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Table of Contents
REVIEW ARTICLE
Year : 2020  |  Volume : 3  |  Issue : 4  |  Page : 322-328

Mesenchymal stem cell infusion as a promising therapeutic approach to treat coronavirus disease 2019 patients


Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia

Date of Submission12-May-2020
Date of Decision18-Jun-2020
Date of Acceptance01-Jul-2020
Date of Web Publication02-Oct-2020

Correspondence Address:
Nihal AlMuraikhi
Department of Anatomy, Stem Cell Unit, College of Medicine, King Saud University, Riyadh 11461
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JNSM.JNSM_46_20

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  Abstract 


Coronavirus disease 2019 (COVID-19) is a highly contagious respiratory infection that emerges as a serious healthcare problem and becomes a global pandemic. The disease is caused by a novel virus called SARS-CoV-2. The initial site of infection is the pulmonary epithelial cells when the surface spike protein of the virus binds to their angiotensin I converting enzyme 2 receptor receptor triggering the immune system to release a huge number of inflammatory cytokines that may result in a cytokine storm. The clinical spectrum of the infections ranges from asymptomatic cases to severe viral pneumonia with multiple organ dysfunction that may lead to death. Currently, no specific antiviral drugs or vaccine has been confirmed to cure COVID-19. Mesenchymal stem cells (MSCs) present a potential therapeutic approach for treating COVID-19 patients through their regeneration of damaged tissues, anti-inflammatory, and immunomodulatory features. Preclinical data suggest that they can reduce pro-inflammatory cytokines, mitigate cytokine storm, and repair microenvironment of damaged tissues. MSCs are allogeneic stem cells that mainly get trapped in the lung when they are infused intravenously. Since the lung is the main affected organ in COVID-19 patients, this therapeutic approach seems to be advantageous. In this manuscript, we are describing this novel disease and its mechanism of infection, and stating the urgent need for treatment. Although many treatments are now being investigated for their effectiveness, this review has been dedicated to introducing all the supportive evidence in favor of utilizing the MSC therapy as a powerful therapeutic approach to improve the immunological response of COVID-19 patients.

Keywords: Angiotensin I-converting enzyme 2 receptor, anti-inflammation, coronavirus disease 2019, cytokine storm, immunomodulation, mesenchymal stem cells, regeneration


How to cite this article:
AlMuraikhi N. Mesenchymal stem cell infusion as a promising therapeutic approach to treat coronavirus disease 2019 patients. J Nat Sci Med 2020;3:322-8

How to cite this URL:
AlMuraikhi N. Mesenchymal stem cell infusion as a promising therapeutic approach to treat coronavirus disease 2019 patients. J Nat Sci Med [serial online] 2020 [cited 2020 Oct 24];3:322-8. Available from: https://www.jnsmonline.org/text.asp?2020/3/4/322/297117




  Introduction Top


Coronavirus disease 2019 (COVID-19) is a highly contagious respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).[1],[2],[3] COVID-19 has widely spread to be a serious healthcare problem with a substantial increase in the number of infected cases. It was first identified at the end of 2019 in Wuhan, Hubei province, China, when a high number of virus-borne severe pneumonia reported with unknown etiology at the beginning.[4],[5] Since then, the COVID-19 has become a global pandemic and transmitted worldwide.[4],[5] The common mild symptoms are fever and cough.[5],[6],[7] A sudden and rapid deterioration could happen in some patients later within a short period.[4],[5] The genome analysis of the virus revealed high similarity (79.6% sequence identity) to SARS-CoV, identified in 2003, which was responsible for the SARS outbreak.[8],[9] Subsequently, this novel virus was given the name SARS-CoV-2 by World Health Organization, and COVID-19 to the disease it causes.[2],[10]

It is likely that the spread of COVID-19 has emerged from a seafood/live wild animal market,[2],[5],[11] an initial zoonotic transmission of the disease,[2],[5],[11] but the first transmission and exact dynamics are unclear yet.[11] However, it is confirmed now that it can also be transmitted from person-to-person.[2],[5] The clinical spectrum of the infections ranges from asymptomatic cases to severe viral pneumonia with respiratory failure requiring mechanical ventilation and intensive care, or even worse with shock and multiple organ dysfunction that may lead to death [Figure 1].[2],[3],[5],[9],[10],[12]
Figure 1: Classification of COVID-19 severity based on clinical findings. Abbreviations: SpO2: Oxygen saturation; PaO2: Arterial partial pressure of oxygen; FiO2: Fraction of inspiration O2

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Mechanism of the pathogenesis of coronavirus disease 2019

Similar to SARS, the first step of COVID-19 pathogenesis starts once the virus enters the host cell when the S protein on the surface of CoV recognizes and binds to the spike protein on angiotensin I-converting enzyme 2 receptor (ACE2)-expressing cells.[6],[9],[13],[14],[15] Moreover, it has been shown that the cellular transmembrane protease serine 2 (TMPRSS2) helps to enable the host cell entry by priming the spike protein of CoVs.[15],[16] Both the ACE2 receptor and TMPRSS2 are highly expressed on the surfaces of lung alveolar epithelial cells.[16],[17] Severe pneumonia caused by SARS-CoV-2 is attributed to rapid virus replication due to suppression of early-type 1 interferon responses, uncontrolled infiltration of inflammatory cells, and massive pro-inflammatory cytokine and chemokine responses leading to diffuse alveolar damage and acute respiratory failure, the main pulmonary dysfunction upon the infection.[18],[19],[20],[21] This viral infection within the lungs highly triggers the immune system for an augmented immune response to kill the virus that may result in a cytokine storm caused by the high level of pro-inflammatory cytokines and chemokines produced including IL-2, IL-6, IL-7, GSCF, IP10, MCP1, MIP1A, and TNFα, that leads to edema, air exchange dysfunction, and acute respiratory distress syndrome.[1],[3],[4],[22],[23] The cytokine storm is the hallmark of SARS-CoV-2 infection, visible as inflammatory lesions with ground-glass cloudiness by computed tomography (CT) scans.[1],[10]

Unfortunately, in addition to alveolar cells, ACE2 is also abundantly expressed on many other human tissues and organs, such as the endothelial cells, liver, kidney, pancreas, stomach, small intestine, and smooth muscles.[17],[24],[25] Thus, any ACE2-expressing tissues and organs could be a combat zone of the virus and the immune cells.[3] The pathogenesis of COVID-19 is characterized by systemic thrombotic microangiopathy, plasma leakage, vascular coagulation and permeability, and endothelial dysfunction, which could contribute to the pathology of pneumonia and acute respiratory syndrome, and to microcirculation disorders.[23],[26],[27],[28],[29] In critical cases, patients may develop an acute myocardial injury, arrhythmia, acute kidney injury, and shock, as complications besides the respiratory illness, which may lead to death from multiple organ dysfunction syndrome.[3],[23],[28],[30],[31]

Available treatment/vaccine of coronavirus disease 2019

COVID-19 has attracted many researchers from different biomedical science specialties to participate in discovering a vaccine, treatments, or management strategies of this outbreak. Any vaccine should successfully pass safety and efficacy assessments before it can be approved for a disease, which usually takes several months.[32],[33] Thus, no vaccine is currently available to treat or prevent COVID-19.[23],[34] Currently, no specific antiviral drugs or treatment strategy has been confirmed to cure COVID-19.[3],[4],[35] Meanwhile, clinical management and supportive care are provided for the infected patients such as supplemental oxygen and mechanical ventilators,[4],[11] in addition to accessory therapies including nonspecific antivirals such as remdesivir and hydroxychloroquine,[36],[37],[38],[39] corticosteroids to reduce inflammation,[2],[6],[40] antibiotics to treat secondary bacterial sepsis,[2] neutralizing antibodies,[11] interferons,[35] and passive antibody transfer from convalescent patient's plasma.[1],[11],[41] However, the safety and efficacy of those therapies are yet to be determined.[42]

Mesenchymal stem cells

The two urgent needs in the COVID-19 pandemic are to decrease the infection rate, where most of the research focuses on, and to reduce the mortality rate among severely infected patients as low as possible by conducting clinical researches on how to provide them with the best life-saving therapeutic strategy.

Stem cell-based therapy has recently become a promising therapeutic tool to substitute conventional therapies in curing incurable diseases.[43] However, many obstacles, that have not been solved yet for many stem cell types hinder the development of this field such as immunogenicity, limited cell source, and the associated ethical issues.[43] Hence, huge attention has been focused on using mesenchymal stem cells (MSCs) due to their regeneration ability to damaged tissue, multipotency characteristic, immunomodulatory and anti-inflammatory effect, easy accessibility, low immunogenicity, high expanding rate to clinical therapeutic volume, and freedom of ethical issues, in comparison to other types.[3],[4],[44],[45],[46],[47],[48],[49] In general, MSC-based therapy seems to be more clinically advantageous for many reasons, (1) it involves less invasive procedure;[4],[45] (2) cells can be isolated from many adult tissues including bone marrow (BM), peripheral blood, adipose tissues, dental pulp (DP), liver, menstrual-blood, and neonatal tissues including placenta, umbilical cord (UC), cord blood, Warton jelly (WJ), and amniotic fluid, and can be stored for future application;[4],[44],[50] (3) MSCs have shown safety and efficacy in preclinical and clinical trials for the treatment of acute respiratory distress syndrome,[44],[45],[51] and immune-related diseases including graft-versus-host disease and systemic lupus erythematosus, with no adverse reactions so far.[3],[4]

Cytokine storm, caused by an overproduction of immune cells and cytokines, has been proposed as one of the key factors that activate the pathological processes observed in COVID-19 patients and accounting for life-threatening respiratory symptoms.[23] Therefore, MSC therapy was proposed as an ideal candidate for the treatment of COVID-19 patients owing to their advantageous immunomodulation feature that may reflect a natural immunity to the virus.[2],[11],[49] MSCs release paracrine secretions that interact with different immune cells, including T-cells, B-cells, dendritic cells, macrophages, and natural killer cells resulting in immunomodulation.[3] MSCs have also the ability to mitigate the inflammatory response and prevent the storm by secreting powerful anti-inflammatory factors to moderate the release of the cytokines, thus preventing organ damage and lasting functional disability in those who survive the severe disease.[11],[45],[49] In addition, the main purpose of MSC therapy is tissue regeneration, as MSCs can improve the microenvironment and promote endogenous tissue repair upon injection,[11],[45],[52] which may theoretically recover the pulmonary microenvironment, regenerate alveolar epithelial cells, prevent fibrosis and thus, restore lung function of COVID-19 patients.[3],[52]


  Possible Mesenchymal Stem Cell Types to Treat Coronavirus Disease 2019 Top


Although BM has been always considered as the main source of MSCs,[53] MSC therapy using BM-derived MSCs (BM-MSCs) is not favored because of the reduced number and potency/expansion capacity of the obtained cells, in addition to the invasive procedure involved.[53] Therefore, finding alternative sources of MSCs was mandatory for clinical applications. Among the other potential sources, UC-MSCs and Adipose tissue-derived MSCs (AD-MSCs) seem to be the most preferable for clinical use in systemic condition like CoV where millions of stem cells are needed for clinical efficacy.[3],[54] UC is one of the richest sources of MSCs.[50] UC-MSCs share a similar gene profiling with Embryonic stem cells, which reflect more potency and plasticity, with less immunological rejection upon transplantation.[3] However, they are not tumorigenic.[3],[50] Since UC-MSCs can be isolated non-invasively as they are medical wastes, there are no controversial issues associated with their use.[3],[50] Besides, UC-MSCs are expandable and scalablein vitro with a fast doubling time,[3],[50] which makes them desirable for MSC therapy.[3],[50] On the other hand, AD-MSCs offers a significant advantage over other sources because of the easily accessible procedure involved that requires local anesthesia only, the high number of cells that can be obtained, and the very simple isolation method from the adipose tissue performed in the lab.[55],[56]


  Highlighting Possible Role of Mesenchymal Stem Cells in the Treatment of Coronavirus Disease 2019 Top


Few clinical trials have been conducted recently evaluating MSCs infusion as a therapeutic approach to treat patients with COVID-19 to inspire more similar clinical strategies owing to the differentiation ability,[57] regenerative potential,[44] immunomodulation,[11] anti-inflammatory secretions,[11] and reparative properties of MSCs.[3] The first COVID-19 case treated with UC-MSCs was described in China for a 65-year-old female diagnosed with severe pneumonia, Acute respiratory distress syndrome, multi-organ failure, and other symptoms.[22] She showed no response to glucocorticoid, antiviral drugs, and antibiotics and she was dependent on mechanical ventilation.[22] She was given three doses of UC-MSCs, 3 days apart.[22] As a result, the patient recovered with stable vital signs, organ failure signs, and laboratory indexes, and she was no longer requiring the ventilator as her lung CT scan significantly improved.[22]

A newly published pilot study of a small target size performed in China reported that intravenous (IV) infusions of allogeneic human MSCs into seven patients diagnosed with COVID-19 resulted in multiple improved clinical outcomes and helped recovery.[52] Before receiving the MSC infusions, all patients were presented with fever, respiratory symptoms, pneumonia, in addition to low oxygen saturation in severe cases, and shock or organ failure in critical cases.[52] The diagnosis of patients varied between common, serious, and critical cases, who did not respond to available treatments.[52] The total number of transplanted clinical-grade MSCs were calculated by 1 × 106 cells per kilogram of weight.[52] The patients were observed for 14 days; all the seven patients recovered with no complications or adverse reactions.[52] Within few days, significant improvements were observed in the oxygen saturation level, radiological signs in post-infusion CT scans of the lungs, and inflammation biomarkers, including a decreased level of tumor necrosis factor-alpha, a major pro-inflammatory cytokine, with a concurrent increase in the level of interleukin-10.[52] Moreover, the number of peripheral lymphocytes was increased together with regulatory dendritic cell population, whereas C-reactive protein and overactivated cytokine-secreting immune cells were decreased.[52] In addition, using the 10× Genomics high throughput RNA sequencing clustering analysis on the administered MSCs showed that cells were ACE2-and TMPRSS2-, indicating that they were free from SARS-CoV-2 infection.[52] Besides, the expression profiles of the MSCs showed high levels of anti-inflammatory factors, including TGFβ, HGF, LIF, GAL, NOA1, FGF, VEGF, EGF, BDNF, and NGF, confirming the long-term immunomodulatory properties of the MSC.[52] Accordingly, the mechanisms highlighting the health improvement in COVID-19 patients after MSC infusion seems to be the strong anti-inflammatory capacity of MSCs to mitigate the overactivated immune system and help to repair the microenvironment of lung and other affected organs by after COVID-19 infection.[11],[52]

MSC therapy was also an approach to treat virus-induced pneumonia, Acute respiratory distress syndrome, and respiratory failure associated with the epidemic influenza A (H7N9) infections in 2013.[58] Seventeen patients with H7N9-infection were transplanted with allogeneic menstrual-blood-derived MSCs.[58] It was reported that MSC transplantation significantly improved the survival rate of the patients with no adverse reactions on a 5-year follow-up period.[58] Because H7N9 infection shares similar complications with COVID-19 infection, MSC-therapy was suggested as a possible strategy for treating COVID-19.

The reported clinical trials imply that IV administration of MSCs is a safe and effective approach for the treatment of patients with COVID-19, including elderly patients and critical cases.[22],[52] However, the limitations are the small sample sizes and the lack of long-term follow-up of the recruited patients.[3],[22],[52] Therefore, additional studies in a larger cohort of patients are needed to validate this therapeutic approach.[3] Several clinical trials have been newly registered at www.clinicaltrials.gov to evaluate the MSC IV infusions as a possible therapeutic approach in treating COVID-19 in larger numbers of patients. Different types of MSCs will be used in these trials, including UC-MSCs, AD-MSCs, BM-MSCs, WJ-MSCs, DP-MSCs, and menstrual blood-derived MSCs. [Table 1] is listing each registered clinical trial, the type of MSCs will be used, the target size and the status of the study, and the location where it will take place. [Figure 2] illustrates the geographical distribution of COVID-19 registered clinical trials globally.
Table 1: List of registered clinical trials for treating coronavirus disease in 2019 with mesenchymal stem cells

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Figure 2: The global geographical distribution of registered clinical trials for treating COVID-19 with MSCs

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Based on the promising results reported from the recent clinical trials, it was concluded that IV infusion appears to be the most suitable route of administration of MSCs to treat COVID-19 patients and the least invasive compared to intra-arterial or tissue injection.[3],[4] Luckily, most of the IV injected stem cells reside and entrapped in the lungs, the most affected organ in COVID-19 patients, which should likely be advantageous in such cases although it is a common limitation in any systemic infusion.[3],[4] In addition, according to these promising reports, even other affected organs would be positively affected due to the paracrine effect of the injected MSCs or by their production of secretary exosomes that circulate to the distant affected organs for endogenous tissue repair and immunomodulation.[3],[11]


  Conclusion Top


SARS-CoV-2 is a novel CoV responsible for COVID-19.[3],[4],[5],[6],[11] It showed a similar genome analysis and mechanism of action to SARS-CoV.[3],[5] The spike protein on the surface of both viruses binds to the ACE2 receptors on the surface of the host cell, to initiate the infection. Alveolar cells in the lung highly express the ACE2 receptors, and thus, they are the most affected cells in COVID-19 patients.[3],[5],[6],[11] However, all tissues and organs expressing the ACE2 receptor are affected by the SARS-CoV-2 infection.[3],[5],[6],[11] The infection could trigger an overactivation of the immune system resulting in a cytokine storm that leads to severe viral pneumonia with respiratory failure, shock, multiple organ dysfunction, and in some severe cases, to death.[3],[5],[6],[11],[22] IV administration of MSCs in COVID-19 patients has been shown to highly improve patient's health by mitigating the storm through secreting powerful anti-inflammatory factors, and by improving the microenvironment and promote endogenous tissue repair.[3],[4],[11],[52] In this review, we have discussed the pathogenesis of CoV, the urgent need for treatment to control this pandemic, recent limited but promising evidence reported for MSC therapy to treat COVID-19 patients, and the associated considerations, and strongly placed our argument in support of this potential therapeutic strategy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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