The promising approach of MSCs therapy for COVID-19 treatment

Abstract

Several ongoing investigations have been founded on the development of an optimized therapeutic strategy for the COVID-19 virus as an undeniable acute challenge for human life. Cell-based therapy and particularly, mesenchymal stem cells (MSCs) therapy has obtained desired outcomes in decreasing the mortality rate of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), mainly owing to its immunoregulatory impact that prevents the overactivation of the immune system. Also, these cells with their multipotent nature, are capable of repairing the damaged tissue of the lung which leads to reducing the probability of acute respiratory distress syndrome (ARDS). Although this cell-based method is not quite cost-effective for developing countries, regarding its promising results in order to treat SARS-COV-2, more economical evaluation as well as clinical trials should be performed for improving this therapeutic approach. Here in this article, the functional mechanism of MSCs therapy for the treatment of COVID-19 and the clinical trials based on this method will be reviewed. Moreover, its economic efficiency will be discussed.

Introduction

Around the beginning of the year 2020, humankind was confronted with an unpredictable incident. At first, growing mortality cases caused by respiratory restrictions were reported in Wuhan, China (Rajarshi et al. 2020). The cause behind this illness was mistaken for flu since they both comprised the same symptoms; such as cough, fever, runny nose, and eye. The severe symptoms of this unknown virus progressed to acute respiratory distress syndrome (ARDS) which obligated mechanical intubation in order to restore the patients’ respiratory system and resuscitate them. The virus was announced to be novel on January 1 (Wu et al. 2020a). It was indicated that the virus composed of 89.1% nucleotides of another type of virus-based syndrome called severe acute respiratory syndrome (SARS), was discovered in bats (Hu et al. 2018; Wu et al. 2020a). Since then, the novel virus was nominated as SARS-COV-2 or COVID-19. Because of the worldwide prevalence of the virus, it was declared a global health challenge leading to a growing race among developed countries to find an optimum treatment strategy (Golchin 2021). Although the authoritative pharmaceutical companies have released promising vaccines to terminate the pandemic disease, with several gene mutations of the virus which made it more comparatively contagious, other sorts of therapies are still ongoing and many trials including plasma therapy, antibiotics, inflammation decrease by corticosteroid, etc. are being implemented. Among the mentioned trials, cell-based therapy and specifically, mesenchymal stem cell (MSC) therapy was followed by desirable clinical results that are guesstimated to be long-term effective (Metcalfe 2020; Ye et al. 2020). Thus, in this article, functional mechanisms as well as the acceptable clinical outcomes of MSCs therapy will be reviewed.

How does the COVID-19 disrupt the lungs function?

COVID-19 as a single-strand RNA virus, initialize its infectious process by binding its surface spike protein to the angiotensin I converting enzyme 2 (ACE2) receptor of the host cell (Pandey et al. 2020; Zhou et al. 2020). This virus internalizes through the cell membrane utilizing cellular transmembrane protease, serine 2 (TMPRSS2) (Leng et al. 2020; Lu et al. 2020). Capillary endothelial cells and alveolar type II cells are mostly responsible for expressing ACE2 as well as TMPRSS2. Hence, besides the common symptoms such as pain in the throat, body ache, cough, fever, etc., serious lung issues are the consequences of the SARS-COV-2 progressive stages (Hoffmann et al. 2020; Rajarshi et al. 2020).

The viral infection caused by the virus proliferation and its cellular internalization leads to the secretion of several pro-inflammatory cytokines (Zhou et al. 2020). It is hypothesized that the main cause of lung-related complications including ARDS, difficulties in air exchange, and eventually organ failure resulting in mortality, could be cytokine storming (Lai et al. 2020; Rajarshi et al. 2020). On the other hand, it is reported that COVID-19 affected people are struggling with increasing White blood cell (WBC) and lymphocytopenia (Fan 2020; Li et al. 2020a). Moreover, decreasing the cells’ density (CD4 + and CD8 + T cells) but increasing their activity rate which causes immunogenic damage (Zhai et al. 2020). Therefore, the crucial therapeutic procedure should be based on extreme immunogenic response suppression (Li et al. 2020a).

MSCs therapy

In recent years, cell-based therapies have contained favorable therapeutic results for many of the diseases that were assumed not to be curable (Golchin and Farahany 2019). Among these therapeutic approaches, MSCs were followed by acceptable outcomes from various aspects. Several sources are available in order to achieve MSCs including bone marrow, adipose tissue (from abdominal fat, patellar fat, etc.), and dental pulp (Rajarshi et al. 2020). Moreover, multipotent stem cells (differential potential to several cell lines with a great rate of proliferation) could be obtained from the umbilical cord, amnion fluid, and placenta of newborns (Yen et al. 2020). MSCs could be stored as cell banks and passaged frequently for the purpose of different treatments in a relatively short time (Golchin 2021). Also, the safety and efficiency of MSCs have been validated in multiple clinical trials (Li et al. 2020a). Particularly, in the case of COVID-19, the negativity of ACE2 and TMPRSS2 for MSCs as well as the interferon-stimulated gene expression which performs a key function of avoiding viral infection has been proven. Therefore, these cells would be unaffected by the infection of COVID-19. Also, it has been indicated that the MSC-based strategy is capable of reducing the viral infection by suppressing the aforementioned cytokines leading to the recovery of the targeted tissue (Leng et al. 2020, Rajarshi et al. 2020).

MSCs therapy versus COVID-19

In order to combat with corona virus, the lung employs both innate and adaptive immunity as its defensive strategy, however, concerning the fact that these viruses are capable of escaping from the natural immune system and disrupting their recognition by the body, these approaches might be inadequate (Wu et al. 2020b). It has been stated that MSCs would modify innate immune reactions by affecting dendritic cells (DCs), neutrophils, macrophages, and natural killers (NKs). In addition, adaptive immunity including T lymphocytes, B lymphocytes, regulatory T cells, and antigen-presenting cells could also be regulated by MSCs (Le Blanc and Mougiakakos 2012). Furthermore, the local immunity system which is equipped for the immediate extermination of foreign viruses via CD4 + and CD8 + T cells may also be enhanced by MSCs (Sette and Crotty 2021). In other words, the invading virus would be mobilized more influential and inhibited from further progressing through the additional production of soluble factors (such as PGE2, TGF-β1, indoleamine 2,30dioxygenase (IDO), HGF, nitric oxide, and IL-10) by MSCs (Shi et al. 2018). Conversely, it has been revealed that MSCs are capable of suppressing the excessive immune reactions in infected patients with Corona virus through regulating the immune cells. Specifically, the profile of T cells’ cytokine secretion would be modified by MSCs which results in the interdiction of TH1 and TH17 activating (Aggarwal and Pittenger 2005). Also, the over-proliferation and differentiation of B cells to plasma cell lines by MSCs can reduce the immunoglobulin release (Khare et al. 2018). Moreover, MSCs would adjust the activation of DCs as well as the expression of the receptors of the NK cells and reduce their exaggerated cytotoxic influence (Morrison et al. 2017; Li et al. 2020a). Also, the toxicity of neutrophils could be inhibited by MSCs through hindering the production of hydrogen peroxide (Morrison et al. 2017; Galipeau and Sensébé 2018; Basiri et al. 2021).

Another considerable key mechanism of MSCs can be the paracrine secretion of anti-inflammatory factors (chemokines, growth factors, and cytokines) which could be claimed that is the most essential therapeutic impact of MSCs in struggling with Corona virus. The pathological evaluation indicated that the ability of MSCs in essential biomolecules secretion for lung tissue regeneration could be efficient in immunomodulation through cooperating with the immune cells (via ligand-receptor interaction), repairing the damages of alveolar epithelium cells and blood vessels which eventually may lead to their serious lung injuries or ARDS in corona-infected patients (Di Rocco, Baldari et al. Spees et al. 2016; Xu et al. 2022). Therefore, as was noted, MSCs enhance the microenvironment of the injured lung tissue by secreting health-beneficial growth factors such as KGF and VEGF and promoting the release of alveolar surface-active elements (Spees et al. 2016). These factors and elements would interact with the aimed cells, redesign the extra-cellular matrix structure, and improve the angiogenesis and fibrotic tissue repair rate as a consequence (Li et al. 2020a). Furthermore, the related investigations have shown that various inflammatory factors such as IFN-γ, IFN inducible protein-10, and MCP-1 were observed in the blood sample of SARS-COV-2 infected patients. Also, the amount of other inflammatory factors was found to be higher in ICU patients rather than in non-ICU patients, for instance, G-CSF, MCP-1, and TNF-α. On this basis, as was previously mentioned, COVID-19 triggers a cytokine storm in the lungs that would interrupt the blood vessels’ diastolic functions, hypoxia of the organs, and eventually ARDS. It has been reported in the literature that effective inflammatory factors of cytokine storms (for example IL-1a, TNF -α, etc.) may be reduced and the anti-inflammatory factors would be up-regulated in case of utilizing MSCs (Wang et al. 2014; Yao et al. 2022). In addition, the function of crucial immune sensors known as toll-like receptors for identifying invasive pathogens such as viruses could be regulated by MSCs in order to debarment of cytokine storms (Pevsner-Fischer et al. 2007; Tomchuck  et al. 2008). In a study by Fathi et al. lymphopenia and inflammation as corona-mediated complications were recovered utilizing MSCs via increasing the number of peripheral lymphocytes and the cytokines which was proved to be anti-inflammatory (Fathi and Rezaei 2020).

According to the previous literature, regarding the multipotency of MSCs, they have the potential to be regulated to differentiate to respiratory epithelial cells as well as vascular endothelial cells via utilizing certain growth factors and thus may be beneficial for recovering lung functionality and repairing the local injury caused by the viral infection of COVID-19 (Khaki et al. Ma et al. 2011; Chen et al. 2022). In a recent study by Liu et al. (2021) the human umbilical cord-derived MSCs were successfully induced to differentiate to alveolar epithelial cells and consequently lower the mortality rate of pulmonary fibrosis in mice (Liu et al. 2021; Javed et al. 2022).

Another noteworthy feature of MSCs which might be advantageous for the aim of repairing the damaged lung and improving their desired therapeutic impact is migration and homing which is initiated via their chemotaxis (Nitzsche et al. 2017; Liesveld et al. 2020). This process which is primarily stimulated by the release of chemokines from the targeted damaged tissue (in this case the lungs), required three steps after the injection procedure: Inflowing to the circulation of blood, creation of a gradient in the lymphocytes amount adjacent to the lesion, and mobility towards the lung interstitium (Nitzsche et al. 2017). The key chemokines which could be mentioned in this regard are SDF-1, G-CSF, CXCR4, CXCR7, HIF-1α, CCR2, MCP-1, α4/β1 integrin, and CD44 molecules. Moreover, some adhesion molecules of endothelial cells such as vascular cell adhesion molecule-1 which is capable of mediating the homing process can be distinguished by MSCs (Ullah et al. 2019; Chen et al. 2022).

Based on the performed investigations, various levels of apoptosis due to the exhaustion of T cells and lymphopenia caused by the viral infection were observed in COVID-19 patients as a result of the host defense mechanism against the virus (Lee et al. 2019; Zheng et al. 2020). It has been revealed in the pulmonary disorders and cardiac ischemia researches that MSCs are able to prohibit the apoptosis of the cells caused by chemical or mechanical damage as well as hypoxia by the expression induction of growth factors such as TGF-β1, HGF, and VEGF (Murphy et al. 2013).

Furthermore, the antiviral impact of MSCs specifically in the inhibition of virus shedding and replication has been demonstrated in the previous literature (Khatri et al. 2018). For instance, the influenza virus replication rate has shown to be reduced by the antiviral peptide LL37 which is produced by MSCs and degrades the viral membrane (Tripathi et al. 2013). Also, as was aforementioned, COVID-19 entry to the cells is occurred by ACE2 receptors. Concerning the evaluations of RNA-sequence, MSCs have found to be ACE2 negative and thus resistant against COVID-19 replication which could lead to the prevention of fibrosis due to acute corona infections (Metcalfe 2020).

The extracellular vesicles (EVs) such as microvesicles, apoptotic bodies, and extracellular bodies, play a critical role in cellular communication under pathological criteria (Hur et al. 2020). Recent investigations have revealed that MSC-derived EVs are capable of the treatment of ARDS, idiopathic pulmonary fibrosis, hypertension of pulmonary, and COVID-19 (Abraham and Krasnodembskaya 2020; Abreu et al. 2021). The mitochondrial function of the alveolar cells and their lung-repairing ability could be enhanced by the transmission of functional mitochondria from MSC-EVs (Khatri et al. 2018). In addition, the inflammation of pulmonary may be decreased by utilizing EVs and subsequently the reduction of macrophages and neutrophils requirement (Monsel et al. 2015). Also, these vesicles are able to diminish endothelial permeability and pulmonary edema. Therefore, MSC-EVs can be considered as a therapeutic medium for corona virus (Wei Li et al. 2019; Chen et al. 2022) (Fig. 1).

Fig. 1.

The MSCs therapy functional mechanism for COVID-19 treatment

MSCs therapy of COVID-19 in clinical trials

Prior to the pandemic, the potential efficiency of MSCs in ARDS treatment had been evidenced. Considering the previous literature, the mortality rate of ARDS in the treated patients with MSCs therapy reduced from 49 to 16%. Although the provided data was not significant from the statistical point of view, it has suggested the capability of MSCs in obviating ARDS as a consequence of corona virus (Qu et al. 2020). Furthermore, the pulmonary function, particularly the tidal volumes as well as the compliance of the lungs, has been reported to be improved remarkably in several studies. Also, the imaging results from the chest area indicated the enhancement of opacity which suggested the treatment of lung fibrosis. According to the aforementioned hints, the cytokines storm as an immunogenic response to COVID-19 which eventually may lead to ARDS could be decreased by utilizing MSCs (Simonson et al. 2015; Wilson et al. 2015; Leng et al. 2020; Yip et al. 2020). Moreover, neutralizing free particles of the virus by MSCs through the increasing of antibiotic proteins that bridge between the virus and the binding sites of the cells has been raised in previous investigations (Krasnodembskaya et al. 2010). It is noteworthy that the safety of MSCs as a therapeutic approach for ARDs has been previously proved (Arentz et al. 2020; Bydon et al. 2020). On the other hand, the clinical utilization of MSCs in lowering the probability of organ failure (such as heart and kidney) which is considered as one of the corona virus complications, has been reported Li et al. (2020b).

Among the many trials based on the COVID-19 treatment, one of the first minor clinical trials was performed in China evaluating the impact of MSCs therapy in seven patients. The patients suffered from mild to severe corona symptoms (such as fever, low oxygen saturation, pneumonia, etc.) and did not heal with the common treatment strategies. Also, three patients with a severe state of the disease were considered to be the control group. The selected MSCs were allogenic bone marrow derived which were not positive for ACE2 and TMPRSS2 (the identified Corona virus receptors), thus it could be claimed that the possibility of COVID-19 infection of these stem cells was rare. The patients were followed up for 14 days. No reaction of sensitivity or further infection for the treated patients were reported after the MSCs infusion. After 2–4 days of the MSCs treatment, the amount of oxygen saturation increased to 95% on average. After 6 days, it was revealed that the overactivity of T cells and NK cells significantly lessened to reach their normal state in comparison with the control group. The results of the CT scan of the chest area showed that the pneumonia progression was notably cured. None of the treated patients required the mechanical ventilator and all of them finally recovered after 7–14 days, but there was a case report of death in the control group. It should be mentioned that a severely infected old patient was in the healed group (Leng et al. 2020; Yen et al. 2020).

The other investigation was performed on a COVID-infected patient who was urgent to utilize a ventilator for respiration. This patient was treated with human umbilical cord mesenchymal stem cells. After 2 orders of infusion with no serious side effects, on day 4, the amount of T cells was decreased to its normal count and the patient regained his ability to walk (Liang et al. 2020).

Recently, in an evaluation by Sengupta et al., 24 COVID-19 infected patients with mild to severe symptoms were targeted to be cured by a single dose of derived exosomes from allogenic bone marrow mesenchymal stem cells (BMMSCs). The safety, as well as efficiency of the exosomes, were monitored for 14 days. The enhanced oxygen saturation, remarkably increased amount of lymphocyte and neutrophils, and improvement in the clinical state of 83% of the patients indicated that the BMMSCs-derived exosomes could be a promising therapeutic candidate for SARS-COV-2 (Atashi et al. 2015).

Currently, there are a total of 97 trials that have been registered for MSC therapy in COVID-19. Out of 97 registered trials, only 21 trials are in completed status (Table 1).

Table 1.

Summarized clinical trial (marked “completed”) studies on the MSCs in the COVID-19 (https://www.clinicaltrials.gov)

Trial ID	Title	Sponsor/ location	Population	Methods of cell therapy	Phase	Results or aims
NCT05122234	Effectiveness and safety profile of mesenchymal stem cell secretomes as a treatment for severe cases of COVID-19	Indonesia University/ Indonesia	40	Biological: Injection of secretome - MSC Other: Placebo Drug: Standard treatment of Covid-19	III	Clinical presentation, inflammatory marker, laboratory and radiological parameters, real time-PCR conversion, safety profile, and mortality rate will be monitored for a maximum of 14 days after intervention.
NCT04713878	A 8-week trial of mesenchymal stem cells therapy in patients with COVID-19 pneumonia	Kanuni Sultan Suleyman Training and Research Hospital/ Turkey	21	Intravenous infusion of MSC	Not Applicable	Improvement of clinical symptoms, reduction of cytokine storm Secondary outcome: Recovery of patients; from mechanical ventilation
NCT04898088	A proof of concept study for the DNA repair driven by the mesenchymal Stem cells in critical COVID-19 patients	SBÜ Dr. Sadi Konuk Eğitim ve Araştırma Hastanesi/Turkey	30	MSC transplantation	Not Applicable	Determine the positive effect of stem cell therapy applied on critically ill patients with coronavirus infection on DNA repair genes.
NCT04315987	Exploratory clinical study to assess the efficacy of NestaCell® mesenchymal stem cell to treat patients with severe COVID-19 pneumonia	Azidus Brasil/ Brazil	90	NestaCell® (MSC) A dose of 2 × 10^7 cells (20 million cells) will be administered IV on days 1, 3, 5 and 7 in all subjects. Biological: Placebo	II	Assessment of the efficacy of NestCell® as an add-on therapy to standard treatment to treat patients with severe COVID-19 pneumonia.
NCT04288102	A phase II, multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of human umbilical cord-derived mesenchymal stem cells in the treatment of severe COVID-19 patients	Beijing 302 Hospital/ China	100	Umbilical cord-derived mesenchymal stem cell (UC-MSC)s 3 does of UC-MSCs (4.0 × 10^7 cells per time) intravenously at Day 0, Day 3, Day 6. Biological: Saline containing 1% Human serum albumin(solution without UC-MSCs)	II	Change in lesion proportion (%) of full lung volume from baseline to day 10, day28 and 90, change in consolidation/ ground-glass lesion proportion (%) of full lung volume from baseline to day 10, 28 and 90, time to clinical improvement in 28 days, Modified Medical Research Council dyspnea scale, 6-minute walk test, maximum vital capacity, diffusing capacity, oxygen saturation, oxygenation index, duration of oxygen therapy, side effects, immunological characteristics (immune cells, inflammatory factors, etc.) were be evaluated during the 90 days follow up.
NCT04349631	A phase II, open label, single-center, clinical trial to assess efficacy of HB-adMSCs to provide immune support against coronavirus disease	Hope Biosciences Stem Cell Research Foundation/ United States	56	Hope Biosciences autologous adipose-derived mesenchymal stem cells (HB-adMSC)s	II	The primary endpoint of this study was to provide immune support against COVID-19, measured by the percentage of participants in each category of a 7-point ordinal scale and the presence or absence of adverse events and serious adverse events related to the study drug.
NCT04348435	A randomized, double-blind, single center, efficacy and safety study of allogeneic HB-adMSCs to provide immune support against COVID-19	Hope Biosciences Stem Cell Research Foundation/ United States	55	HB-adMSCs Other: Placebos	II	Participants were be monitored for overall clinical status by standard clinical laboratories and inflammatory markers. Participants were complete Short Form Health Survey (SF-36) and depression module (PHQ-9) questionnaires.
NCT04625738	Efficacy of infusions of mesenchymal stem cells from wharton jelly in the woderate to severe SARS-Cov-2 related acute respiratory distress syndrome (COVID-19): A phase IIa double-blind randomized controlled trial	Central Hospital, Nancy/ France	30	Ex vivo expanded wharton’s jelly derived MSCs will be infused at day 0, day 3 and day 5 (+/- 1 day), in patients with moderate to severe ARDS with a mechanical ventilation. day 0: 1 × 10^6 MSC/kg day 3: 0.5 × 10^6 MSC/kg day 5: 0.5 × 10^6 MSC/kg Biological: Placebo Only the vehicle solution, without MSCs, containing albumin 4%, NaCl 0,9% and ACD will be injected to patients at day 0, 3 and 5 (+/-1 day).	II	The investigators were analyzing the effect of 3 iterative infusions of ex vivo expanded wharton’s jelly MSCs (total dose 2 × 10^6/kg) in patients with ARDS due to COVID19, who require mechanical ventilation.
NCT04573270	A pilot phase study evaluating the effects of a single mesenchymal stem cell injection in patients with suspected or confirmed COVID-19 infection and healthcare providers exposed to coronavirus patients	Thomas Advanced Medical LLC/ United States	40	PrimePro Intravenous Injection Other: Placebo	I	This study investigated the efficacy and safety of a single UC-MSCs intravenous injection in patients with suspected or confirmed COVID-19 infection with fever and respiratory illness. A second arm were tested efficacy and safety of a single umbilical cord derived stem cell intravenous injection to healthcare providers at high exposure rates to COVID-19 infection.
NCT04382547	Treatment of covid-19 associated pneumonia with allogenic pooled olfactory mucosa-derived mesenchymal stem cells	Institute of Biophysics and Cell Engineering of National Academy of Sciences of Belarus/ Belarus	32	Allogenic pooled olfactory mucosa-derived MSCs	I/II	The positive outlook for the effectiveness of MSCs was due to the following: knowledge of the leading role of immunopathogenetic mechanisms in the development of acute interstitial lung diseases and the pronounced immunomodulating properties of MSCs; high tropism of MSCs to lung tissue when administered intravenously; the ability of MSCs to stimulate tissue regeneration and the effective use of MSCs in the treatment of acute damage to the myocardium and kidneys, which will contribute to the treatment of multiple organ failure; positive results of preclinical studies of the method of treatment of viral pneumonia in animals, and the first clinical studies in patients.
NCT04355728	Umbilical cord-derived mesenchymal stem cells for COVID-19 patients with acute respiratory distress syndrome (ARDS)	Camillo Ricordi, University of Miami/ United States	24	Umbilical Cord MSCs + Heparin along with best supportive care. UC-MSC will be administered at 100 × 10^6 cells/infusion administered intravenously in addition to the standard of care treatment.	I/II	The purpose of this research study was to learn about the safety and efficacy of human UC-MSC for treatment of COVID-19 patients with severe complications of Acute Lung Injury/ ARDS.
NCT04535856	Therapeutic study to evaluate the safety and efficacy of DW-MSC in COVID-19 patients: randomized, double-blind, and placebo-controlled	Ina-Respond/ Indonesia	9	Assignment of administration group allogeneic MSC: Low-dose group (5 × 10^7cells) High-dose group (1 × 10^8 cells)	I	This was a phase I clinical trial to verify the safety and efficacy of DW-MSC in COVID-19 patients. A total of 9 subjects were randomly allocated. After the completion of the trial, the randomization code was disclosed after unlocking the database and unblinding procedures. Follow Up period: observed for 28 days after a single administration
NCT04366323	Phase I/II clinical trial, multicenter, randomized and controlled, to assess the safety and efficacy of intravenous administration of allogeneic adult mesenchymal stem cells of expanded adipose tissue in patients with severe pneumonia due to COVID-19	Andalusian Network for Design and Translation of Advanced Therapies/ Spain	26	Allogenic and expanded adMSCs Two doses of 80 million adipose-tissue derived MSCs	I/II	Phase I/II clinical trial to evaluate the safety and efficacy of Allogenic adMSCs expanded in patients were severed COVID-19 pneumonia.
NCT04493242	Bone marrow mesenchymal stem cell derived extracellular vesicles infusion treatment for COVID-19 associated acute respiratory distress syndrome (ARDS): A phase II clinical trial	Direct Biologics, LLC/ United States	120	Intravenous administration of bone marrow MSC derived extracellular vesicles	II	To evaluate the safety and efficacy of intravenous administration of bone marrow derived extracellular vesicles, ExoFlo, versus placebo as treatment for moderate-to-severe ARDS in patients with severe COVID-19.
NCT04492501	Role of investigational therapies alone or in combination to treat moderate, severe and critical COVID-19	UNICEF/Pakistan	600	Procedure: Therapeutic plasma exchange Biological: Convalescent Plasma Drug: Tocilizumab Drug: Remdesivir Biological: MSC therapy	Not Applicable	In an attempt to treat COVID-19, investigator used different investigational treatment either alone or in combination to see mortality and morbidity benefit on the basis of limited evidence available so far. These investigational modalities included therapeutic plasma exchange, convalescent plasma, remdesivir, tocilizumab and MSC therapy in addition to standard supportive treatment.
NCT04522986	An exploratory study of ADR-001 in patients with severe pneumonia caused by SARS-CoV-2 infection	Rohto Pharmaceutical Co., Ltd./ Japan	6	MSC 1 × 10^8 cells were administered once a week, total four times intravenously.	I	Patients with Severe Pneumonia caused by SARS-CoV-2 infection were enrolled to the study. adMSCs were administered once a week, total four times intravenously. Safety and efficacy of adMSCs were evaluated for 12 weeks after first administer.
NCT04392778	What is the effect of mesenchymal stem cell therapy on seriously Ill patients with Covid 19 in intensive care? (Prospective double controlled study)	SBÜ Dr. Sadi Konuk Eğitim ve Araştırma Hastanesi / Turkey	30	MSC Treatment Biological: Saline Control	I/II	This study aimed to use the regenerative and repair abilities of stem cells to fight against the harmful effects of the novel coronavirus Covid-19 and therefore develop a treatment strategy. It was known that fatalities from this virus was largely caused by its damage to lungs and other organs. As the disease progressed, these organs failed and lead to mortality. Their hope was that the stem cell transplantation from healthy donors repaired the damage caused by the virus and result in a healthy recovery.
NCT04361942	Double blind, placebo-controlled, phase II trial to evaluate safety and efficacy of allogenic mesenchymal stromal cells MSV-allo for treatment of acute respiratory failure in patients with COVID-19 pneumonia (COVID_MSV)	Red de Terapia Celular/ Spain	24	Intravenous injection of 1 million MSV cells/Kg diluted in 100 ml saline	II	These immunomodulatory properties of MSCs supported performance of the Phase I/II, double-blind (neither the participant nor the investigator will know if active drug or placebo is assigned), placebo-controlled, randomized (assigned by chance), in which subjects with severed COVID-19 pneumonia were received either MSCs (1 million cells/kg) or placebo by intravenous injection. The administration of cells was done only once.
NCT05019287	Safety and efficacy study of allogeneic human menstrual blood stem cells secretome to treat severe Covid-19 patients, clinical trial phase I/II	Avicenna Research Institute/ Iran	29	Intravenous injection of allogeneic human menstrual blood stem cells secretome	I/II	This study investigated the clinical outcomes of severe COVID-19 patients with several comorbidities treated with S-MSCs in Indonesia. These were characterized as CD90+, CD73+, CD105+, and CD45-based on multiparameter flow cytometry.
NCT04400032	Cellular immuno-therapy for COVID-19 ARDS (CIRCA-19)	Ottawa Hospital Research Institute/ Canada	15	Intravenous injection of MSCs	I/II	This trial demonstrated tolerability, and potential signs of efficacy. In addition, the investigators had established expertise in producing clinical-grade MSCs and have received approval from Health Canada for the use of MSCs in three different clinical studies.
NCT04333368	Cell therapy using umbilical cord-derived mesenchymal stromal cells in SARS-CoV-2-related ARDS	Assistance Publique - Hôpitaux de Paris/ France	47	Umbilical cord Wharton’s jelly-derived human MSC (at the dose of 1 million / kg) will be administered via a peripheral or central venous line over 60 min, using tubing with a 200-µm filter. Cells, in a 150 mL volume, will be delivered at day1, day3 and day5.	I/II	The feasibility of the project is supported by the expertise of the Meary cell and gene therapy center, which was approved for the production of Advanced Therapy Medicinal Products and had already successfully prepared the first batches of cells, as well as by the involvement of a cardiac surgery team which were leverage its experience with stem cells for the treatment of heart failure to make it relevant to the Stroma-Cov-2 project.

Financial aspects of MSCs therapy

Although in recent years cell-based therapies and specifically stem cell therapies have gained attention owing to their desired outcomes in the field of regenerative medicine, these therapeutic approaches are considered as a relatively expensive strategy. Based on a computational model created by Lopes et al. (2018) the final manufacturing costs of cell therapy could exceed $100,000 for every patient (Lopes et al. 2018). Therefore, an important drawback of cell-based therapies compared to the other conventional therapeutic methods is the financial issue. On the other hand, obtaining the optimum clinical results from these treatments required innovative protocols as well as the capability of the labor. Therefore, the majority of cell-based therapies are exclusively performed in developed countries. In the US, the cost of stem cell therapy varies between $4000 and $8000 for each patient. However, it should be noted that the final cost as well as the clinical outcomes could be optimized through utilizing novel protocols such as cell-tissue banking procedures (Golchin 2021). Hence, regarding the appropriate outcomes for the treatment of COVID-19 in the current emergency situation, more investigations are required to achieve a reasonable cost of MSCs therapy for the aim of progressing the technology to low-income regions.

Conclusion

Among the several attempts aimed to treat COVID-19 mild to severe complications, MSCs therapy has gained attention thanks to its favorable outcomes in reducing the mortality rate as a consequence of ARDS in patients with the severe state. According to the investigations focused on the MSCs therapy of SARS-COV-2, it can be revealed that the reason behind the efficiency of these stem cells is their immunoregulatory impact which will prevent the overactivation of the infected body’s immune system. On the other hand, the multipotency, the antiviral impact, and the anti-apoptotic of the MSCs besides its health-beneficial growth factor secretion could lead to the repairment of the damaged tissue, particularly the lungs. Also, the EVs extracted from MSCs could be considered as another MSC-based therapeutic strategy for COVID-19. Nevertheless, the functional mechanism of MSCs for immunoregulation requires more clinical trials to be claimed. Furthermore, considering the unreasonable price of these therapeutic strategies for developing countries, the investigations should be focused on optimizing the manufacturing cost of MSCs-based therapy.

Funding

No funding was received to assist with the preparation of this manuscript.

Data availability

All data generated or analyzed during this study are included in this manuscript (and its supplementary information files).