key: cord-1046996-w2ijv830
authors: Jeyaraman, Madhan; John, Albin; Koshy, Santhosh; Ranjan, Rajni; TalagavadiChannaiahAnudeep,; Jain, Rashmi; Swati, Kumari; Jha, Niraj Kumar; Sharma, Ankur; Kesari, Kavindra Kumar; Prakash, Anand; Nand, Parma; Jha, Saurabh Kumar; Reddy, P. Hemachandra
title: Fostering Mesenchymal Stem Cell Therapy to Halt Cytokine Storm in COVID-19
date: 2020-11-22
journal: Biochim Biophys Acta Mol Basis Dis
DOI: 10.1016/j.bbadis.2020.166014
sha: 0e8314882a5d32024f32e41bf28234e9a8c12c58
doc_id: 1046996
cord_uid: w2ijv830

The coronavirus disease 2019 (COVID-19) has been threatening the globe since the end of November 2019. The disease revealed cracks in the health care system as health care providers across the world were left without guidelines on definitive usage of pharmaceutical agents or vaccines. The World Health Organization (WHO) declared COVID-19 as a pandemic on the 11thof March, 2020. Individuals with underlying systemic disorders have reported complications, such as cytokine storms, when infected with the virus. As the number of positive cases and the death toll across the globe continue to rise, various researchers have turned to cell based therapy using stem cells to combat COVID-19. The field of stem cells and regenerative medicine has provided a paradigm shift in treating a disease with minimally invasive techniques that provides maximal clinical and functional outcome for patients. With the available evidence of immunomodulatory and immune-privilege actions, mesenchymal stem cells (MSCs) can repair, regenerate and remodulate the native homeostasis of pulmonary parenchyma with improved pulmonary compliance. This article revolves around the usage of novel MSCs therapy for combating COVID-19.

The first known case of COVID-19 was recorded on the 1 st of December, 2019 in the city of Wuhan, China as pneumonia of unknown aetiology. Soon, there was a surge of similar cases [1] . This sudden emergence was initially attributed to the seasonal flu. However, later investigatory findings of the point of outbreak uncovered a newer aetiology. The famous Hunan Seafood Market was found as the point of outbreak and the virus was suggested to have a zoonotic origin [2, 3] . Some reports that showed the doubling of cases every 7.5 days suggested that this virus was highly contagious [4] . On January 1 st 2020, a common aetiological agent was found in four out of the total nine hospitalised patients. This newly emerged strain of coronavirus has a hereditary correlation of 5% with severe acute respiratory syndrome (SARS) and is a subclass of Sarbecovirus [1] . The virus was named SARS-CoV-2 and the disease it causes is called coronavirus disease 2019 (COVID-19) as per the World Health Organization (WHO). On the 30 th of January, 2020, the WHO declared an International Public Health Emergency due to the rampant spread of COVID-19 around the world. The outbreak of SARS-CoV-2 was declared as a pandemic by the WHO on the 11 th of March, 2020. As a result, all clinicians and researchers from various disciplines of biomedicine have come together in search of a definitive therapy to combat this pandemic effectively [5] .

Researchers around the globe have greatly explored the potential uses of mesenchymal stem cells (MSCs) in repairing damaged regions and in re-establishing regional homeostasis. MSCs are immature heterogeneous population of stromal progenitor cells. They possess the property of selfrenewal, plasticity, lineage priming and homing, and differentiation of native environment cells [6] .

MSCs can take on the properties of a particular lineage or shift into another lineage under the influence of growth factors, cytokines and chemokines [7] .

The purpose of our article is to highlight recent developments of pathogenesis of COVID-19, with a particular focus on Stem Cells. This article also summarizes the usage of novel MSCs therapy for combating COVID-19. Our article updates the current status clinical trials of MSCs in COVID-19.

MSCs possess unique non-differentiating cell surface markers such as CD146 and CD200 [8] [9] and expresses matrix and MSC markers such as CD 105, CD 44, CD 29, CD 71 and CD 73 [10] .

They serve as an immunotolerant and immunomodulant cell in damaged tissues. They help regenerate and rejuvenate the environment [11] by exerting their effects on T cells, B cells, Dendritic cells, and macrophages.

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MSCs produce their immunomodulatory action on T cells through any of the following three mechanisms:

1. Inhibition of T Cell proliferation: It is a well-known fact that T cell mediated immunity plays a key protective role against various autoimmune disorders, malignancies, and infections [12] . Baboon MSCs, however, inhibit the proliferation of T cells [13] . Similar results have been seen in in-vitro human bone marrow MSCs. By arresting T-cells at the G1 phase via TGF-β (Transforming Growth Factor beta) and HGF (Hepatocyte growth factor), MSCs inhibit the proliferation of T cells [14] [15] .

Apoptosis of activated T cells is mediated by Fas/Fas liganddependent pathway with the production of kynurenine from tryptophan [16] [17] .

MSCs induce the production of IL-10 and inhibit the production of both IFN-γ and IL-17. Therefore, they reduce production of regulatory T-cells. They also regulate dendritic cells and natural killer cells [18] [19] [20] .

4. Anti-inflammatory: MSCs induce the production of IL-1Ra and IL-1β, which anticipates the anti-inflammatory effects and proceeds to heal such damaged tissues [21] . 5 . Immunomodulatory: The immunomodulatory potential of MSCs is triggered when they are stimulated by the inflammatory cytokines like IFN-γ and tumor necrosis factor (TNF)-α, inter-leukin (IL-) 1α, or IL-1β, which leads to the production of Nitrous oxide (NO) and

Prostaglandin E2 (PGE2) via upregulation of iNOS and COX-2 (as shown in figure 1 & 2) [22] [23] [24] .

The effect of MSCs on B cells is mediated by CCL-2 via STAT3 inactivation and PAX5

induction. As a result, MSCs go on to cause: 5 7. Induction of regulatory B cells which in turn produces IL-10 (Anti-inflammatory) [25] [26] [27] [28] [29] [30] [31] [32] . 

Macrophages can be separated into M1 macrophages that produce various pro inflammatory molecules to combat the microbes and M2 macrophages that are involved in tissue regeneration because of their immunomodulatory action via the production of IL-10 [35] . MSCs have the potential to augment macrophage regenerative activity at the site of injury [36] . When MSCs are cultured with macrophages, they differentiate into M2 macrophages which will lead to high levels of antiinflammatory IL-10 and low levels of pro-inflammatory molecules [37] . MSC's interaction with macrophages can combat local inflammation by both increasing IL-10 and by decreasing the production of TNF-α and IL-6 [38] .

Natural killer cells play a key role in the elimination and cytotoxicity of tumor cells and viral infected cells. High ratios of MSCs to NK cells restrains NK cell proliferation, production of proinflammatory molecules, and cytotoxicity. These effects are mediated by IDO, PGE2, HLA-5, and

EVs. Blocking these molecules can reverse the effects of MSCs [39] [40] [41] [42] [43] [44] .

Neutrophils play a key role in acute inflammation. MSCs have the capacity to interact with neutrophils to suppress apoptosis of resting neutrophils (IL-6 mediated) and to increase recruitment of neutrophils (via IL-8 and macrophage migration inhibitory factor-MIF) [45] [46] . Furthermore, Superoxide dismutase 3 mediated inhibition of uncontrolled inflammation in a murine vasculitis model demonstrates the anti-inflammatory properties of MSCs which decreases tissue damage [46] . MSC J o u r n a l P r e -p r o o f Journal Pre-proof 6 derived micro vesicles have been shown to inhibit migration of neutrophils into the pulmonary parenchyma of mice in E-coli endotoxin medicated acute lung injury [47] .

As is evident from the above discussion, MSCs have the innate ability to interact with almost all immune cells. Their action is either mediated through the various growth and immunomodulatory factors or through direct cell-cell contact. Due to their immunomodulatory properties, they have been used in many immune-mediated diseases for their known interaction with NK cells, polymorphonuclear (PMN) cells, dendritic cells, macrophages, T and B cells [48] [49] [50] [51] .

SARS-CoV-2 belongs to the Nidovirales order, a member of the genus ß-coronavirus (ß-CoV) [21] . It is an encapsulated, positive-sense, single-stranded RNA virus (nucleocapsid) with a 79.6% similar sequence to SARS-CoV and accounts for having the largest genomic specifications among RNA viruses [51] .

With the help of ACE-2 receptors, this virus gets access into pulmonary alveolar cells. ACE-2 receptors are found not only in the pulmonary epithelium but also in renal, cardiac and liver parenchymal cells, which explains the reason for development of multi organ dysfunction syndrome (MODS) that often presents in the late stages of COVID-19 [52] . With the entry of SARS-CoV-2 into the pulmonary parenchyma, it undergoes replication, transcription and translation of viral proteins and gets assembled in the Golgi apparatus. By exocytosis, millions of the newly assembled viral bodies leave the infected cell and infect the new pulmonary epithelium. The exocytosis causes further epithelial and endothelial damage that leads to increased vascular permeability inside the pulmonary environment. As a result of these events, initiation of a 'cytokine storm' leads to secretion of proinflammatory cytokines (IFN-α, TNF-γ, IL-1β, IL-6, IL-12, IL-8, IL-33, and TGF-β) [53] . The mechanism of the cytokine storm leads to increased mortality in patients with systemic debilitating illnesses. As a result of the cytokine storm, the patient develops acute respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), multi-organ dysfunction syndrome (MODS), and death. The immune-inflammatory mechanism leads to damage of pulmonary epithelium at a cellular level as depicted in figure 3 .

Amidst the COVID-19 rush for various vaccines and drugs, like Hydroxychloroquine and Remdesivir, some researchers have turned to MSCs as a new avenue for treating COVID-19. At

Journal Pre-proof 7 present, cell-based therapy, and stem cell therapy, in particular, is a ground-breaking medical area with great potential to cure incurable diseases [54] . MSCs have drawn interest due to their source, high rate of proliferation, minimally intrusive treatment protocols, and lack of ethical problems. Furthermore, MSC rehabilitation is significantly better in comparison to that of other therapies. It is useful in the treatment of COVID-19 for the following reasons:

1. COVID-19 causes a depletion of the CD4 and CD8 T Cells. MSCs can help in remodelling the function of these immune cells and thus improve pulmonary function. 

BM-MSCs are versatile in nature, are easily accessible, and require less technical prowess to procure. BM-MSCs possess enhanced osteogenic and chondrogenic potentiality [55] . In bone marrow, after density gradient centrifugation, the yield of progenitor cell accounts for up to 0.001% to 0.01% [56] . Although the yield of progenitor cells is low, the quality of progenitor cells remain preserved with all properties of MSCs. These BM-MSCs can be cultured in vitro to exponentially increase the concentration of progenitor cells and can be transplanted to the site of action.

The beginning of the 21 st century marked the addition of adipose derived stem cell to the adult stem cell population. The mesoderm-derived adipose tissue is ubiquitously present in the subcutaneous plane and comprises of a plethora of cells. The stromal vascular fraction (SVF) of adipose tissues is considered the warehouse of MSC-like cells [57] . The cellular components of SVF mixture have the property of multi lineage differentiation and can differentiate along the mesenchymal lineage [58] .

These cells are easily accessible [59] . Furthermore, isolation of these MSCs requires minimal manipulation (mechanical centrifugation followed by filtration or by either automatic or manual enzymatic digestion).The SVF mixture has a higher yield of nucleated cells (2%) than other sources, J o u r n a l P r e -p r o o f Journal Pre-proof 8 such as bone marrow (0.001-0.004%) [60] . However, due to the presence of various components of cells in SVF mixture, the use of SVF in allogenic clinical setting is questionable.

Due to the consideration of umbilical cord as a medical waste, the collection of MSC from UC needs no ethical approval [61] . 

An immuno-regulatory organ, the placenta maintains feto-maternal interface.The placental stem cells are amnion MSC, chorion MSC, chorionic villi MSC, and decidua MSC [64] . Due to its primitive origin, placental stem cells possess higher differentiative potential than other sources of stem cells [65] . These cells also display very low immunogenicity in both in-vivo and in-vitro studies as they are from an immunoprivileged organ. P-MSCs can be used for autologous and allogenic preparation. They represent more homogeneous and primitive population of cells with homing and priming potential. They have a high proliferative rate in culture than BM-MSCs [66] . P-MSCs are safe in regenerating a tissue as they possess low telomerase activity. P-MSCs are widely used in treating cancer, neurological diseases, and critical limb ischemia [66] .

Synovium derived MSC-like cells (S-MSC) are found in the surface, the stroma, and the perivascular region of synovial lining [67] . S-MSCs have a higher propensity for osteogenic and chondrogenic differentiation [68] . The details of the other trials are listed in the below table.

(https://clinicaltrials.gov/) Table 2 . Of the 8 participants enrolled in NCT01385644, no patients experienced adverse effects of the two infusion amounts.

Both groups were also able to walk a greater distance (104% of baseline) in 6 minutes, 6 months after MSC infusion. Other outcomes measured included FVC and DLCO. The study was limited by its sample size. The NCT02097641 study noted that one dose of MSC is safe for patients with moderate to severe ARDS.

Concentrations of angiopoietin 2, a predictor of poor outcomes in ARDS patients, were significantly lower after J o u r n a l P r e -p r o o f Journal Pre-proof MSC infusion. While oxygen contented was measured, it was not statistically different from the placebo group.

The study was limited by its sample size [72] . After 24 hours, all the patients were assessed for mortality.

The secondary parameters of PaO2:FiO2, SOFA score, lung injury score, oxygenation index, number of ventilator free days, IL-6 & 8, angiopoietin 2 and nonpulmonary organ failure days were analysed in both the groups.

Stem cells are a ray of hope in many diseases but their efficacy and safety profile are of utmost concern [73] . Regulating the use of these cellular products was an uphill task that the US FDA started The US FDA, through section 351 of Public Health Service (PHS), regulates these biological products [73] and categorizes the cultured cells into two categories named: "minimally manipulated"

and "more than minimally manipulated" [74] . If the processing of cells/tissues does not alter its biological characteristics, it is considered "minimal manipulation". Section 361 provides the criteria for minimal manipulation of human cellular and tissue based therapies or products (HCT/Ps) [73] .

Density-gradient separation, cell selection, centrifugation, and cryopreservation constitute minimal manipulation. Whereas, more-than-minimal manipulations includes cell activation, encapsulation, exvivo expansion, and gene modifications. Pre-market review is not necessary for minimally manipulated products. [73] .

Being anti-inflammatory, immunomodulatory, and regenerative in nature, mesenchymal stem cells (MSCs) have shown the capacity to control immune dysfunction and inflammation. After intravenous infusion, MSCs are entrapped in the lung vasculature before they enter other organ systems. Therefore, they may be effective in treating lung diseases. There are various mechanisms by which MSCs can be used to treat bronchial asthma, ARDS, chronic obstruction lung disease, and interstitial lung diseases [75] [76] . The safety and efficacy of MSCs in human application have been confirmed through small-and large-scale clinical trials. MSCs can home to the site of injury in ARDS and repair the damage via secretion of paracrine factors such as keratinocyte growth factor, angiopoietin-1, and prostaglandin E2 that can further improve MSC migration and tissue repair especially through direct MSC interaction [77] . The MSCs can also promote alveolar fluid clearance, membrane permeability, and reduce inflammation. There is also a direct transfer of mitochondria by MSCs to increase ATP concentrations to reactivate the alveolar cells [78] . Areas for future study include improving homing of MSC to damaged lung tissue.

In the context of COVID-19, MSCs are not affected by the COVID-19 infection as per the noteworthy ACE2and TMPRSS2gene expression profiling of these cells [70] . As a result, they can be used to therapy of tissues that are affected. Furthermore, MSCs attenuate the cytokine storm There are ways to improve MSC therapy for COVID-19. Researchers have noticed that preconditioning the stem cells to the environment (hypoxic, ischemic environments), can improve the function and survival of the stem cells when transplanted into the area of injury [79] . Experimental methods, such as culturing of MSCs in spheroids (approximately 500 μM) for short periods of time (3 days) can improve the adhesion of stem cells to their environments via increased expression of CXCR4 [80] . Finding the optimal conditions, such as size of spheroid and incubation periods, can improve the use of MSC therapy in COVID-19. Treatment of MSCs with drugs and supplements such as Vitamin E can help counteract injury of MSCs [81] . Understanding dosages of drugs and supplements can also help MSC activity and protection.

Implementation of MSCs as a treatment for COVID-19 has a few limitations. They are as follows:

1. Standardization of isolation and harvesting protocols 2. Dose, frequency, and route of MSC delivery 3. Autologous or allogenic preparation protocols 4. Ethical concern in selection and utility among wide array of sources of mesenchymal stem cells 5. Randomized controlled trials to be conducted with aforementioned sources of mesenchymal stem cells.

Furthermore, further study into MSCs and their mechanism in immune regulation is required for better homing of MSCs as well as efficacy at site of damage. Unfortunately, high doses of MSC have been noted to increase risk of hypercoagulability and organ failure. As a result of the side-effects of MSCs, researchers are looking into modifying the MSC to improve its efficacy. Researchers are looking into use of the cytokine products, or the MSC secretome, to improve potency, production capability, storage, specificity of use, and to reduce costs. Of note, the MSC derived exosomes are particularly interesting as they are easy to produce and store while having comparable therapeutic efficacy as that to MSC administration. While research is still in its infancy, there are multiple different methods of embracing the MSC capabilities that can be further explored [82] .

The field of stem cells and regenerative medicine has galvanized global researchers with a ray of hope for treating various disorders with minimally invasive procedures. Due to their multipotent nature and high differentiation potential, MSCs, can be used to treat severely ill COVID-19 J o u r n a l P r e -p r o o f Journal Pre-proof pneumonia patients. However, to reiterate, the safety and efficacy of MSCs for curbing pneumonia in COVID-19 patients have to be tested in large randomized controlled trials before full implementation to win the battle against COVID-19.

Authors would like to thank the Sharda University senior management for encouragement and facility. P.H.R acknowledged NIH for funding various projects(R01AG042178, R01AG47812, R01NS105473, AG060767, AG069333 and AG66347). Authors sincerely thank Ms. Hallie Morton for critical reading of the manuscript.

The authors declare no conflict of interests.

The authors declare no conflict of interests. 

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