lesion decrease and angiogenesis. Neuroreport 21, 575–579. doi: 10.1097/WNR.0b013e32833a7d2c

PubMed Abstract | CrossRef Full Text | Google Scholar

Nandy, S. B., Mohanty, S., Singh, M., Behari, M., and Airan, B. (2014). Fibroblast Growth Factor-2 alone as an efficient inducer for differentiation of human bone marrow mesenchymal stem cells into dopaminergic neurons. J. Biomed. Sci. 21:83. doi: 10.1186/s12929-014-0083-1

PubMed Abstract | CrossRef Full Text | Google Scholar

Oki, K., Tatarishvili, J., Wood, J., Koch, P., Wattananit, S., Mine, Y., et al. (2012). Human-induced pluripotent stem cells form functional neurons and improve recovery after grafting in stroke-damaged brain. Stem Cells 30, 1120–1133. doi: 10.1002/stem.1104

PubMed Abstract | CrossRef Full Text | Google Scholar

Otero, L., Zurita, M., Bonilla, C., Aguayo, C., Rico, M. A., Rodríguez, A., et al. (2012). Allogeneic bone marrow stromal cell transplantation after cerebral hemorrhage achieves cell transdifferentiation and modulates endogenous neurogenesis. Cytotherapy 14, 34–44. doi: 10.3109/14653249.2011.608349

PubMed Abstract | CrossRef Full Text | Google Scholar

Ourednik, J., Ourednik, V., Lynch, W. P., Schachner, M., and Snyder, E. Y. (2002). Neural stem cells display an inherent mechanism for rescuing dysfunctional neurons. Nat. Biotechnol. 20, 1103–1110. doi: 10.1038/nbt750

PubMed Abstract | CrossRef Full Text | Google Scholar

Polezhaev, L. V., and Alexandrova, M. A. (1984). Transplantation of embryonic brain tissue into the brain of adult rats after hypoxic hypoxia. J. Hirnforsch. 25, 99–106.

PubMed Abstract | Google Scholar

Polezhaev, L. V., Alexandrova, M. A., Vitvitsky, V. N., Girman, S. V., and Golovina, I. L. (1985). Morphological, biochemical and physiological changes in brain nervous tissue of adult intact and hypoxia-subjected rats after transplantation of embryonic nervous tissue. J. Hirnforsch 26, 281–289.

PubMed Abstract | Google Scholar

Prasad, K., Sharma, A., Garg, A., Mohanty, S., Bhatnagar, S., Johri, S., et al. (2014). Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: a multicentric, randomized trial. Stroke 45, 3618–3624. doi: 10.1161/STROKEAHA.114.007028

PubMed Abstract | CrossRef Full Text | Google Scholar

Ra, J. C., Shin, I. S., Kim, S. H., Kang, S. K., Kang, B. C., Lee, H. Y., et al. (2011). Safety of intravenous infusion of human adipose tissue-derived mesenchymal stem cells in animals and humans. Stem Cells Dev. 20, 1297–1308. doi: 10.1089/scd.2010.0466

PubMed Abstract | CrossRef Full Text | Google Scholar

Redmond, D. E., Bjugstad, K. B., Teng, Y. D., Ourednik, V., Ourednik, J., Wakeman, D. R., et al. (2007). Behavioral improvement in a primate Parkinson’s model is associated with multiple homeostatic effects of human neural stem cells. Proc. Natl. Acad. Sci. U.S.A. 104, 12175–12180. doi: 10.1073/pnas.0704091104

CrossRef Full Text | Google Scholar

Rodríguez-Frutos, B., Otero-Ortega, L., Gutiérrez-Fernández, M., Fuentes, B., Ramos-Cejudo, J., and Díez-Tejedor, E. (2016). Stem cell therapy and administration routes after stroke. Transl. Stroke Res. 7, 378–387. doi: 10.1007/s12975-016-0482-6

PubMed Abstract | CrossRef Full Text | Google Scholar

Russell, A. L., Lefavor, R., Durand, N., Glover, L., and Zubair, A. C. (2018). Modifiers of mesenchymal stem cell quantity and quality. Transfusion 58, 1434–1440. doi: 10.1111/trf.14597

PubMed Abstract | CrossRef Full Text | Google Scholar

Ryu, S., Lee, S. H., Kim, S. U., and Yoon, B. W. (2016). Human neural stem cells promote proliferation of endogenous neural stem cells and enhance angiogenesis in ischemic rat brain. Neural. Regen. Res. 11, 298–304. doi: 10.4103/1673-5374.177739

PubMed Abstract | CrossRef Full Text | Google Scholar

Shen, L. H., Li, Y., Chen, J., Zacharek, A., Gao, Q., Kapke, A., et al. (2007). Therapeutic benefit of bone marrow stromal cells administered 1 month after stroke. J. Cereb. Blood Flow Metab. 27, 6–13. doi: 10.1038/sj.jcbfm.9600311

PubMed Abstract | CrossRef Full Text | Google Scholar

Shyu, W. C., Lin, S. Z., Chiang, M. F., Su, C. Y., and Li, H. (2006). Intracerebral peripheral blood stem cell (CD34+) implantation induces neuroplasticity by enhancing β1 integrin-mediated angiogenesis in chronic stroke rats. J. Neurosci. 26, 3444–3453. doi: 10.1523/JNEUROSCI.5165-05.2006

CrossRef Full Text | Google Scholar

Singh, M., Kakkar, A., Sharma, R., Kharbanda, O. P., Monga, N., Kumar, M., et al. (2017). Synergistic Effect of BDNF and FGF2 in Efficient Generation of Functional Dopaminergic Neurons from human Mesenchymal Stem Cells. Sci. Rep. 7:10378. doi: 10.1038/s41598-017-11028-z

PubMed Abstract | CrossRef Full Text | Google Scholar

Smith, E. J., Stroemer, R. P., Gorenkova, N., Nakajima, M., Crum, W. R., Tang, E., et al. (2012). Implantation site and lesion topology determine efficacy of a human neural stem cell line in a rat model of chronic stroke. Stem Cells 30, 785–796. doi: 10.1002/stem.1024

PubMed Abstract | CrossRef Full Text | Google Scholar

Song, M., Kim, Y. J., Kim, Y. H., Roh, J., Kim, E. C., Lee, H. J., et al. (2015). Long-term effects of magnetically targeted ferumoxide-labeled human neural stem cells in focal cerebral ischemia. Cell Transplant 24, 183–190. doi: 10.3727/096368913X675755

PubMed Abstract | CrossRef Full Text | Google Scholar

Steven, C. C. (2008). Repairing the human brain after stroke: I. Mechanisms of spontaneous recovery. Ann. Neurol. 63, 272–287. doi: 10.1002/ana.21393

PubMed Abstract | CrossRef Full Text | Google Scholar

Tae-Hoon, L., and Yoon-Seok, L. (2012). Transplantation of mouse embryonic stem cell after middle cerebral artery occlusion. Acta Cir. Bras. 27, 333–339. doi: 10.1590/s0102-86502012000400009

PubMed Abstract | CrossRef Full Text | Google Scholar

Taguchi, A., Soma, T., Tanaka, H., Kanda, T., Nishimura, H., Yoshikawa, H., et al. (2004). Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesis in a mouse model. J. Clin. Invest. 114, 330–338. doi: 10.1172/JCI200420622

PubMed Abstract | CrossRef Full Text | Google Scholar

Takahashi, K., and Yamanaka, S. (2006). Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell 126, 663–676. doi: 10.1016/j.cell.2006.07.024

PubMed Abstract | CrossRef Full Text | Google Scholar

Takahashi, K., Yasuhara, T., Shingo, T., Muraoka, K., Kameda, M., Takeuchi, A., et al. (2008). Embryonic neural stem cells transplanted in middle cerebral artery occlusion model of rats demonstrated potent therapeutic effects, compared to adult neural stem cells. Brain Res. 1234, 172–182. doi: 10.1016/j.brainres.2008.07.086

PubMed Abstract | CrossRef Full Text | Google Scholar

Thomson, J. A. (1998). Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147. doi: 10.1126/science.282.5391.1145

PubMed Abstract | CrossRef Full Text | Google Scholar

Thwaites, J. W., Reebye, V., Mintz, P., Levicar, N., and Habib, N. (2012). Cellular replacement and regenerative medicine therapies in ischemic stroke. Regen. Med. 7, 387–395. doi: 10.2217/rme.12.2

PubMed Abstract | CrossRef Full Text | Google Scholar

Toda, H., Takahashi, J., Iwakami, N., Kimura, T., Hoki, S., Mozumi-Kitamura, K., et al. (2001). Grafting neural stem cells improved the impaired spatial recognition in ischemic rats. Neurosci. Lett. 316, 9–12. doi: 10.1016/S0304-3940(01)02331-X

PubMed Abstract | CrossRef Full Text | Google Scholar

Turnbull, M. T., Zubair, A. C., Meschia, J. F., and Freeman, W. D. (2019). Mesenchymal stem cells for hemorrhagic stroke: status of preclinical and clinical research. NPJ Regen. Med. 4:10. doi: 10.1038/s41536-019-0073-8

PubMed Abstract | CrossRef Full Text | Google Scholar

Uccelli, A., Moretta, L., and Pistoia, V. (2008). Mesenchymal stem cells in health and disease. Nat. Rev. Immunol. 8, 726–736. doi: 10.1038/nri2395

PubMed Abstract | CrossRef Full Text | Google Scholar

Vahidy, F. S., Haque, M. E., Rahbar, M. H., Zhu, H., Rowan, P., Aisiku, I. P., et al. (2019). Intravenous bone marrow mononuclear cells for acute ischemic stroke: safety, feasibility, and effect size from a phase i clinical trial. Stem Cells 37, 1481–1491. doi: 10.1002/stem.3080

PubMed Abstract | CrossRef Full Text | Google Scholar

Vaquero, J., Otero, L., Bonilla, C., Aguayo, C., Rico, M. A., Rodriguez, A., et al. (2013). Cell therapy with bone marrow stromal cells after intracerebral hemorrhage: impact of platelet-rich plasma scaffolds. Cytotherapy 15, 33–43. doi: 10.1016/j.jcyt.2012.10.005

PubMed Abstract | CrossRef Full Text | Google Scholar

Wichterle, H., Lieberam, I., Porter, J. A., and Jessell, T. M. (2002). Directed differentiation of embryonic stem cells into motor neurons. Cell 110, 385–397. doi: 10.1016/S0092-8674(02)00835-8

PubMed Abstract | CrossRef Full Text | Google Scholar

Xie, J., Wang, B., Wang, L., Dong, F., Bai, G., and Liu, Y. (2016). Intracerebral and intravenous transplantation represents a favorable approach for application of human umbilical cord mesenchymal stromal cells in intracerebral hemorrhage rats. Med. Sci. Monit. 22, 3552–3561. doi: 10.12659/MSM.900512

PubMed Abstract | CrossRef Full Text | Google Scholar

Xin, H., Li, Y., Cui, Y., Yang, J. J., Zhang, Z. G., and Chopp, M. (2013). Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J. Cereb. Blood Flow Metab. 33, 1711–1715. doi: 10.1038/jcbfm.2013.152

PubMed Abstract | CrossRef Full Text | Google Scholar

Xiong, X., Gu, L., Wang, Y., Luo, Y., Zhang, H., Lee, J., et al. (2016). Glycyrrhizin protects against focal cerebral ischemia via inhibition of T cell activity and HMGB1-mediated mechanisms. J. Neuroinflam. 13:241. doi: 10.1186/s12974-016-0705-5

PubMed Abstract | CrossRef Full Text | Google Scholar

Yang, K. L., Lee, J. T., Pang, C. Y., Lee, T. Y., Chen, S. P., Liew, H. K., et al. (2012). Human adipose-derived stem cells for the treatment of intracerebral hemorrhage in rats via femoral intravenous injection. Cell Mol. Biol. Lett. 17, 376–392. doi: 10.2478/s11658-012-0016-5

PubMed Abstract | CrossRef Full Text | Google Scholar

Yao, R. Q., Qi, D. S., Yu, H. L., Liu, J., Yang, L. H., and Wu, X. X. (2012). Quercetin attenuates cell apoptosis in focal cerebral ischemia rat brain via activation of BDNF-TrkB-PI3K/Akt signaling pathway. Neurochem. Res. 37, 2777–2786. doi: 10.1007/s11064-012-0871-5

PubMed Abstract | CrossRef Full Text | Google Scholar

Yu, S. P., Wei, Z., and Wei, L. (2013). Preconditioning strategy in stem cell transplantation therapy. Transl. Stroke Res. 4, 76–88. doi: 10.1007/s12975-012-0251-0

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, B., Yin, Y., Lai, R. C., Tan, S. S., Choo, A. B. H., and Lim, S. K. (2014). Mesenchymal stem cells secrete immunologically active exosomes. Stem Cells Dev. 23, 1233–1244. doi: 10.1089/scd.2013.0479

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, G., Li, Y., Reuss, J. L., Liu, N., Wu, C., Li, J., et al. (2019). Stable intracerebral transplantation of neural stem cells for the treatment of paralysis due to ischemic stroke. Stem Cells Transl. Med. 8, 999–1007. doi: 10.1002/sctm.18-0220

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, H., Huang, Z., Xu, Y., and Zhang, S. (2006). Differentiation and neurological benefit of the mesenchymal stem cells transplanted into the rat brain following intracerebral hemorrhage. Neurol. Res. 28, 104–112. doi: 10.1179/016164106X91960

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, Q., Shang, X., Hao, M., Zheng, M., Li, Y., Liang, Z., et al. (2015). Effects of human umbilical cord mesenchymal stem cell transplantation combined with minimally invasive hematoma aspiration on intracerebral hemorrhage in rats. Am. J. Transl. Res. 7, 2176–2186.

PubMed Abstract | Google Scholar

Zhang, Y., Chopp, M., Meng, Y., Katakowski, M., Xin, H., Mahmood, A., et al. (2015). Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury. J. Neurosurg. 122, 856–867. doi: 10.3171/2014.11.JNS14770

PubMed Abstract | CrossRef Full Text | Google Scholar

Zheng, H., Zhang, B., Chhatbar, P. Y., Dong, Y., Alawieh, A., Lowe, F., et al. (2018). Mesenchymal stem cell therapy in stroke: a systematic review of literature in pre-clinical and clinical research. Cell Transplant 27, 1723–1730. doi: 10.1177/0963689718806846

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhu, J. R., Lu, H. D., Guo, C., Fang, W. R., Zhao, H. D., Zhou, J. S., et al. (2018). Berberine attenuates ischemia–reperfusion injury through inhibiting HMGB1 release and NF-κB nuclear translocation. Acta Pharmacol. Sin. 39, 1706–1715. doi: 10.1038/s41401-018-0160-1

CrossRef Full Text | Google Scholar

Keywords: stroke, stem cells, mesenchymal stem cells, clinical trials, pre-clinical studies

Citation: Singh M, Pandey PK, Bhasin A, Padma MV and Mohanty S (2020) Application of Stem Cells in Stroke: A Multifactorial Approach. Front. Neurosci. 14:473. doi: 10.3389/fnins.2020.00473

Received: 04 February 2020; Accepted: 16 April 2020;
Published: 09 June 2020.

Edited by:

Syed Shadab Raza, ERA’s Lucknow Medical College, India

Reviewed by:

Niyaz Ahmad, Imam Abdulrahman Bin Faisal University, Saudi Arabia
Mohd Farooq Shaikh, Monash University, MalaysiaFDA
Saif Ahmad, Barrow Neurological Institute (BNI), United States

Copyright © 2020 Singh, Pandey, Bhasin, Padma and Mohanty. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Sujata Mohanty, drmohantysujata@gmail.com

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