Stem cell therapy: a novel approach against emerging and re-emerging viral infections with special reference to SARS-CoV-2

Abstract

The past several decades have witnessed the emergence and re-emergence of many infectious viral agents, flaviviruses, influenza, filoviruses, alphaviruses, and coronaviruses since the advent of human deficiency virus (HIV). Some of them even become serious threats to public health and have raised major global health concerns. Several different medicinal compounds such as anti-viral, anti-malarial, and anti-inflammatory agents, are under investigation for the treatment of these viral diseases. These therapies are effective improving recovery rates and overall survival of patients but are unable to heal lung damage caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, there is a critical need to identify effective treatments to combat this unmet clinical need. Due to its antioxidant and immunomodulatory properties, stem cell therapy is considered a novel approach to regenerate damaged lungs and reduce inflammation. Stem cell therapy uses a heterogeneous subset of regenerative cells that can be harvested from various adult tissue types and is gaining popularity due to its prodigious regenerative potential as well as immunomodulatory and anti-inflammatory properties. These cells retain expression of cluster of differentiation markers (CD markers), interferon-stimulated gene (ISG), reduce expression of pro-inflammatory cytokines and, show a rapid proliferation rate, which makes them an attractive tool for cellular therapies and to treat various inflammatory and viral-induced injuries. By examining various clinical studies, this review demonstrates positive considerations for the implications of stem cell therapy and presents a necessary approach for treating virally induced infections in patients.

Introduction

Over the past several decades, the news frenzy surrounding many emerging and re-emerging infectious diseases has alerted us to their presence [1]. Such diseases have become a public threat and a source of concern due to there virulence, mortality, mode of transmission, and impact on Patient’s quality of life [1]. As elucidated by the World Health Organization (WHO), emergent infectious diseases are “ones that have appeared in the population for the first time, or that may have existed previously but are rapidly increasing incidence or geographic range”[2]. Since the 1970s, with the emergence of acquired immunodeficiency syndrome (AIDS) in 1978 and severe acute respiratory syndrome coronavirus (SARS-CoV-2) in 2019, infectious diseases have continued to be a major cause of morbidity and mortality for patients [3]. It has been estimated that 60% of emerging infections are zoonotic in nature, while 70% of them originate in wildlife [4]. Some infectious agents have been extenuated to such low levels that they were once excluded from the list of public health hazards [5]. Some infectious agents are exhibiting an upward trend in incidence or prevalence worldwide because of some factors involving mutation, development of resistance to ongoing therapeutics, and evolution of pathogens [6].

Since the beginning of the twenty-first century, the emergence of more than ten crucial epidemic/pandemic level of viruses incidences have already been recorded, which also includes the ongoing and devastating SARS-CoV-2 (COVID-19) pandemic, responsible for the loss of unemployment for millions and causing enormous economic losses [7]. Despite being aware of the deadly 1918 influenza outbreak, the world was unprepared for a SARS-CoV-2 outbreak, despite the fact that the SARS-CoV (2003) and Middle East respiratory syndrome coronavirus (MERS-CoV) (2012) outbreaks had warned of an increased risk of these strains circulating in bats [7, 8]. Revolutionary advances in fundamental research in virology, cell biology, biochemistry, and immunology have led to antiviral products and novel vaccines in record time, yet their distribution to 7 billion individuals across the world seems intimidating [9]. Simultaneously, the rapid spread of rumors and misinformation continues to create confusion and affect public confidence in these medical interventions [10]. The ongoing SARS-CoV-2 pandemic has generated an urge to invest in readiness for a global outbreak of infectious agents, along with systemic investment in diagnosis and intervention technologies [11]. They are crucial to developing family-wise or group-specific therapeutics for highly heterogeneous emerging and re-emerging viral infections in the future [11]. Mesenchymal Stem Cells (MSCs) therapy proposes a providential perspective towards the derogation of insentient effects of infectious viral diseases [6]. Stem cell therapy consists of a heterogenous subset of self-renewing progenitor cells that are possible to harvest from various adult tissue types [12]. This includes umbilical cord blood, amniotic fluid, dental pulp, bone marrow, menstrual blood, fetal liver, Bichat’s fat pad, abdominal fat pad, and endometrium [13]. This review will look back on emerging and re-emerging viral outbreaks with specific emphasis on the recent SARS-CoV-2 outbreak to confer high risk and stem cell therapy as a potential therapeutic agent.

Emerging and re-emerging viral infections all over the world

Some viral zoonoses are also considered “emerging infectious diseases” as they have recently been distinguished and show significant changes in their epidemiological characteristics and geographical distributions [14]. The main cause of the emergences of viruses, particularly their continuously increasing contact with wild animals, is that viruses existing only in non-human host are transmitted to a new human host [15, 16]. Some climatic changes are also responsible for the emergence of viruses. Variants of newly emerging viruses can also cause severe epidemics and appear in drug-resistant forms termed “re-emerging viruses” Fig. 1 [17].

Fig. 1.

A timeline of major emerging viral infections. Case fatality rate (CFR), Severe acute respiratory syndrome corona- virus (SARS-CoV); Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); Marburg virus (MARV); Middle East respiratory syndrome coronavirus (MERS-CoV); Yellow Fever Virus (YFV); and Lassa virus (LASV)

Therapeutic achievements of stem cell therapy

Stem cell therapy is currently showing great promise in the treatment of a wide range of diseases in the human body, including neurodegenerative disorders, Amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease, autoimmune disease, Rheumatoid arthritis, Type 1 diabetes, cardiovascular disease, cancers, and many others [18]. Data extracted from the last decade shows a significant increase in registered clinical trials of MSCs in East Asia, mainly China, followed by North America and Europe, and continuously increasing day by day [6].

Perpetual self-renewal and efficiency to differentiate into specialized adult cell type make characteristic definition of stem cells which include pluripotent stem cells that can be developed into any cell type in body whereas multipotent has limitations to becoming a more definite population of cells [19]. Relative ease of isolation from different tissues and differentiation capacity in all type of lineages have made them an attractive option to treat a variety of clinical manifestations including viral infections as illustrated by researchers in recent [20].

Human MSCs are paradigms of non-hematopoietic stem cells furnished with certain specific cell surface markers and clusters of differentiation (CD29, CD44, CD73, CD90) with the ability to differentiate into endodermal (hepatocytes), mesodermal (osteocytes, adipocytes, chondrocytes) and ectodermal (neurocytes) lineages [21]. Interferon-stimulated gene (ISG) expression makes these cells resistant to virus entry by targeting the viral cycle, blocking the endocytic route, genome integration/amplification, mRNA transcription, and avoiding entry via the cell membrane and protein translation [22]. PMAIP1, ISG15, IFI6, IFITM3, SAT1, p21/CDKN1A, SERPINE1 and CCL2 are examples of reported MSC ISG expression genes [22]. ISGs are found to suppress the infection of dengue, influenza, SARS, and Ebola in vitro, where p21/CDKN1A and IFITM3 are directly found to affect the susceptibility of chikungunya, yellow fever, and zika viruses, respectively [23]. Kane and their colleagues Discovered that indoleamine-pyrrole 2,3-dioxygenase (IDO), ISG, when primed with IFN-γ, reduced the yield of HIV virion by tryptophan depletion. Thus, it was suggested as a useful antiviral strategy against herpes, measles, and Hepatitis B virus (HBV) [24]. MSCs regulate the microenvironment in host tissues with the help of immunomodulatory features as they can inhibit natural killer (NK) cells and T-cells [18]. They exhibit downregulation of inflammatory cytokines and upregulation of regulatory cytokines by different pathways, which makes them effective tools against certain clinical manifestations [18]. The immunomodulatory action of stem cells is governed by toll-like receptors (TLRs), especially TLR3 and TLR4 found on their surface [25]. These receptors are activated upon encounter by ribonucleic acid (RNA) viruses, which work as pathogen-associated molecular patterns (PAMP) and stimulate the secretion of anti-inflammatory agents in the form of certain chemokines like MIP-1α and MIP-1β, RANTES, CXCL9, CXCL10, and CXCL11, known as “cytokine storm” [26]. This hyperimmune response triggers stem cells to present anti-inflammatory molecules IL-10 along with hepatocyte growth factor (HGF), transforming growth factor-β1 (TGF-β1), prostaglandin E2 (PGE2), IDO, and nitric oxide (NO) [27]. The interaction of mesenchymal stem cells with host immune cells and cytokine release is diagrammatically illustrated in Fig. 2.

Fig. 2.

Proposed interaction of Mesenchymal stem cells (MSCs) with host immune system and its response during a viral infection: Presence of cell surface marker, expression of Inteferon-stimulating genes, downregulation and upregulation of inflammatory and regulatory cytokines respectively

Rational for uses of stem cell therapy in COVID-19

Multiple clinical trials have established the safety and efficacy of MSCs in the treatment of COVID-19. As of June 2022, 104 clinical trials for stem cell-based COVID-19 therapy had been registered on http://www.clinicaltrials.gov/ and http://www.chictr.org.cn/. Multiple studies have demonstrated that MSC therapy can considerably lower the incidence and death of critical illnesses (discussed in Tables 1, 2, 3). For instance, Shu et al. discovered that there was no mortality in the MSC therapy group [28]. In addition, Xu et al. found that patients treated with MSC had a significantly greater survival rate (92.31%) than those in the standard treatment group (66.67%) [29]. Another study found that MSC-treated patients had a 91% 28-day survival rate compared to 42% in the control group, with the control group also having a greater risk of death (hazard ratio (HR) of 8.76; 95% confidence interval [CI] 1.07–71.4) [30]. In addition, serious adverse event-free survival improved significantly with MSC treatment compared to the control group (HR 6.22; 95% CI 1.30–28.96). These findings indicate an apparent safety and efficacy of MSC treatment in reducing mortality and enhancing survival.

Table 1.

Studies conducted for the treatment of viral infections via stem cell therapy

Infectious agent	Stem cell type used	Outcome of the study	Reference/National Clinical Trial number (NCT)
HIV	MSCs from adipose tissue	The outcomes of the study involve the incidence of adverse reactions, the incidence of opportunistic diseases, changes in CD4 + cell count, CD4+/CD8 + ratio, and T CD4 +/µl count evolution throughout 48 weeks.	NCT02290041
HIV	UC-MSCs	The total number of CD4 T cells was compared with the CD4 T cells at baseline, the CD38 expression on CD8 T cells, the ratio of CD4 and CD8 T cells, the HLA-DR expression on CD8 T cells, the occurring rate of tumors, and the occurring rate of opportunistic infections.	NCT01213186
HIV	MSCs	MSC-secreted agents ameliorate the competence of latency-reversing agents. Effective transplantation of cells attenuates the tenacious HIV-1 reservoirs in HIV-infected individuals.	[66]
HIV	UC-MSCs	UC-MSC increased CD4 T-cell counts and restored HIV-1-specific (IFN-γ) and IL-2 production.	[62]
HBV	UC-MSCs	Liver functioning improved with an increase in serum albumin and total serum bilirubin. The sodium model for end-stage liver disease scores decreased, reducing ascites in patients with decompensated LC.	[75]
HBV	UC-MSCs	Groups treated with UC-MSC + PE showed the lowest death rate and discrepant outcomes at 30, 60, and 90 days. There was a significant reduction in total bilirubin, alanine aminotransferase, aspartate transaminase, and MELD score.	[70]
HBV	BM-MSCs	Furthermore, patients who received transplants had elevated levels of ALB, TBIL, PT, and MELD scores within 2–3 weeks. After 192 weeks, no dramatic difference was found in the incidence of hepatocellular carcinoma (HCC) or death rate between the two groups.	[76]
HBV	BM-MSCs	Improve clinical laboratory measurements (biochemical parameters), mainly Model for End Stage Liver Disease scores, serum, and total bilirubin. The incidence of severe infection, organ failure, and mortality was found higher in the SMT group than in the MSCs treated group, indicating a decreased mortality rate (death rate) by reducing multiple organ failure and improving severe infection.	[69]
HBV	UC-MSCs	UC-MSC therapy was found to be safe and effective in ACLF patients treated with plasma exchange and entecavir.	[77]
HBV	UC-MSCs	Enhance survival, reduce the model for end-stage liver disease scores, and improve hematological (blood) parameters.	[78]
Influenza A	MSCs conditioned media	MSC-conditioned media showed immunomodulatory effects on macrophages and dendritic cells by modulating the expression of their cytokines.	[79]
H9N2	Mouse BM MSCs	Inflammation is also reduced with H9N2-induced ALI in in vivo trials (mice models).	[53].
H1N1/ H7N2/ H9N5	Swine BM MSCs derived Evs	Reduce virus replication and dropping in nasal swabs, as well as virus-induced pro-inflammatory cytokines. In vitro, it inhibits viral replication and virus-induced cell death in lung epithelial cells. In vivo, it inhibits viral replication and virus-induced apoptosis in the epithelial cells of the animal (pig).	[80]
H5N1	Human BM MSCs	In vitro-reduction in AFC, APP, and proinflammatory cytokine responses and showed prevention from down-regulated sodium and chloride transporters. In vivo-prevent virus associated ALI and the survival of infected mice increased.	[52]
H7N9	MSCs	There is a decrease in lung injury and alveolar fluid clearance during A/H5N1 infection.	[81]
H5N1	Human UC MSCs	In vitro-regulation of inflammatory responses, refining of impaired AFC, APP, and restoring ion transporters In Vivo, the body weight of the animal increased with an improved survival rate.	[82]
Influenza virus	Human BM MSCs	Inhibit the prevalence of virus specific CD8 + T cells and their secretion after treatment.	[54]
H1N1	Human/murine BM MSCs	Under the influence of MSCs, pulmonary inflammation decreased, but these cells were not able to improve survival.	[83]
H1N1	Human/murine BM MSCs	It effectively reduced the viral load, but it did not reduce the severity of infection.	[84]
H1N1	TPR63+/KRT5 + BCs	TPR63+/KRT5 + BCs cells start a repairing process for the mature epithelium to keep normal lung function.	[85]
H1N1	LNEP cells	Cells were able to animate a TPR63+/KRT5 + remodeling program with the help of Notch signaling.	[86]
H1N1	KRT5-progenitor cells	SOX2+/SCGB1A-/KRT5-progenitor cells gave rise to nascent KRT5 + cells.	[87]
H1N1	KRT5-progenitor cells	Rare cell population named p63 + Krt5 was also found to respond against virus-induced injury and generate KRT5 cells.	[88]

Table 2.

Clinical trials completed for the treatment of COVID-19 with stem cell therapy

Registration ID	Title	Trial design	Number of patients	Interventions/ Cell type used & Dose	Outcome of the study.	Refs
NCT04288102	Human mesenchymal stem cells treatment for severe COVID-19: 1-year follow-up results of a randomized, double-blind, placebo-controlled trial	Phase 2, randomized, double-blind, placebo controlled trial	100	UC-MSCs 4 × 107 cells/dose	UC-MSC administration achieves a long-term benefit in the recovery of lung lesions and symptoms in COVID-19 patients	[89]
NCT04713878	MSCs Therapy in Patients With COVID-19 Pneumonia	Randomized, Open Label	21	MSCs (1 million cell/kg)	Mortality status, procalcitonin and C-reactive protein levels, leukocyte counts, concomitant disorders, interleukin-2, interleukin-6, tumor necrosis factor-alpha-beta, and CD4 and CD8 levels are all recorded.	[90]
NCT04473170	Study Evaluating the Safety and Efficacy of Autologous Non-Hematopoietic Peripheral Blood Stem Cells in COVID-19	An adaptive, multicentric, open-label, and randomized controlled phase I/II clinical trial	146	Autologous Non-Hematopoietic Peripheral Blood Stem Cells (NHPBSC)	Cocktail treatment improved clinical results. Nebulizing PB-NHESC-C was shown to be safe and effective.	[91]
NCT04573270	MSCs for the Treatment of COVID-19	Phase 1, Randomized, Single Group Assignment	40	UC-MSCs	Survival rate of infected patients, Contraction Rate of COVID-19 in healthy healthcare workers.	[92]
NCT04535856	Therapeutic Study to Evaluate the Safety and Efficacy of DW-MSC in COVID-19 Patients (DW-MSC)	Phase 1, Randomized, Double-blind, and Placebo-controlled Clinical Trial	9	DW-MSCs Low-dose group (5 × 107cells) High-dose group (1 × 108 cells)	Identification of Treatment-Emergent Adverse Event (TEAE) between groups, survival rate, hospitalization, oxidation index, improvement in lungs, assessment of the changes in inflammation markers	[93]
NCT04400032	Cellular Immuno-therapy for COVID-19 Acute Respiratory Distress Syndrome—Vanguard (CIRCA-19)	Phase 1/ 2, non-Randomized	15	75 × 106 ,150 × 106 and 270 × 106 BM-MSCs given to 2 sets of groups	CIRCA-1901 is a dose-escalating and safety trial using a 3 + 3 + 3 design to determine the safety, and maximum feasible tolerated dose (MFTD) of intravenously (IV) delivered umbilical cord derived MSCs (UC-MSCs).	[94]
NCT04276987	A Pilot Clinical Study on Inhalation of MSCs Exosomes Treating Severe Novel Coronavirus Pneumonia	Phase 1, Single Group Assignment, Open Label	24	MSC-derived exosomes 5 times, aerosol inhalations of MSC-derived exosomes (2.0 × 108 nano vesicles/3 mL at Days 1, 2, 3,4 and 5)	Adverse and severe adverse reaction, Time to clinical improvement, Ventilation, Duration(days) of ICU monitoring, mortality rate, Immunological changes.	[95]
NCT04348461	Adipose-derived mesenchymal stromal cells for the treatment of patients with severe SARS-CoV-2 pneumonia requiring mechanical ventilation. A proof-of-concept study	Phase 2 randomized controlled trial	13	Adipose tissue derived mesenchymal stromal cells (AT-MSCs)	Seven patients out of ten extubated and discharged from the ICU showed an inflammatory decrease after treatment. There were significant parameters (CRP, IL-6, ferritin, LDH, and D-dimer) while lymphocytes were elevated. Significantly, the acute phase reactants declined, and the cells were found to be potent oxygenation returns, down-regulated cytokine storms, and have the capacity to enhance immune system activity.	[96]
https://directbiologics.com	Exosomes Derived from Bone Marrow MSCs as Treatment for Severe COVID-19	Prospective nonblinded nonrandomized primary safety trial at a single hospital center	27	ExoFlo™, a bmMSC-derived exosome agent	Following a single intravenous injection of bone marrow-derived exosomes (ExoFlo), patients hospitalized with severe COVID-19 had significant reversal of hypoxia and cytokine storm with minimal side effects.	[97]
ChiCTR2000029990	Transplantation of ACE2-MSCs Improves the Outcome of Patients with COVID-19 Pneumonia	A pilot trial of intravenous MSCs transplantation	7	ACE2-MSCs	After treatment with ACE2-MSCs, the levels of peripheral lymphocytes, CD14 + CD11c + CD11bmid regulatory dendritic cells, and TNF-α were all increased, while CRP was decreased. MSC transplantation through intravenous injection seems to be a successful treatment for COVID patients.	[73]
IRCT20200217046526N2	MSCs derived from perinatal tissues for treatment of critically ill COVID-19-induced ARDS patients: a case series	Phase 1 clinical trial for safety, feasibility and tolerability of high dose MSCs	11	UC-MSCs & PL-MSCs (200 × 106cells)	11 patient required mechanical ventilation were treated with UC-MSCs (6 patients), PL-MSCs (5 patients), dyspnea decreased, SpO2 increased, significant decrease in TNF-α (6 patients), IL-6 (5 patients), IL-8 (6 patients), CRP (6 patients), IFN-γ (4 patients). Patients with sepsis or multi-organ failure may not be suitable for stem cell treatment.	[32]
NCT04252118	Human umbilical cord-derived mesenchymal stem cell therapy in patients with COVID-19: a phase 1 clinical trial	Phase 2/3 trials	18	UC-MSCs (3 × 107cells/infusion)	All 18 patients recovered and were discharged after treatment, and the intravenous infusion of COVID-19 was found to be safe and well tolerated. Patients with high IL-6 might get more benefit. Improvement in PaO2/FiO2 ratio, cytokine levels (interferon, membrane cofactor protein, and interleukins) were simultaneously decreased after 14 days of treatment.	[98]

Table 3.

Clinical trials registered for the treatment of COVID-19 with stem cell therapy

Registration ID	Year	Stage of trial	Cell type used & Dose	Excepted Outcome of the study
NCT04269525	February 2020–Dec 2020	Recruiting	UC-MSCs (3.3 × 107 cell number / 50ml / bag)	The key indicators of this clinical trial include oxygenation index, hospital stay with 28 days of mortality, 2019-nCoV antibody and nucleic acid test, determination of lung improvement by imaging examinations after treatment, WBC and lymphocyte count, and detection of interleukin (IL)-2, IL-4, IL-6, IL-10, TNF-IL-α, IFN-γ, CD4 + T-Lymphocytopenia, CD8 + T-Lymphocytopenia, C-reactive protein (CRP), and NK cells.
ChiCTR2000029606	January 2020– December 2022	Recruiting	Menstrual blood-derived stem cells	This clinical trial is aimed at determining improvement, mortality, incidence of shock, multiple organ failure, intubation-assisted ventilation modes and parameters, non-invasive ventilation modes and parameters, and extracorporeal membrane oxygenation patterns and parameters.
NCT04416139	May 2020– May 2021	Recruiting	MSCs (1 × 106Kg)	The outcome measures of this study include functional respiratory changes, clinical cardiac changes, body temperature, changes in immune cells (leukocytes, lymphocytes, platelets, fibrinogens, procalcitonin, ferritin, D-dimer), inflammatory changes (CRP, TNF-α, IL-10, IL-1, IL-6, IL-7), immune changes (T cells, dendritic cells, NK cells).
NCT04336254	May 2020– December 2021	Recruiting	Dental pulp derived MSCs (3.0 × 107)	Expected results of this ongoing clinical trial include how long it takes for people to get better and how well their immune systems work with Th1 and Th2 cytokines, cytokines, immunoglobulins, and lymphocyte counts.
NCT04389450	October 2020– March 2022	Recruiting	Allogeneic expanded placental mesenchymal-like adherent stromal cells	Determination of mortality and longanimity of mechanical ventilation/ventilation free days.
NCT03042143	January 2019– October 2022	Recruiting	Human UC-CD362 enriched MSCs	This clinical trial aimed to illustrate the following: oxygenation index, incidence of serious adverse events (SAE), sequential organ failure assessment score (SOFA), respiratory complications and P/F ratio, 28-day and 90-day mortality, length of ICU and hospital stay, and ventilation free days at day 28.
NCT04333368	April 2020– April 2022	Active nit Recruiting	WJ MSCs (1 million /kg body weight)	Respiratory efficacy is evaluated with the increase in PaO2/FiO2 ratio as compared with control, determination of lung injury score, oxygenation index, estimation of plasmatic cytokine level, quality of life at one year, determination of treatment-induced toxicity and adverse effects, Cumulative use of neuromuscular blocking agents, mortality, ventilator free days.
NCT04366063	April 2020– Dec 2020	Recruiting	MSCs 100 × 106	Evaluation of pneumonia improvement, assessment of adverse events, respiratory efficacy, biomarker concentration in plasma.
NCT04486001	Dec 2020–Jan 2022	Recruiting	AD-MSCs	Frequency of mild and severe adverse events associated with infusions, mortality, ventilation, ICU, and hospital discharge
NCT04348435	May 2020– July 2021	Active not recruiting	Hope Biosciences AD-MSCs (50, 100, 200 million cells/dose)	Symptom assessment, hospitalization requirement, estimation of immunological and biochemical, hematological parameters.
NCT04349631	April 2020– May 2–21	Active not recruiting	HB-adMSCs	Incidence of hospitalization and symptom assessment with estimation of hematological, biochemical, and immunological parameters.
NCT04252118	Jan 2020–Dec 2021	Recruiting	MSCs 3.0 × 107	Estimation of lesions in the chest, adverse effect of MSCs, improvement in clinical signals, mortality rate, CD4 + and CD8 + T cell count, CRP, and creatine kinase estimation.
NCT04437823	June 2020– June 2021	Recruiting	5 × 105 UCMSCs per Kg body weight	Safety, efficacy assessment with adverse events, clinical respiratory effects, CT scan, quantitation by RTPCR, Sequential Organ Failure Assessment Score, and mortality.
NCT04346368	April 2020– Dec 2020	Not recruiting	BM-MSCs (1 × 106 /kg body weight	Changes in oxygenation index (PaO2/FiO2), assessment of adverse effects, mortality, clinical outcome, hospital stay, viral load, CRP, and CD4 + and CD8 + cell estimation.
NCT04392778	April 2020– Sept 2020	Recruiting	MSCs 3 million cells/kg	Improvement in clinical features and lung damage, Sars-Cov-2 viral infection and blood laboratory test.
NCT04447833	Jan 2020– June 2025	Active not recruiting	BM-MSCs 2 × 106 MSC/kg	Safety, mortality, estimation of biochemical parameters after infusion, changes in oxygenation (PaO2/FiO2), need for ventilation, lung function, lung fibrosis, effect on quality of life, blood biomarkers, estimation of plasma.
NCT04461925	May 2020– Dec 2021	Recruiting	Placenta-Derived MMSCs  1 million cells/kg	Changes in oxygenation index, PaO2/FiO2, hospital stay, mortality, improvement in pneumonia and respiratory symptoms, blood cell count.
NCT04313322	March 2020– Sept 2020	Recruiting	WJ-MSCs	Assessment of clinical outcome, CT scan, RT-PCR results
NCT04299152	Nov 2020–Nov 2021	Not yet recruiting	Combination Product: Stem Cell Educator-Treated Mononuclear Cells Apheresis	Determination of total infected patients unable to complete therapy, percentage of activated T cells, Th17 cells, CT scan, quantification of viral load.
NCT04382547	May 2020– June 2021	Enrolled by invitation	Mucosa derived MSCs	Estimation of cured patients; assessment of adverse effects.
NCT04371601	March 2020– Dec 2022	Active not recruiting	UC-MSCs 106/Kg body weight	Changes in oxygenation index (PaO2/FiO2), CRP proteins, and immune cells secreting cytokines.
NCT04753476	June 2020– August 2021	Enrolling by invitation	Secretome-MSCs	Changes in clinical manifestation, the need for and duration of ventilator support, hospital stay, and blood gas analysis.
NCT04527224	Dec 2021– April 2023	Not yet Recruiting	AD-MSCs	Assessment of treatment related adverse effects, PaO2/FiO2 ratio, improvement in pneumonia, 2019 nCOV nucleic acid test, and mortality.
NCT04339660	Feb 2020– June 2020	Recruiting	1 × 106 UC-MSCs /kg body weigh	Assessment of immune function, blood oxygen saturation, mortality rate, lesion size by CT scan, CD4 + and CD8 + T cell count, duration of respiratory symptoms.
NCT04457609	July 2020– Sept 2020	Recruiting	UC-MSCs 1 × 106 unit	Presence of dyspnea, sputum, fever, ventilation status, clinical manifestation, estimation of immunological and biochemical parameters.
NCT04611256	Aug 2020– Dec 2020	Recruiting	AD-MSCs 1 × 106	Changes in arterial oxygen saturation, duration of clinical improvement, immune cell changes, and cytokines and immunoglobulin levels
NCT04390152	Jan 2020– April 2022	Recruiting	WJ MSC 50 × 106	A difference in mortality between groups, adverse effects after treatment, need for mechanical ventilation, difference in “Sequential Organ Failure Assessment” score, Murray score, APACHE II score, lymphocyte count between groups, hospital stay, oxygen demand, changes in cytokine secretion, changes in pulmonary computed tomography scan, 6-minute walk, spirometry, and quality of life between groups.
NCT04565665	July 2020– April 2021	Recruiting	CB-MSCs	Events with a high probability of causing serious harm Patients alive without grade 3, 4 fusional toxicity, survival rate, clinical parameters, need for ventilators, oxygen demand, respiratory parameters, laboratory markers.
NCT04728698	March 2021–Sept 2021	Not yet Recruiting	COVI-MSCs1 × 106 MSCs/kg or 1.5 × 106MSCs/kg, depending on CRP level	Mortality at 28, 60, and 90 days, as well as improvements in oxygenation, ventilator-free days, and SOFA assessment.
NCT04428801	June 2021–June 2014	Not yet Recruiting	AD-MSCs 200 million	Tolerability and acute safety of AdMSC infusion, assessment of adverse events and severe adverse events with or without medication, COVID incidence rate, measurement by PCR, change in proportion of developing IgM/IgG antibodies against infectious agents, Change of pro-type B natriuretic peptide (pro-BNP), mortality rate, changes in some biochemical parameters, Quantification of viral RNA in stool.
NCT04444271	May 2020– Sept 2020	Recruiting	MSCs 2 × 106 cells/kg	Overall survival, clinical and radiological improvement, and the time it took to receive a COVID-19 PCR negative report.
NCT04798716	April 2021–December 2021	Not yet Recruiting	MSC-exosomes	Treatment-related-adverse events receiving ARDOXSO™ and perinatal MSC-derived exosome therapy, organ failure report analyses, associated with ICU mortality in participants, Analyze and record respiratory data.
NCT04345601	April 2020– March 2021	Recruiting	MSCs 1 × 108	Treatment-related serious adverse events (tSAEs), changes in clinical status
NCT04362189	June 2020– October 2021	Active not Recruiting	HB-adMSC	IL-6, CRP, TNF-α, Return to room air (RTRA), oxygenation, estimation of some biological and hematological parameters.
NCT04452097	June 2021– March 2022	Nit yet recruiting	UC-MSCs 0.5 million cells/kg, 1 million cells/kg, 1.5 million cells/kg	Prevalence of infusion-related adverse events/treatment-emerged adverse events/treatment emerged serious adverse events, dose assessment for Phase 2 study, death rate, ICU stay, hospital stay, Changes in blood cytokine levels.
NCT04331613	January 2020–Dec 2020	Recruiting	MSCs 3, 5 or 10 million cells/kg	Adverse reaction (AE) and severe adverse reaction (SAE), changes in lung imaging examinations, fever, blood parameter evaluation, biochemical and immunological parameter evaluation.
NCT04366323	April 2020– October 2021	Active not Recruiting	AD-MSCs Two doses of 80 million	Safety of the administration of D-MSCs assessed by Adverse Event Rate, Efficacy of the administration of AD-MSCs assessed by Survival Rate.
NCT04390139	May 2020– December 2021	Recruiting	WJ-MSCs	Mortality rate, Safety of WJ-MSC, Evolution of the PaO2/FiO2 ratio, the need for ventilation, evolution of the APACHE II score and SOFA score, Feasibility of WJ-MSC administration, genetic variability in the genotype of patients after treatment. Genetic variability of the genotype of SARS-CoV-2 response to treatment.
NCT04490486	Sept 2021– June 2024	Not yet Recruiting	UC-MSCs 100 × 106 (100 million)	The percentage of patients who experienced Serious Adverse Events (SAE) because of their treatment. Changes in the level of inflammatory markers, viral load, SOFA score, percent of participants with altered immune marker expression, mortality rate, change in electrolyte levels, and LDL level.
NCT04429763	June 2020– Nov 2020	Not yet Recruiting	UC-MSCs 1 × 106 cells/kg	Clinical deterioration or death.
NCT04537351	August 2020– March 2021	Recruiting	Cymerus MSCs 2 million/kg body weight	Determination of PaO2/FiO2 ratio between groups, incident and severity of treatment, respiratory rate, oxygenation index.
NCT04494386	July 2020– Dec 2021	Recruiting	Umbilical cord lining MSCs 100 million cells per dose	Incidence of Dose Limiting Toxicity, serious adverse event, suspected adverse effects, Treatment-emergent adverse events and serious adverse events, Changes in Complete Blood Count (CBC), number of ventilator free days, assessment of some biochemical parameters.
NCT04302519	March 2020– July 2021	Not yet Recruiting	Dental pulp derived MSCs	Disappear time of ground-glass shadow in the lungs, CT scan of Chest, Change in blood oxygen.
NCT04397796	August 2020– June 2021	Recruiting	BM-MSCs	Incidence of AE, mortality, death rate, ventilator free days, hospital stay, Sequential Organ Failure Assessment (SOFA), need of oxygen, SAEs.
NCT04361942	March 2020– Dec 2021	Recruiting	1 million MSV cells/Kg	Rate of mortality, ratio of patients who have achieved withdrawal of invasive mechanical ventilation, clinical and radiological response of patients, estimation of some immunological markers.
NCT04467047	July 2020– Dec 2020	Not yet Recruiting	MSCs 1 × 10E6 MSCs/kg body weight	Overall survival, COVID19 PCR negativity, radiological improvement, and improvement in Liao’s score, changes in inflammatory CRP, hospital stay, and change in oxygenation index.
NCT04377334	Oct 2020– July 2021	Not yet Recruiting	MSCs	Lung injury score, level of cytokine and chemokines, survival rate, SARS-CoV-2-specific antibody titers, complement molecules (C5-C9), D-dimers, pro-resolving lipid mediators.
NCT04780685	March 2021– Dec 2021	Recruiting	BM-MSCs	Estimation of patients having treatment-related adverse events.
NCT04393415	May 2020– Sept 2020	Recruiting	MSCs	The number of COVID-19 patients improved after receiving stem cells.
NCT04315987	June 2020– Aug 2020	Not yet Recruiting	MSCs 2 × 107 cells	Change in clinical conditions, mortality rate, clinical symptoms-respiratory rate, hypoxia, biochemical parameters, PaO2/FiO2 ratio, CD4 + and CD8 + T cell count
NCT04522986	Aug 2020– Feb 2021	Complete	MSCs 1 × 108 cells	Safety from adverse events
NCT04629105	July 2020– July 2025	Recruiting	Longeron MSCs 100 million	Incidence of Serious Adverse Events after treatment, Number of Patients with; disturbed hematological clinical values, Changes in Echocardiography Overall Assessment, Changes to overall assessment of Electrocardiogram, Abnormal Clinically Significant Lab Values, changes in significant Clinical Lab Values of the Coagulation.
NCT04367077	April 2020– Dec 2023	Recruiting	MultiStem intravenous infusion	Safety and Tolerability of cells measured with incidence of treatment-emergent adverse events, cause of mortality, ventilator free days.
NCT04398303	May 2020– October 2020	Not yet Recruiting	ACT-20-MSCs 1 million cells/kg	Mortality rate, need for ventilation, need for high-flow O2 support subjects.
NCT04371393	April 2020– Feb 2022	Active, not Recruiting	2 × 106 MSC/kg	Cause of mortality, need for ventilation, number of candidates alive, number of patients with improvement in ARDS, severity of ARDS, improvement scale, immunological changes.
NCT04397471	May 2020– Dec 2021	Not yet Recruiting	BM-MSCs	Determine the feasibility of recruiting healthy volunteers and manufacturing a cell-based product suitable for clinical use.
NCT03042143	Jan 2019–Oct 2022	Recruiting	UC derived CD362 enriched MSCs	Oxygenation index, incidence of serious adverse events, SOFA score, respiratory complications, length of ICU, mortality rate.

Lanzoni et al. [30] demonstrated a substantially shorter COVID-19 recovery time following MSC treatment, with a recovery HR of 0.29 (95% confidence interval [CI] 0.09–0.95) in the control group compared to the MSC-treated group. Multiple further investigations have proven that MSC treatment dramatically accelerates patient recovery. Recent research comparing pulmonary function recovery and comprehensive reserve capacity based on a 6-minute walk test (6-MWT) revealed that walk distance was greater in MSC-treated patients than in controls, even though maximal forced vital capacity (VCmax), diffusing lung capacity for carbon monoxide (DLCO), six-category scale, oxygen therapy status, and modified Medical Research Council (mMRC) dyspnea score did not significantly differ between the two groups [31]. In addition to clinical symptoms, analytical measures such as C-reactive protein (CRP), alanine aminotransferase (ALT), creatinine, serum ferritin (SF), and platelet levels were evaluated, and all returned to the normal range following MSC administration. These findings indicate that MSCs not only alleviate pulmonary symptoms but also positively influence the functional recovery of various organs, including the liver and kidney [32]. It has been demonstrated that MSCs affect the immune system during lung injury caused by respiratory viruses; this may be one of the mechanisms underpinning the treatment of COVID-19 by MSCs. In a rat model of avian influenza virus (H5N1)-induced lung damage, for instance, UC-MSCs restored the function of alveolar epithelial cells, as indicated by decreased permeability and increased alveolar fluid clearance [33]. In addition, the function of MSCs is not significantly affected by viral infections, which may be partially attributed to the fact that intrinsically expressed ISGs prevent viruses from “attacking” MSCs, as the induction of intrinsic ISGs in human MSCs induces the expression of anti-viral factors such as SAT1, PMAIP1, ISG15, IF16, CCL2, and interferon-induced transmembrane protein 1 (IFITM1).

Influence of stem cells on host immune system

Autologous or allogenic MSCs attenuate cytokine storm, improve lung compliance, modulate inflammatory response, maintain a functional alveolar milieu, and stimulate endogenous regeneration and repair with no or minimum adverse effects. MSCs are associated with bimodal immunological activities, indicating that they are capable of exerting both immunosuppressive and immunostimulatory effects. The size of the stimulus appears to alter the effect of MSCs. Regardless of the immunological effects, the equilibrium between host NK cells and MSCs influences both types of stem-cell transplantation. NK cells have the ability to lyse MSCs, whereas MSCs inhibit the growth of NK cells. It has been established that the expression of MHC-I on MSCs prevents NK-mediated killing of stem cell transplants, hence enhancing tissue tolerance. IFN-γ, which imparts resistance to MSCs, is involved in the suggested process. Despite these achievements, MHC incompatibility is an issue during stem-cell transplantation, as it promotes the development of graft-versus-host disease (GVHD) in allogeneic transplants. Autologous transplants typically avoid this potential difficulty [34].

Role of MSCs to prevent emerging and re-emerging zoonotic viral infections

Viral zoonotic diseases, occurring on every continent of the world except Antarctica, are transmissible from vertebrate animals (all tetrapods and probably amphibians) to human beings [35]. Transmission of such viruses may opt for different routes via direct, indirect contact; nosocomial; aerosol transmission; vertical and vector-or arthropod-borne [27, 35]. Here, we discussed the several studies conducted for the treatment of different viral infections via stem cell therapy Table 1.

Coronaviruses

Coronaviruses are member of the family Coronaviridae, and are, responsible for mild respiratory diseases to severe acute respiratory syndrome (SARS) [7]. The explosion of SARS in late 2002 was one of the first outbreaks of coronaviruses caused by one member of the SARS-CoV family in the twenty-first century [36]. Soon, one more infectious agent from the same family emerged in 2012 in Saudi Arabia with a sporadic outbreak named Middle East respiratory syndrome coronavirus (MERS-CoV) [37]. Recently, SARS-CoV-2 made an appearance in China (2019), leading to the turbulence of the current COVID-19 pandemic, which is still going on. All members of this Coronaviridae family have been traced back to bat origin, while some use intermediate hosts such as camels and civet cats [38]. Apart from sharing the same homology, MERS-CoV, SARS-CoV and SARS-CoV show the same pathophysiology of disease with the occurrence of acute respiratory distress syndrome (ARDS) [36, 38]. Stem cells underlie the category of efficacious agents against various emerging and re-emerging viral infections and ISGs, as they have the capacity to reduce inflammation, secrete cell protective substances, anti-oxidative effects, decrease cell death and improve the overall immune system [39]. COVID mediated damage to the respiratory system is the collective result of intrinsic viral pathogenicity and the response of the host immune system towards them [40]. As studied by Huang and their colleagues, infected patients with COVID-19 showed high levels of circulating proinflammatory cytokines in their bodies, but patients admitted to the Intensive care units (ICUs) showed a reduction in MCP1, MIP-1α, GCSF, IP10, and TNF-α in comparison to non-admitted individuals. This indicates the occurrence of a cytokine storm in the lungs of an infected person. Such a change in cytokine levels is accused of being associated with a cluster of immune cell responses and extensive lung damage after pulmonary inflammation, which in combination leads to death [41, 42]. Thus, the key to treating lung injuries caused by members of Coronaviridae family (SARS, MERS, and SARS-CoV-2) is to target the cytokine storm and thereby suppress the super-inflammatory immunological responses, directly related to repair and regeneration of the lung tissue structure and function [27].

Flaviviruses

Flaviviruses are a class of mosquito-borne viruses that include dengue, Zika, West Nile, and yellow fever viruses (YFV) and are either new or re-emerging pathogens [43]. Dengue virus (DENV) has reported its presence every few years, especially in Southeast Asia and America, with the emergence of novel strains that have been causing major epidemics since the 2000 [44]. After that, one new virus arrived in Polynesia that emerged in Brazil and soon swept throughout South and Central America and the Caribbean resulting in devastating cases of central nervous system abnormalities, mainly microcephaly [45]. The YEV re-emerged in 2016 in Angola, covering the neighboring countries of Africa and traveling through China [46].

Influenza viruses

Influenza viruses are the most frequent causes of pandemics and epidemics among humans. They occurred earlier in 1918 with the emergence of H1N1 influenza and were followed by Asian flu (1957), Hong Kong flu (1968), Russian flu (1977) and the recent pandemic of 2009 H1N1. In the twenty-first century, a series of events started with the emergence of the H1N1 swine flu pandemic strain (2009), causing about 250,000 global deaths. This triple reassortment viral strain of swine, avian and humans was closely related to the H1N1 virus of 1918, which also originated in pigs [47]. The twenty-first century is facing continuous sporadic outbreaks of avian H5N1, H7N9, and other influenza strains with high mortality rates in humans [48]. Through genetic re-assortment, virus recycling, and the most important capability of direct transfer from host to humans, a series of genetic variations in virus antigen leads to the emergence of different strains of influenza pandemic [49]. Avian influenza virus (AIV) subtypes such as H5N1, H7N9, and H9N2 have recently been found to cross species barriers and cause disease among mammals [49].

In the current scenario, antiviral drugs have been given preference as primary therapeutics to fight against influenza-induced manifestations, but most of the time, they are found unable to ameliorate damaged lung cells and tissues [50]. As demonstrated in a study, H5N1 virus infection reduces the enhanced alveolar protein permeability (APP) in human alveolar epithelial cells and elevates the level of alveolar fluid clearance (AFC), which can be inhibited with the treatment of human bone marrow-derived MSCs. Mechanistically, this process is regulated by human keratinocyte growth factor (KGF) and Bone marrow mesenchymal stromal cells secreted angiopoietin-1 (Ang1) [51, 52]. In vivo experiments showed BM-MSCs to be significant anti-inflammatory agents that have the potency to increase the number of M2 macrophages responsible for various cytokine and chemokine secretions, including IL-1β, IL-4, IL-6, IL-8, and IL-17 [52]. Similar MSCs -induced results were attained by Li et al., with another lung injury induced by virus where H9N2 virus-infected mice received mesenchymal stromal cells through intravenous injection and significantly attenuated pulmonary inflammation by reducing chemokines (GM-CSF, MCP-1, KC, MIP-1α, and MIG), proinflammatory cytokines (IL-1α, IL-6, TNF-α, and IFN-γ) as well as inflammatory cell recruitment into the lungs [53]. In another study, mesenchymal stromal cells co-cultured with CD8 + T cells supposed to inhibit the release of IFN-γ and proliferation of virus-specific CD8 + T cells [54]. Mesenchymal stromal cells transplantation effectively decreased the mortality rate and did not result in any adverse effect on the body of the patient. Thus, the above clinical studies indicate the ability of mesenchymal stromal cells to improve the overall survival of influenza virus patients.

Filoviruses

A group of filoviruses includes Ebola virus (EBOV) and Marburg virus (MARV). There have been two major outbreaks of the Ebola virus in the last decade. The first epidemic occurred in 2013–2016, primarily in West African countries, and infected over 30,000 people with 40% mortality [55], followed by a second outbreak with 65% mortality in 2018–2020 in the Democratic Republic of the Congo, infecting around 3,500 people at a single time [56].

Some other zoonotic-originated viruses

Viruses of the order Bunyavirales have the potential to infect humans; some of them include the Rift Valley fever virus, hanta viruses, Lassa fever virus, and Crimean–Congo hemorrhagic fever virus [57]. Multiple small outbreaks of henipaviruses have been recoded many times, but the outbreak of Nipah virus in 2018 (India) showed high mortality rates (60–90%) and was considered a major outbreak [58]. Bats are the reservoir of these viruses, whereas pigs and horses are intermediate hosts [59]. Norovirus has also been found to trigger multiple epidemics in the last two decades, responsible for causing severe diseases in immunocompromised individuals and projecting around 70,000–200,000 deaths per year globally [60].

Stem cell therapy for the treatment and prevention of human immunodeficiency virus (HIV)

HIV pathogenesis is defined by a continuous deficit in immune cells, especially CD4+T cells, that eventually leads to significant immunodeficiency in patients [61]. Mesenchymal Stem Cell therapy is proposed to improve host immune reconstitution in highly active anti-retroviral therapy (HAART), which significantly reduces plasma HIV viral load by suppressing overstimulated CD8+T cells responsible for reducing CD4+T cell restoration, thereby lowering HIV morbidity and mortality [62]. As illustrated by Allam et al., under the influence of MSCs, the level of CD4+T cells and cytokine production increased when exposed to HIV antigen, although their susceptibility and outcome of the infection are important matters of concern [63]. Stem cell-based therapies provide a ray of hope for HIV-distressed diseases. Hematopoietic stem cells represent themselves at center stage in this lineage after curing the ‘Berlin patient’ from HIV, as transplantation of hematopoietic stem cells (HSCs) from donor cells to recipient cells did not allow the expression of C–C chemokine receptor type 5 (CCR5), which is compulsory for HIV virus antigen entry and processing [64]. Subsequently, that second beneficiary was the “Landon patient.” Similarly underwent stem cell transplantation with cells lacking CCR5. HSCs have some limitations, mainly immunogenicity and chances of rejection via graft versus-host disease during transplantation. Thus, MSCs gain attraction due to their hypo-immunogenicity and unique immunosuppressive properties [63]. In 2013, Zhang and their co-workers conducted a pilot study to evaluate the safety and efficacy of umbilical cord derived MSCs (UC-MSCs) in HIV-infected patients, and it was found to be clinically and biologically tolerable by all patients without any significant harmful effects throughout the trial. The UC-MSC transfusion was found to induce an elevation in CD4 T-cell count and reduce the secretion of proinflammatory cytokines [62]. However, there is still a need to understand the mechanisms of reduction and over activation of the immune system. Although HAART was found to be effective in improving clinical outcomes and suppressing HIV replication, it was unable to cure HIV due to the inability to eliminate latent HIV reservoirs [65]. Thus, it is necessary to investigate novel strategies that have the capacity to reactivate latent HIV reservoirs, after enhancing their clearance. An in vitro study conducted by Chandra et al., shows a considerable role of MSCs and MSC-secretome in HIV-1 latency-reactivation via PI3K and NF-κB signaling pathways [66]. However, further research is needed to determine the efficacy of MSCs in its reactivation.

Stem cell therapy for the treatment and prevention of Hepatitis B virus (HBV)

Hepatitis B is a very common infectious disease in the human population, with 0.6 million deaths each year and about 360 million cases of chronic HBV infection related to liver abnormalities and hepatocellular carcinoma worldwide [67]. Lack of therapeutic strategies limits its treatment to orthotopic liver transplantation (OLT), which also depends upon the availability of organ donors and the vulnerability of the transplanted tissue to re-infection by viral agents. In this era of regenerative medicine, transplantation of MSCs has been found to improve HBV related liver disease as they have the ability to differentiate into hepatocyte like cells. The strength of these cells is to express a subset of hepatic genes and hepatic functions, including albumin secretion and glycogen production, as they are accused of improving liver functioning in HBV patients with last stage liver disease [68]. In the last decade, four clinical trials have been registered to find the clinical application, efficacy, and safety of MSCs in HBV-infected patients. Lin and their coworkers enlisted the findings of a prospective phase II clinical trial, whose results showed the absence of any serious adverse effects of allogeneic BM-MSC infusion in patients with HBV-ACLF (HBV-related acute-on-chronic liver failure) [69]. Moreover, this treatment can improve hepatic function by modulating total bilirubin and model for end stage liver disease (MELD) scores and decreasing the mortality and morbidity that can be a result of the immunomodulatory potential of MSCs. Another clinical study by Xu et al., determines the safety and efficacy of umbilical cord derived MSCs transplantation grouped with plasma exchange (PE) therapy. Results showed this combined treatment to be safe for HBV-ACLF patients [70]. A study by Wang et al., (2014) propounds adipose derived MSCs as an additional source of hepatic cells [71]. This study demonstrated that adipose tissue derived mesenchymal stem cells (AD-MSCs) have the ability to differentiate into functional hepatocyte-like cells. Interestingly, they undergo hepatic differentiation, which is not vulnerable to HBV infection in in vitro conditions. However, further long-term investigations into the transplantation of MSCs to cure HBV infected livers in vivo and in randomized clinical trials are needed.

Therapeutic achievement of stem cell therapy against COVID-19

MSCs are known for their tremendous achievements in the treatment of chronic and autoimmune diseases as they possess multi-potential differentiation and immunomodulatory functions. Recently, a novel coronavirus pandemic, COVID-19, has become a global public health emergency. As discussed in Tables 1 and 2, the therapeutic potential of stem cell therapy against COVID-19 is investigated in several studies and clinical trials. Of note the entrance of SARS-CoV-2 virus was shown to be restricted in MSCs as illustrated by Cao and their colleagues in their experiment conducted on mice [72]. They utilize three types of MSCs; umbilical cord (UC-MSCs), placenta (PD-MSC), and adipose-derived (AD-MSC) to examine the presence of angiotensin converting enzyme (ACE2) and transmembrane serine protease 2 (TMPRSS2) receptors required for viral endocytosis in host epithelial cells. Their study estimated that under variable inflammatory challenges, MSCs are not able to induce expression of both markers (ACE2, TMPRSS2) in epithelial cells and macrophages as they failed to regulate the expression of both receptors in the lung tissues of mice [72]. Thus, the study shows the failure of the SARS-CoV-2 pseudo virus to infect MSCs and decrease the risk of infection during treatment.

Leng et al., conducted a study in which ten COVID-infected individuals were taken as subjects, from which seven SARS-CoV-2 patients were selected for study, out of which two showed common symptoms, four severe symptoms, and one was critically ill. The remaining three patients were enrolled for placebo control [73]. All seven patients were treated with clinical-grade human MSCs by intravenous administration. In severe conditions, patients were treated with 1 × 10⁶ MSCs/kg body weight and observed for a period of 14 days. In all patients, after the infusion of MSCs, there was a significant decrease in body temperature, reduced oxygen saturation, and pneumonia in all patients. Immune system profiling by mass cytometry (CyTOF) indicates an elevated level of lymphocytes with a shift towards the regulatory phenotype of CD4 + T cells and dendritic cells just like in control patients (treated with placebo treatment). The numbers of CXCR3 + natural killer cells, CXCR3+CD+T cells, and CXCR3+CD4+T cells were also increased as compared to the healthy control, before the MSC infusion resulted in the triggering of a cytokine storm, which normalized within 6 days. Within 7–14 days of treatment, most of the patients were marked negative for infection. In another study conducted by Liang et al., (2020), a critically ill patient surviving on a ventilator was treated with 3 infusions of 5 × 10⁷ human umbilical cord derived MSC (hUMSC) at an interval of 3 days [74]. The patient showed great improvement and was able to walk within 4 days of her second cell infusion without any observable side effects.

We have summarized several clinical trials completed (Table 2) and registered ongoing (Table 3) from https://clinicaltrials.gov. Most of them suggested positive deliberations for the treatment of respiratory disorders using MSCs.

Self-renewing progenitors: hope or hype

Stem cell therapy has been associated with high expectations and has been intensively investigated in the last few years. However, this emerging technology is also associated with some major complications, specifically graft rejection, GvHD, and delayed immune reconstitution, leading to viral infections and relapse. To overcome the concern of graft rejection, lifetime immunosuppression is required, although its potential risks are considered in terms of long-lasting observations. Stem cells are used to show remarkable differentiation capacity into a wide range of cell types in vitro. Although these cells have a normal karyotype, it is still common to attain chromosomal abnormalities and epigenetic changes associated with their prolonged culture. For sustainable production of these cells, “Good Manufacturing Practices” (GMP) are advertised by the European Medicines Agency and the American Code of Federal Regulation of the Food and Drug Administration (FDA) [99].

The GvHD controversy is a noticeable matter of concern during treatment as it comprises downregulation of immune response and could increase the opportunity for infections, especially in patients receiving immunosuppressive therapy. MSC infusion has also been shown to limit the antimicrobial immune response. A clinical trial conducted by Ning and coworkers revealed the occurrence of acute and chronic GvHD in patients with a history of MSCs transplantation and found that patients treated with BM-MSCs and hematopoietic stem cell transplantation (HSCT) showed severe infections including Cytomegalovirus (CMV) interstitial pneumonia and/or fungal infections [100]. Recent studies postulated BM-MSCs as viral transmitters and found that patients treated with BM-MSCs, and hematopoietic stem cell transplantation (HSCT) showed severe infections including CMV interstitial pneumonia and/or fungal infections [100]. Several author’s studies also shown that BM-MSCs as viral transmitters and found them to modulate the tumor microenvironment, encouraging tumor growth [101, 102]. Ringden and his group listed adverse effects like relapse; pneumonia; bacterial, viral, and fungal infection; and graft failure that were faced after transplantation of decidual placenta derived MSCs in the treatment of GvHD [103]. The effects of MSCs during treatment of orthopedics, neurology, and cardiovascular diseases have been reported by many researchers. Thus, the above investigations suggest that the direct regenerative potential of MSCs with differentiation capacity is not as effective as expected. This suggests there is a need to standardize therapeutic abilities, ex vivo preparations, and protocols for MSCs isolation (Fig. 3).

Fig. 3.

Clinical challenges associated with MSC-based therapies. There are several major challenges to overcome, including immunocompatibility, survival, heterogeneity, differentiation, and optimal dose, number of MSCs and frequency of MSCs transplantation

Conclusion

Despite extraordinary advances in the evolution of countermeasures, the emergence, re-emergence, and prevalence of new infectious diseases can’t be controlled. In former times, we have demonstrated our commendable efforts across the disciplines to evolve vaccines and drugs against these infectious agents. More efforts, however, are required to protect the world from future pandemics and disasters. The interaction between viruses and stem cells can be defined as a double-edged sword in this battle. Clinical experience of stem cells and viral infections needs more future clinical trials addressing the deportment of stem cells in an infectious environment. As reviewed above, stem cell therapy have serve antiviral, anti-inflammatory, immunomodulatory, anti-fibrotic, anti-apoptotic, and angiogenic properties. There is a need to explore innate recognition of viruses in stem cells and pre activation of these molecules before infusion can help to prompt innate response pathways by which viral replication in stem cells can be inhibited. There is also a need to develop primary protocols to improve the quality of MSCs along with enhanced clinical approaches for upcoming and ongoing viral infections and their manifestations.

Author contributions

Vishal Khandelwal, Tarubala Sharma, Saurabh Gupta, and Shoorvir Singh collected the data and wrote and edited the manuscript. Deepak Parashar and Vivek Kashyap conceived the idea and wrote the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Data availability

None to declare.

Declarations

Conflict of interest

Deepak Parashar is serving as an associate editor of Molecular Biology Reports and declared that he was not involved in overseeing peer review for this manuscript. The remaining authors declare no competing interests.

Research involving human and/or animal participants

This article does not contain any studies with human or animal participants performed by any of the authors.