Received: 30 June 2020 | Revised: 4 August 2020 | Accepted: 5 August 2020

DOI: 10.1002/cbin.11440

Cell Biology
REVIEW International

Stem cell therapy for COVID‐19: Possibilities and challenges

Mahmood S. Choudhery1 | David T. Harris2

1
Tissue Engineering and Regenerative
Medicine Laboratory, Department of Abstract
Biomedical Sciences, King Edward Medical
University, Lahore, Pakistan Since its eruption in China, novel coronavirus disease (COVID‐19) has been reported
2
Department of Immunobiology, The in most of the countries and territories (>200) of the world with ∼18 million con-
University of Arizona, Tucson, Arizona
firmed cases (as of August 3, 2020). In most of the countries, COVID‐19 upsurge is
Correspondence uncontrolled with a significant mortality rate. Currently, no treatment effective for
Mahmood S. Choudhery, Tissue Engineering
COVID‐19 is available in the form of vaccines or antiviral drugs and patients are
and Regenerative Medicine Laboratory,
Department of Biomedical Sciences, King currently treated symptomatically. Although the majority of the patients develop
Edward Medical University, Nila Gumbad
mild symptoms and recover without mechanical ventilation for respiratory man-
Chowk, Anarkali Bazaar, Lahore, Punjab
54000, Pakistan. agement, severe respiratory illness develops in a significant portion of affected
Email: [email protected] and
patients and may result in death. While the scientific community is working to
[email protected]
develop vaccines and drugs against the COVID‐19 pandemic, novel alternative
therapies may reduce the mortality rate. Recent use of stem cells for critically ill
COVID‐19 patients in a small group of patients in China and subsequent Emergency
Use Authorization of stem cells by Food and Drug Administration to Global Institute
of Stem Cell Therapy and Research and Athersys has created excitement among the
medical community. As a result, several clinical trials have been registered using
stem cells for COVID‐19 treatment that aim to use different cell sources, dosage,
and importantly diverse targeted patient groups. In this brief review, the possibilities
of stem cell use in COVID‐19 patients and relevant challenges in their use have been
discussed.

KEYWORDS

acellular therapy, coronavirus, COVID‐19, mesenchymal stem cells, pandemic, stem cells

1 | INTRODUCTION syndrome (ARDS). As a result, COVID‐19 is currently associated with

a high mortality rate (∼697,700 deaths as of August 3, 2020). With
Novel coronavirus disease (COVID‐19) is proliferating quickly over ∼6.06 million active cases of COVID‐19 (as of August 3, 2020;
worldwide and had been announced pandemic by the World Health https://www.worldometers.info/coronavirus/), there is currently no
Organization on March 11, 2020. Severe acute respiratory syndrome vaccine or other antiviral treatment available. The affected patients
coronavirus (SARS‐CoV)‐19, the virus responsible for COVID‐19 is an are only left with symptomatic management of disease because the
enveloped, positive sense, single‐stranded RNA virus of the family frantic search for an effective COVID‐19 treatment is not much
Coronaviridae (Zhou, Yang, & Wang, 2020). It causes mild respiratory successful. Drugs such as remdesivir, lopinavir/ritonavir, interferon
tract infection, fever, and cough in most of the patients. However, in β1 (IFN‐β1; H. Li, Wang, Xu, & Cao, 2020), convalescent plasma (Shen,
a significant portion of the affected patients, these symptoms are Wang, & Zhao, 2020), and Food and Drug Administration (FDA) ap-
accompanied by pneumonia and severe acute respiratory distress proved hydroxychloroquine (Cohen, 2020) are although under

Abbreviations: ARDS, severe acute respiratory distress syndrome; AT‐MSCs, adipose tissue‐derived mesenchymal stem cells; CB‐MSCs, cord blood‐derived mesenchymal stem cells;
COVID‐19, novel coronavirus disease; CT‐MSCs, cord tissue‐derived mesenchymal stem cells; DCs, dendritic cells; EUA, Emergency Use Authorization; GvHD, graft vs host disease;
IFN‐γ, interferon‐γ; IL, interleukin; MSCs, mesenchymal stem cells; TGF‐β, transforming growth factor β.

2182 | © 2020 International Federation for Cell Biology wileyonlinelibrary.com/journal/cbin Cell Biol Int. 2020;44:2182–2191.
CHOUDHERY AND HARRIS Cell Biology | 2183
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investigation but their safety and potential efficacy remain to be severe or critical symptoms. The inclusion criteria for critically ill
determined. Considering the extensive and continuous increase in COVID‐19 patients include respiratory rate ≥30 times/min, pulse
patient numbers and resulting in substantial deaths, novel ther- oxygen saturation at rest ≤93%, the partial pressure of PaO2/
apeutic strategies are required to reduce the mortality rate and to FiO2 ≤ 300 mmHg, a requirement for mechanical ventilation and
make the recovery better. Stem cell‐based regenerative medicine shock (S. Liu et al., 2020). Such critically ill COVID‐19 patients may
therapy may be an option for COVID‐19 patients (Leng, Zhu, & require alternative therapeutic treatment options for better re-
Hou, 2020; Liang et al., 2020). Stem cell‐based regenerative therapies covery. According to recent reports, stem cells administered in a
were initiated recently in China (Leng et al., 2020; Liang et al., 2020) small group of severely affected COVID‐19 patients showed bene-
and approval of Emergency Use Authorization (EUA) of stem cell use ficial effects (Leng et al., 2020; Liang et al., 2020). All patients in these
by FDA for COVID‐19 patients has created an excitement among the studies showed improvement in lung function after stem cell ad-
medical community. ministration (please see Section 5 for detail).
Mesenchymal stem cells (MSCs), a type of adult stem cells are Older COVID‐19 patients with comorbidities such as diabetes,
found in various autologous and allogenic sources and have high asthma, and heart diseases are also in danger as the highest mor-
proliferative potential and multilinage differentiation capacity. Pre- bidity was observed in this group. The immune system and re-
vious studies have shown that the immunomodulatory properties of generative potential of these patients are compromised with
MSCs help in modulation of proliferation, activation, and function of advancing age and disease, resulting in this segment of the popula-
various immune cells (Harrell, Sadikot, & Pascual, 2019) and thus are tion being badly hit by a coronavirus. Due to a compromised immune
able to alter the innate and adoptive immune responses (S. Liu, Peng, system in such patients, antibody production takes a longer time to
& Qiu, 2020). MSCs were used previously for the treatment of graft fight the coronavirus and the patients often develop critical condi-
vs host diseases (GvHDs) as well as for the treatment of other virus‐ tions of pneumonia and ARDS. Stem cell therapy may be particularly
associated diseases such as immunologic abnormality in human im- useful for such patients because the chances of recovery in such
munodeficiency virus, chronic hepatitis in hepatitis B virus, and acute patients are significantly low. It is pertinent to mention that stem cell
lung injury in influenza virus (Maytawan, Suradej, & Arunee, 2015). administration in this group of patients may also improve underlying
The immunomodulatory characteristics of MSCs indicate that MSCs morbidities.
can be used as a supportive treatment option for better recovery of
critically ill COVID‐19 patients (Leng et al., 2020; Liang et al., 2020).
The use of stem cells in COVID‐19 patients in China at the beginning 3 | POSSIBLE STEM CELL SOURCES AND
of the pandemic suggests possible benefits for patients. Similarly, the T Y P E S FO R C O V I D ‐19 P ATIENT S
FDA has recently granted EUA of stem cells for COVID‐19 patients.
Considering initial promising results in a small group of critically ill Stem cells are unspecialized cells in the body that have the potential
COVID‐19 patients, a number of clinical trials have been registered to make more stem cells as well as differentiate into specialized cells
using MSCs (Tables 1–3). These stem cell‐based trials for COVID‐19 of the body if appropriate signals are given in vitro or in vivo. Em-
will evaluate different sources, numbers, and patient groups for bryonic stem cells (ESCs) can be isolated from the inner cell mass of
treatment. It is therefore imperative to understand the logic, asso- 5–8 days old embryos and possess high regenerative potential.
ciated mechanisms, and challenges for a successful stem cell therapy However, the clinical use of ESCs is restricted due to a number of
for COVID‐19 patients. As there is limited available data regarding religious, ethical, and legal controversies. Adult stem cells can be
stem cell use for COVID‐19 patients, the review has discussed a isolated from neonatal sources (such as cord blood, cord tissue,
number of relevant implications imperative for understanding the placenta, and menstrual blood) as well as from adult tissues (such as
logic, associated mechanisms, and relevant problems for a successful bone marrow, adipose tissue, dental pulp, and peripheral blood) are
stem cell therapy for COVID‐19. The discussion of some relevant used for these purposes. MSCs, a type of adult stem cells, are a
challenges and the stem cell‐based acellular therapies will be of special focus of stem cell‐related therapies currently due to their
particular interest for readers. immunomodulatory and regenerative potential (Leng et al., 2020;
Golchin, Seyedjafari, & Ardeshirylajimi, 2020). MSCs can be obtained
in large numbers from autologous sources such as adipose tissue,
2 | P O T E NT IA L G R O UP S O F CO VI D ‐1 9 bone marrow, and from allogenic sources such as cord blood and
PATIENTS FOR S TEM C ELL THERAPY cord tissues. In addition, MSCs are multipotent, could be cryopre-
served for multiple uses and thus are readily available at the time of
Three groups of COVID‐19 patients, that is, (a) critically ill young care (Choudhery, Badowski, Muise, Pierce, & Harris, 2014).
patients, (b) critically ill older patients, and (c) those patients who are Previously published clinical data of stem cell use against virus‐
at high risk of infection due to other comorbidities, are potential induced acute respiratory distress syndrome (ARDS) provides a hint
candidates for stem cell‐based therapies. Current COVID‐19 data for the success of stem cell‐based therapies for COVID‐19 infection.
(https://www.worldometers.info/coronavirus/) indicates that a sub- The selection of a suitable stem cell source and type is important for
stantial portion (∼2%) of coronavirus‐affected people develops the treatment of COVID‐19 patients. The median time from first
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T A B L E 1 Current clinical trials “Recruiting” COVID‐19 patients for stem cells‐based therapies
Trial number/identification Condition or disease Cell type used as an intervention Phase

NCT04313322 COVID‐19 WJ‐MSCs I

NCT04416139 COVID‐19 MSCs II

NCT04336254 COVID‐19 Allogeneic human dental pulp stem cells I

NCT04366323 SARS‐CoV‐2 Allogeneic and expanded adipose tissue‐ I/II

derived MSCs

NCT04252118 COVID‐19 UC‐MSCs I

NCT04366063 COVID‐19 MSCs II, III

NCT04339660 COVID‐19 UC‐MSCs I, II

NCT04392778 COVID‐19, pneumonia, multiple organ failure MSCs I, II

NCT04355728 COVID‐19, ARDS UC‐MSCs I, II

NCT04390139 COVID‐19, ARDS WJ‐MSCs I, II

NCT04389450 COVID‐19, ARDS Allogeneic expanded placental mesenchymal‐ II

like adherent stromal cells

NCT03042143 ARDS Human UC‐CD362 enriched MSCs I/II

NCT04361942 COVID‐19 pneumonia MSCs II

NCT04269525 Viral pneumonia, ventilator‐associated UC‐MSCs II

NCT04333368 SARS‐CoV‐2, ARDS WJ‐MSCs I, II

NCT04288102 COVID‐19 MSCs II

ChiCTR2000030835 Coronavirus disease 19 WJ‐MSCs I

ChiCTR2000030866 Coronavirus disease 19 UC‐MSCs 0

ChiCTR2000030300 Coronavirus disease 19 infection, pulmonary UC‐MSCs I

fibrosis, viral pneumonia

ChiCTR2000029990 Coronavirus disease 19 infection, viral hMSCs I/II

pneumonia

ChiCTR2000030020 Coronavirus disease 19 infection, viral MSCs II

pneumonia

ChiCTR2000029569, Coronavirus infection, pneumonia UC‐MSCs 0

ChiCTR2000029572

ChiCTR2000029580 Coronavirus infection, pneumonia MSCs 0

ChiCTR2000029606 Coronavirus infection, pneumonia Human menstrual blood‐derived stem cells 0

ChiCTR2000030835 Coronavirus disease 19 infection, viral MSCs NA

pneumonia

ChiCTR2000030866 Coronavirus disease 19 infection, viral UC‐MSCs 0

pneumonia

Abbreviations: ARDS, severe acute respiratory distress syndrome; COVID‐19, novel coronavirus disease; hMSC, human mesenchymal stem cell;
MSC, mesenchymal stem cell; NA, not applicable; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2; UC‐MSC, umbilical cord‐derived
mesenchymal stem cell; WJ‐MSC, Wharton's jelly‐derived mesenchymal stem cell.

Trial number/
T A B L E 2 Current clinical trials
identification Condition or disease Cell type used as an intervention Phase “Enrolling” COVID‐19 patients for stem
cells‐based therapies
NCT04348435 COVID‐19 Allogeneic AdMSCs II

NCT04382547 COVID‐19, viral Allogenic‐pooled‐olfactory I/II

pneumonia mucosa‐derived MSCs

NCT04349631 COVID‐19 AT‐MSCs (AdMSCs; autologous) II

Abbreviations: AdMSC, adipose‐derived mesenchymal stem cell; AT‐MSC, adipose tissue‐derived

mesenchymal stem cell; COVID‐19, novel coronavirus disease; MSC, mesenchymal stem cell.
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T A B L E 3 Current registered clinical trials “Not yet Recruiting” COVID‐19 patients for stem cells‐based therapies
Trial number/identification Condition or disease Cell type used as intervention Phase

NCT04428801 COVID‐19 Autologous adipose‐derived stem cells II

NCT04302519 COVID‐19 Dental pulp‐MSCs Early phase I

NCT04429763 COVID‐19 UC‐MSCs II

NCT04315987 COVID‐19 pneumonia MSCs II

NCT04349540 COVID‐19 Allogeneic hematopoietic stem cells NA

NCT04390152 Acute respiratory distress syndrome WJ‐MSCs I, II

NCT04348461 COVID, respiratory distress syndrome Allogeneic and expanded adipose tissue‐ II
derived MSCs

NCT04371601 COVID‐19 pneumonia UC‐MSCs I

NCT04362189 COVID‐19 pneumonia Allogeneic AT‐MSCs II

NCT04393415 COVID‐19 Cord blood (CB) stem cells NA

NCT04397796 COVID Allogenic BM‐MSCs I

NCT04377334 COVID, ARDS Allogeneic BM‐MSCs II

NCT04400032 COVID‐19, ARDS BM‐MSCs I

NCT04398303 COVID‐19 pneumonia Allogenic human umbilical‐derived MSCs and I, II

allogenic human umbilical‐derived MSCs
conditioned medium

NCT04345601 COVID‐19, ARDS BM‐MSCs Early phase I

NCT04299152 SARS pneumonia CB stem cells II

NCT04346368 COVID‐19 BM‐MSCs I, II

NCT04273646 COVID‐19, novel coronavirus UC‐MSCs NA

pneumonia

ChiCTR2000030224 Coronavirus disease 19 MSC II

ChiCTR2000030173 Coronavirus disease 19 UC‐MSCs 0

ChiCTR2000030261 Coronavirus disease 19 infection, viral MSCs‐derived exosomes 0

pneumonia

ChiCTR2000030116 Coronavirus disease 19 infection, UC‐MSCs II

respiratory distress syndrome, viral
pneumonia

ChiCTR2000030138 Coronavirus disease 19 infection, viral UC‐MSCs II

pneumonia

ChiCTR2000030088 Coronavirus disease 19 infection, viral WJ‐MSCs 0

pneumonia

ChiCTR2000029816, Coronavirus disease 19 infection, CB‐NK cells + CB‐MSCs 0

ChiCTR2000029817 pneumonia

NCT04276987 Coronavirus MSCs‐derived exosomes I

Abbreviations: ARDS, severe acute respiratory distress syndrome; AT‐MSC, adipose tissue‐derived mesenchymal stem cell; BM‐MSC,
bone‐marrow‐derived mesenchymal stem cell; COVID‐19, novel coronavirus disease; MSC, mesenchymal stem cell; NK, natural killer; NA, not
applicable; SARS, severe acute respiratory syndrome; UC‐MSC, umbilical cord‐derived mesenchymal stem cell; WJ‐MSC, Wharton's jelly‐derived
mesenchymal stem cell.

symptoms to death in COVID‐19 infection is ∼14 days (Lauer, regarding the time of the start of MSC therapy for maximum bene-
Grantz, & Bi, 2020). This time period provides a narrow window of fits; therefore, studies are required to evaluate the optimal period of
treatment opportunity and therefore starting therapy at an appro- the start of cell‐based therapies. Current registered clinical trials are
priate time is important especially for patients who are older and primarily focused on the use of stem cells obtained from allogenic
have other illnesses. However, no data is currently available sources such as donated Wharton's jelly or umbilical cord tissues
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(Tables 1–3). Autologous stem cells are often preferred for cell‐based 4 | WH Y ST EM CE LLS COU LD B E AN
therapies. However, for active COVID‐19 patients, aspiration of E F F E C T I V E T R E A T M E N T O P T IO N F O R
adipose tissue or bone marrow and subsequent isolation of cells from COVID ‐1 9 P A T I E N T S
these tissues does not seem to readily amenable to this purpose. A
recent study by Rogers, Harman, and Bunnell (2020) provided some Most COVID‐19 patients do not develop any major clinical symptoms
rationale for the clinical use of autologous adipose tissue‐derived during the early stages of infection. Common symptoms include mild
MSCs (AT‐MSCs) for COVID‐19 patients. However, additional injury or high temperature, cough, sore throat, muscle distress, and body
from aspiration of these tissues for AT‐MSC isolation makes this pain. In a few patients, shortness of breath can lead to a sudden de-
approach less desirable. Therefore, for active, severely ill patients, terioration in the health of the patient during the later stages of the
allogenic cell sources (being readily available) seems a better option disease. In severe cases, immune system dysfunction is the major
for treatment. For COVID‐19 patients who are at high risk of de- cause of death in patients as infection stimulates inflammatory cyto-
veloping a severe disease (older patients with comorbidities) due to kines that result in the respiratory system being overwhelmed by a
COVID‐19 infection, autologous sources of stem cells such as adi- storm of inflammatory cytokines such as interleukin 2 (IL‐2), IL‐6,
pose tissue and bone marrow could be used. For such patients, the granulocyte colony stimulating factor, IP10, MCP1, MIP1A, and tumor
time to initiate therapy is very important in order to boost the im- necrosis factor (TNF; Huang, Wang, & Li, 2020). In COVID‐19, the
mune system. The biobanks, however, can play an important role in immune system seems unable to turn itself off and produces an ex-
this regard by preserving the adipose tissue and bone marrow and cessive quantity of cytokines, thus producing an inimical environment
making these tissues or cells available for patients at the time of care. for the infection (Figure 1). Such an unchecked inflammation caused by
It is pertinent to mention here that the use of stem cell therapy in this cytokine storm compromises lung function and patients have
critical patients in the intensive care unit (ICU) is not yet approved, difficulty in breathing and eventually die. The cytokine storm can lead
therefore; precautions must be taken to ensure the safety of the to organ failure followed by edema, secondary infection, cardiac da-
patients. mage, and ARDS. MSCs are thought to balance the immune system
A majority of registered stem cell clinical trials to treat COVID‐ and stop its overactivation. Such a balance of the immune system is
19 have proposed the use of MSCs as a treatment modality for such very important, as complete shutting down of the immune system will
COVID‐19 patients. MSCs are a well‐characterized type of adult affect the infection‐fighting ability of patients.
stem cells with ideal proliferative, differentiation, and im- Control of COVID‐19‐induced cytokine storm during infection
munomodulatory properties. MSCs are also without ethical issues can save patients, as shown by anecdotal reports of successful
and are available for allogenic or autologous use. MSCs regenerate treatment of patients with anti‐IL‐6 receptor monoclonal anti-
and repair damaged tissues by transdifferentiation or secretion of bodies. MSCs possess powerful anti‐inflammatory and im-
various bioactive molecules to stimulate resident cells. MSCs are well munomodulatory properties and therefore can also control
known in the medical community for its promising anti‐inflammatory cytokine storms by inhibiting overactivation of the immune system
properties. Previously, few studies related to the use of stem cells to and by improving endogenous repair of injured tissues (Leng
treat respiratory virus‐related lung injury have been conducted. Al- et al., 2020). MSCs possess special immunoregulatory properties
though reports are conflicting, the systemic administration of MSCs that enable these cells to modulate the functions of various
was protective for influenza respiratory infections (Khoury immune cells (Harrell et al., 2019).
et al., 2020). Interestingly, studies found a greater protective effect MSCs are also able to alter the innate and adoptive immune
of MSCs derived from bone marrow as compared to MSCs derived responses (S. Liu et al., 2020). Previous studies indicated that MSCs
from umbilical cord tissues in influenza A infection (Loy, Kuok, & can induce mature dendritic cells (DCs) into novel Jagged‐2 depen-
Hui, 2019). dent regulatory DCs. These regulatory DCs not only play an

F I G U R E 1 Cytokine storm modulation by mesenchymal stem cells. COVID‐19, novel coronavirus disease; IFN‐γ, interferon‐γ; IL, interleukin;
ROS, reactive oxygen species; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2; TNF‐α, tumor necrosis factor α
CHOUDHERY AND HARRIS Cell Biology | 2187
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important role in immune homeostasis but are immunosuppressive in SARS‐COV‐2 pathogenesis. Another cellular serine protease
(Zhang et al., 2009; X. Liu et al., 2012). In one of the initial MSC‐based TMPRSS2 is essential for the entry of the COVID‐19 virus into host
clinical studies for COVID‐19, it was found that the number of reg- cells (Hoffmann et al., 2020). Interestingly, a recent study indicated
ulatory DC was increased significantly after MSC transplantation that MSCs are negative for ACE2 and TMRSS2 and thus could have a
(Leng et al., 2020). Furthermore, MSC transplantation leads to de- natural resistance to SARS‐COV‐2 (Leng et al., 2020). Previously
creased TNF‐α levels and increased IL‐10 levels in critically ill published clinical data of MSC use for virus‐induced ARDS provides a
COVID‐19 patients in the MSC treatment group compared to the hint for the success of stem cell‐based therapies for COVID‐19.
placebo control group. Overall, the immunomodulatory and regenerative properties of
The immunomodulatory properties of MSCs are due to low levels of MSCs can help in patient recovery by modulating the immune system
MHC class 1 antigen concurrent with the release of IFN‐γ, indoleamine and by repairing the damaged tissue in the lungs. Promising results of
2,3‐dioxygenase, transforming growth factor β, IL‐6, IL‐10, and pros- preclinical studies suggest MSCs are safe and effective therapeutic
taglandin E2 (Aggarwal & Pittenger, 2005; Jiang, Zhang, & Liu, 2005; agents for a number of diseases and disorders. Based on recent
Corcione, Benvenuto, & Ferretti, 2006; Spaggiari, Capobianco, Becchetti, promising results of MSC use in COVID‐19 patients in Chinese stu-
Mingari, & Moretta, 2006; Rasmusson, Uhlin, Blanc, & Levitsky, 2007). dies (Leng et al., 2020; Liang et al., 2020) and overall safety and
With these properties MSCs can inhibit the differentiation of monocytes effectiveness of its use in several American and European clinical
into DCs, can increase the ratio of regulatory cytokines to inflammatory trials, the FDA had granted permission of compassionate use
cytokines, and can inhibit antibody production by B cells and prolifera- of MSCs.
tion of the natural killer cells.
The safety and effectiveness of MSCs in life‐threatening
immune‐mediated inflammatory diseases such as GvHDs and sys- 5 | CURREN T S TEM CE LL‐ BASED CLINICAL
temic lupus erythematosus have previously been documented T RI A L S F O R C O V I D‐19 P ATIENT S
through various clinical trials. An overall increase in survival of GvHD
patients was observed after MSC administration (Morata‐Tarifa, Although many countries including the USA, China, Italy, UK, France,
Macias‐Sanchez, Gutierrez‐Pizarraya, & Sanchez‐Pernaute, 2020). Spain, Germany, Turkey, Iran, Brazil, and Jordon have proposed stem
Furthermore, the efficacy of MSC has also been documented for the cell use for COVID‐19 patients, only a limited number of stem cell‐
treatment of ARDS induced by H9N2 avian influenza viruses, and based studies are available currently to deduce solid limitations or
H5N1 infections in mice and humans (Chan et al., 2016; Y. Li potential of such therapy for COVID‐19. A study recently conducted
et al., 2016). in Beijing's YouAn Hospital, China, from January 23, 2020 to Feb-
If MSCs can reduce the incidence and severity of other virus‐ ruary 16, 2020 suggests a possible role of MSCs administration in
related diseases (Maytawan et al, 2015), they might prevent over- COVID‐19 treatment (Leng et al., 2020). This single‐center open‐
activation of the immune system (Baron and Storb, 2012; Wei labeled study was performed on seven COVID‐19 patients of dif-
et al., 2013), lower levels of inflammatory substances and regenerate ferent degrees of severity (critically severe [n = 1], severe [n = 4], and
the damaged tissues in COVID‐19 patients. Systemic administration common type [n = 2]). A single dose of MSCs (106 cells/kg body
of MSCs results in homing to the pulmonary vascular bed where they weight) was administered and patients were followed for 14 days. No
release soluble factors such as anti‐inflammatory cytokines, anti- adverse events in terms of allergic reactions or secondary infections
microbial peptides, angiogenic growth factors, and extracellular ve- were reported after MSC administration. Most importantly, pul-
sicles (Khoury et al., 2020) and thus could improve the pulmonary monary function and symptoms were significantly improved in all
microenvironment, protect alveolar epithelial cells, prevent pulmon- patients 2 days after MSC injection. In this study, treatment with
ary fibrosis, and improve overall lung function (Leng et al., 2020). In MSCs increased the number of peripheral lymphocytes, decreased C‐
addition, the repair of immune and respiratory epithelial cells can reactive protein (CRP) levels, and numbers of overactivated cytokine
also occur by direct transfer of mitochondria from MSCs (Swati, Ri- secreting immune cells declined. Similarly, TNF‐α levels significantly
tuparna, Anurag, & Sujata, 2018). Previous studies have shown that decreased concurrently with an IL‐10 increase in patients treated
mitochondrial transfer from MSCs can repair the tubular epithelial with MSC as compared to the control group. All patients in the stem
cells in diabetic nephropathy (Naoto, Kanna, Shin, & Mineko, 2019). cell‐treated group survived but not in the control group. Overall, this
Angiotensin‐converting enzyme 2 (ACE2) is the main receptor study demonstrated the potential efficacy and safety of stem cell
for SARS‐COV‐2 (the virus that causes COVID‐19) expressed by infusion in all seven patients.
many types of human cells such as alveolar type 2 cells and capillary In another case report, (Liang et al., 2020) human umbilical cord
epithelium cells. SARS‐COV‐2 infects these cells but not bone mar- tissue‐derived MSCs (CT‐MSCs) were infused in a critically ill
row, lymph nodes, thymus, spleen, and immune cells (such as T and B COVID‐19 patient. The 65 years old female patient had increased
lymphocytes and macrophages) being negative for ACE2 (Hamming, neutrophils, decreased numbers of lymphocytes, and was confirmed
Timens, & Bulthuis, 2004). This receptor plays an important role for positive for SARS‐CoV‐2. Although the patient was treated with the
the entry of SARS‐COV‐2 into these cells (Khoury et al., 2020). Re- antiviral drugs lopinavir/ritonavir, IFN‐α, and iv injection of moxi-
cognition of the ACE2 receptor by viral spike protein is the first step floxacin, methylprednisolone, and immunoglobulin, the patient
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developed a spastic cough, severe diarrhea, and electrolyte dis- findings suggest MSCs as promising candidates for the treatment of a
turbance and was later diagnosed critically ill and was shifted to ICU number of diseases including ARDS, the safety, cell viability, and
and an invasive tracheal cannula was performed to decrease the regulatory issues raises concerns about their use in patients.
respiratory distress. In addition, the noninvasive mechanical venti- Stem cell‐based acellular therapies are gaining significant at-
lator was also used to combat hypoxia and respiratory muscle fatigue tention by avoiding the controversies raised by stem cell‐based
of the patient. Stem cell therapy was proposed by the medical team clinical use. It has been shown that MSCs exert their beneficial ef-
7
and the patient was given three infusions of 5 × 10 CT‐MSCs 3 days fects primarily by paracrine mechanisms in which they release ex-
apart. The patient responded to the MSC administration and within a tracellular vesicles such as microvesicles and exosomes. Exosomes
week pneumonia was greatly relieved. The patient was able to be contain a variety of chemokines, growth factors, messenger RNA, and
transferred from the ICU and further clinical investigation showed microRNA. These products of extracellular vesicles have anti‐
normal levels of laboratory indexes such as creatinine level, albumin, inflammatory and immunomodulatory properties and thus function
alanine aminotransferase, CRP, procalcitonin, D‐dimer. In addition, as regulators of the immune system (Chen, Lai, & Lee, 2010; Lai, Tan,
computed tomography images indicated relief in both the left and & The, 2012). In addition, exosomes also possess a tremendous re-
right lungs. generative potential for repair and regeneration of damaged organs
In another study, Sanchez‐Guijo et al. (2020) determined the and tissues. Interestingly, preclinical studies have shown encouraging
safety and potential use of AT‐MSCs. In this study, 13 COVID‐19 effects of exosomes in animal models of ARDS and other respiratory
adult patients under invasive mechanical ventilation were enrolled. and inflammatory diseases (Katsha et al., 2011; Lee, Park, &
All the patients previously received antiviral and/or anti‐ Lee, 2019; Tang et al., 2017; Zhu et al., 2014). Exosome injections in
inflammatory treatments including steroids, lopinavir/ritonavir, hy- these studies showed reduced alveolar inflammation, enhanced
droxychloroquine and/or tocilizumab, and so forth. Ten out of thir- edema clearance, and restoration of leaky epithelial membranes.
teen patients received two doses (3 days after the first dose) of These findings support a possible role for exosomes in managing the
allogenic AT‐MSCs. The remaining two patients were given a single cytokine storm caused by inflammation.
dose while the third patient received three doses of allogenic AT‐ In a recent nonrandomized, open‐label cohort study, 24 moderate
6
MSCs. Each dose contained 0.98 × 10 AT‐MSC/kg of the recipient's to severe COVID‐19 patients were enrolled in a study that aimed to
body weight. The study observed no cell therapy‐related adverse evaluate the safety and efficacy of allogenic bone marrow MSC‐derived
effects. While 70% of the patients exhibited clinical improvement and exosomes (Sengupta et al., 2020). All of the enrolled patients were
discharged from ICU, four patients remained intubated and two pa- confirmed for SARS‐CoV‐2 infection by polymerase chain reaction
tients died. MSC therapy was related to a decrease in CRP, IL‐6, testing. All patients received a single dose of exosomes (15 ml; please
ferritin, lactate dehydrogenase, and D‐dimer and an increase in lym- see Sengupta et al. [2020] for experimental details) and followed for
phocytes. The study indicates that the administration of AT‐MSCs is 2 weeks to evaluate its safety and efficacy. No adverse effects related to
safe and can improve clinical outcomes in COVID‐19 patients. exosome transplantation were observed in the study. In addition, in
Currently registered clinical trials (Tables 1–3) on the NIH US 83% of patients, the clinical status and oxygenation level was improved.
National Library of Medicine (Clinicaltrials.gov) and on the Chinese Furthermore, absolute neutrophil counts and lymphocyte counts were
Clinical Trial Registry (http://www.chictr.org.cn/abouten.aspx) are significantly increased concurrently with a decrease in acute phase re-
using MSCs derived from various tissues such as CT‐MSCs, bone‐ actants such as CRP, ferritin, and D‐dimer reduction. Overall, the study
marrow‐derived MSCs, dental pulp‐derived MSCs, umbilical cord‐ suggested that allogenic bone marrow MSC‐derived exosomes are safe,
derived MSCs, AT‐MSCs, Wharton's jelly‐derived MSCs, and cord can restore oxygenation, downregulate cytokine storms, and recon-
blood‐derived MSCs. Most of these trials have used MSCs from al- stitute immunity in severe COVID‐19 patients.
logenic sources in order to provide the cells at the time of care. Some Currently, three studies using exosomes for COVID‐19 treat-
of these clinical trials aim to use MSC‐derived products such as ment have been registered on clinicaltrials.gov. One of these studies
exosomes (ChiCTR2000030261, NCT04276987). Overall, these re- (NCT04276987) aims to utilize MSCs derived from allogenic adipose
gistered trials aim to evaluate the safety and effectiveness of stem tissue and the other two studies, NCT04384445 and NCT04276987,
cell use for the treatment of COVID‐19. have proposed the use of human amniotic fluid‐derived exosomes
and T‐cell‐derived exosomes, respectively.

6 | M S C‐ BASED A CEL LULAR TH ERAPIES

FOR C O VI D‐19 7 | CH ALL ENGES

It has been shown that there are multiple mechanisms through which Despite hundreds of registered clinical trials and thousands of pub-
MSCs can exert their immunomodulatory effects. It was previously lished papers, stem cell treatment remains controversial and cur-
thought that MSCs promoted lung regeneration through engraftment rently is not FDA approved for most diseases and disorders. The FDA
and transdifferentiation. However, later studies supported the has only granted compassionate use for stem cell therapy and the
paracrine role of MSCs in lung regeneration. Although clinical ability to use an EUA outside of a clinical trial may be revoked at any
CHOUDHERY AND HARRIS Cell Biology | 2189
International
time. The compassionate permission to use a drug refers to the use of cost, GMP grade reagents, and proper quality testing in current
an unproved new drug for severely ill patients in an emergency si- lockdown conditions is another challenge. In addition, genomic sta-
tuation when no other effective drugs are available. According to the bility and regenerative potential of expanded MSCs may be com-
recent statement of the International Society for Stem Cell Research, promised and raises another concern about the safety of the
“although stem cells are promising candidates for various diseases expanded MSC used clinically.
and disorders, currently there is no stem cell‐based approved ap- Most registered clinical trials have proposed the use of MSCs
proach for prevention or treatment of COVID‐19 infection” due to their immunomodulatory activities. Use of MSCs in im-
(ISSCR, 2020). Although the results of recent clinical studies for munocompromised COVID‐19 patients, however, raises a concern
COVID‐19 are encouraging (Leng et al., 2020; Liang et al., 2020), but regarding a greater risk of viral and other infections in such patients.
on a very small number of patients and without appropriate controls Since the immunosuppressive effect of MSCs is nonspecific, both the
and therefore solid conclusions cannot be drawn. In addition, the alloantigen and viral antigen responses may be repressed leading to
treated groups were given stem cells in conjunction with conven- detrimental clinical outcomes. In addition, stem cell therapies are
tional therapy and therefore it is questionable if the effect on pa- expensive and most people may not be able to afford it. Will it be
tients is due to administered stem cells. Proper randomization, larger possible for federal governments to offer such therapies for all pa-
sample size, proper control groups with longer follow up in multi- tients if such therapies prove affective. Are institutes prepared to
center studies are therefore required to properly assess the effec- provide the required number of cells for such patients? It is only
tiveness and safety of stem cell use for COVID‐19. possible if stem cell banks start collecting the cells from allogenic
Due to the promising results of preclinical studies stem cell‐ tissues (neonatal/birth‐related tissues such as placenta, cord blood,
based therapeutics have a special interest for incurable diseases. cord tissue). However, the selection of donors during a pandemic is
However, these significant developments in the stem cell field also also challenging especially in countries where the COVID‐19 infec-
face the issues of immunogenicity and limited cell numbers. The tion rate is high.
clinical use of MSCs from autologous sources is the best approach in In the absence of proper control groups, the assessment of the
terms of safety and function, however, the production of clinically safety of MSC treatment is difficult. The preparation of MSCs in la-
relevant number of stem cells requires a substantial amount of time boratories compliant with FDA standards is of paramount importance.
which is not always feasible in an emergency situation like the cur- Along with the donors, the scientific staff should be strictly screened for
rent COVID‐19 emergency. As shown in Tables 1–3, most of the the disease. The cells must be checked for any type of contamination
registered clinical trials for COVID‐19 have proposed the use of al- and viability before use in patients. The issue of cell dose, cell number,
logenic stem cell sources (e.g., placenta‐derived tissues). The use of route of administration, and cell passage number must be controlled for
allogenic stem cells in severe conditions (in the ICU) has not been maximum efficacy and safety of cell use in patients.
proven through clinical studies. However, most of the COVID‐19
patients that the registered clinical trials aim to treat will be critically
ill, often requiring mechanical ventilation for respiratory problems. 8 | LIMITATIONS
Therefore, precautions must be taken while using the stem cells for
such patients. Obtaining the required number of cells in a brief time COVID‐19 is a new disease and there is limited information re-
span for treating the critically ill COVID‐19 patients is another garding its pathology and effective treatment. Due to the current
challenge. In vitro expansion is time‐consuming and may reduce the prevalence of the disease, the relevant information regarding infec-
functional potential of the expanded cells. tion and mortality rate changes each day, and therefore the in-
For different groups of patients, different sources of stem cells formation regarding the total number of cases and the mortality rate
could be used. For critically ill older patients with comorbidities, described in this article may be changed in the near future. Currently,
readily available allogenic sources of cells seems the best option, only a few studies have evaluated the use of MSCs for COVID‐19
however, for other patients at risk of developing COVID‐19 auto- patients and therefore we have discussed the results of limited stu-
logous sources such as adipose tissue could be used. For the isolation dies in this review. Because of the absence of solid data from con-
of clinical‐grade MSCs, harvested tissues must be processed in Good trolled, randomized, multicenter trials, confirmed conclusions about
Manufacturing Practice (GMP) Compliant facilities. The availability of stem cell‐based therapies for COVID‐19 cannot be drawn. Although
such GMP compliant cell processing facilities and the resultant sup- theoretically, MSCs could be used in COVID‐19 patients without the
ply of clinical‐grade MSCs is a major challenge for a number of development of severe adverse effects, most of the information in
countries, especially the developing and underdeveloped countries. this review is about critically ill COVID‐19 patients. Currently, MSCs‐
Rapid preparation of optimal numbers of clinical‐grade MSCs and based therapies are being used as an emergency protocol for the
provision at the time of care is another major challenge for stem cell‐ management of cytokine storm in critically ill COVID‐19 patients,.
based therapies. MSCs are scarce in primary tissues and therefore in However, in the near future, such options may be expanded as a
vitro expansion of these cells is required to obtain the hundreds of preventive remedy especially for elderly patients and patients who
millions of cells to be used as a therapeutic dose. Such cellular ex- also have comorbidities. Due to limited available data, although the
pansion in culture requires several weeks. Managing the time, the information regarding MSC‐based therapies is limited in this review
2190 | Cell Biology CHOUDHERY AND HARRIS
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article we have highlighted the arguments relevant to MSC use for Harrell, C. R., Sadikot, R., & Pascual, J. (2019). Mesenchymal stem cell‐
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inhibitor. Cell, 181(2), 271–280. https://doi.org/10.1016/j.cell.2020.
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Stem cells seem to have significant potential to treat COVID‐19. Such
Huang, C., Wang, Y., & Li, X. (2020). Clinical features of patients infected
treatments may decrease the burden on the health system of coun- with 2019 novel coronavirus in Wuhan, China. Lancet, 395, 497–506.
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