key: cord-0702253-8wm95ghd
authors: Choudhery, Mahmood S; Harris, David T
title: Stem Cell Therapy for Covid‐19: Possibilities and Challenges
date: 2020-08-07
journal: Cell Biol Int
DOI: 10.1002/cbin.11440
sha: da8dc7de3ba585050840b0ac84a33b6efe4d6a07
doc_id: 702253
cord_uid: 8wm95ghd

Since its eruption in China, novel coronavirus disease (Covid‐19) has been reported in most of the countries and territories (>200) of the world with ~ 18 million confirmed cases (as of August 3, 2020). In most of the countries, Covid‐19 upsurge is uncontrolled with a significant mortality rate. Currently no treatment effective for Covid‐19 is available in the form of vaccines or antiviral drugs and patients are currently treated symptomatically. Although majority of the patients develop mild symptoms and recover without mechanical ventilation for respiratory management, severe respiratory illness develops in a significant portion of affected patients and may result in death. While the scientific community is working to develop vaccines and drugs against Covid‐19 pandemic, novel alternative therapies may reduce mortality rate. Recent use of stem cells for critically ill Covid‐19 patients in a small group of patients in China and subsequent Emergency Use Authorization (EUA) of stem cells by Food and Drug Administration (FDA) to GIOSTAR (Global Institute of Stem Cell Therapy and Research) and Athersys has created excitement among medical community. As a result, several clinical trials have been registered using stem cells for Covid‐19 treatment that aim to use different cell sources, dosage and importantly diverse targeted patient groups. In this brief review the possibilities of stem cell use in Covid‐19 patients and relevant challenges in their use have been discussed. This article is protected by copyright. All rights reserved.

Novel coronavirus disease (Covid-19) is proliferating quickly worldwide and had been announced pandemic by World Health Organization (WHO) on March 11, 2020. SARS-CoV-19, the virus responsible for Covid-19 is an enveloped, positive sense, single stranded RNA virus of the family Coronaviridae (Zhou et al., 2020) . It causes mild respiratory tract infection, fever, and cough in most of the patients. However, in a This article is protected by copyright. All rights reserved.

Accepted Article significant portion of the affected patients these symptoms are accompanied with pneumonia and severe acute respiratory distress syndrome (ARDS). As a result, is currently associated with high mortality rate (~697,700 deaths as of August 3, 2020) .

With over ~6.06 million active cases of Covid-19 (as of August 3, 2020) (https://www.worldometers.info/coronavirus/), there is currently no vaccine or other antiviral treatment available. The affected patients are only left with symptomatic management of disease because frantic search for an effective Covid-19 treatment is not much successful. Drugs such as remdesivir, lopinavir/ritonavir, interferon β-1 , convalescent plasma (Shen et al., 2020) and FDA approved hydroxychloroquine (Cohen, 2020) are although under investigation but their safety and potential efficacy remains to be determined. Considering extensive and continuous increase in patient number and resulting substantial deaths, novel therapeutic strategies are required to reduce the mortality rate and to make the recovery better. Stem cell based regenerative medicine therapy may be an option for Covid-19 patients (Leng et Similarly, FDA has recently granted Emergency Use Authorization (EUA) of stem cells for Covid-19 patients. Considering initial promising results in a small group of critically ill covid-19 patients, a number of clinical trials have been registered using MSCs (Table   1 -3). These stem cell-based trials for Covid-19 will evaluate different sources, numbers, and patient groups for treatment. It is therefore imperative to understand the logic, associated mechanisms, and challenges for a successful stem cell therapy for Covid -19 patients. As there is limited available data regarding stem cell use for Covid-19 patients, the review has discussed a number of relevant implications imperative for understanding the logic, associated mechanisms and relevant problems for a successful stem cell therapy for Covid-19. The discussion of some hypotheses such as relevant challenges and the stem cell-based acellular therapies will of particular interest for readers. Older Covid-19 patients with co-morbidities such as diabetes, asthma and heart diseases are also in danger as the highest morbidity was observed in this group. The immune system and regenerative potential of these patients is compromised with advancing age and disease, resulting in this segment of the population being badly hit by coronavirus.

Due to a compromised immune system in such patients, antibody production takes a longer time to fight the coronavirus and the patients often develop critical conditions of pneumonia and ARDS. Stem cell therapy may be particularly useful for such patients because the chances of recovery in such patients are significantly low. It is pertinent to mention that stem cell administration in this group of patients may also improve underlying morbidities. This article is protected by copyright. All rights reserved.

Stem cells are unspecialized cells in the body that have potential to make more stem cells as well as differentiate into specialized cells of the body if appropriate signals are given in vitro or in vivo. Embryonic stem cells (ESCs) can be isolated from the inner cell mass of a 5-8 days old embryos and also have regenerative potential. However, clinical use of ESCs is restricted due to number of religious, ethical, and legal controversies. Adult stem cells can be isolated from neonatal sources (such as cord blood, cord tissue, placenta, and menstrual blood) as well as from adult tissues (such as bone marrow, adipose tissue, dental pulp, peripheral blood) and used for these purposes. MSCs, a type of adult stem cells, are a special focus of stem cell related therapies currently due to their infection, autologous sources of stem cells such as adipose tissue and bone marrow could be used. For such patients, the time to initiate therapy is very important in order to boost the immune system. The biobanks however, can play an important role in this regard by preserving the adipose tissue and bone marrow and making these tissues or cells available for patients at the time of care. It is pertinent to mention here that use of stem cells therapy in critical patients in the ICU is not yet approved, therefore; therefore, precautions must be taken to ensure safety of the patients. 

Most Covid-19 patients do not develop any major clinical symptoms during the early stages of infection. Common symptoms include mild or high temperature, cough, sore throat, muscle distress and body pain. In a few patients, shortness of breath can lead to sudden deterioration in the health of the patient during later stages of disease. In severe cases immune system dysfunction is the major cause of death in patients as infection stimulates inflammatory cytokines that results in the respiratory system being overwhelmed by a storm of inflammatory cytokines such as IL-2, IL-6, GSCF, IP10, MCP1, MIP1A, and TNF (Huang et al., 2020) . In Covid-19, the immune system seems unable to turn itself off and produces an excessive quantity of cytokines, thus producing an inimical environment for the infection (Figure 1 ). Such an unchecked inflammation caused by this cytokine storm compromises lung function and patients have difficulty breathing and eventually die. The cytokine storm can lead to organ failure followed by edema, secondary infection, cardiac damage, and acute respiratory distress syndrome Accepted Article (ARDS) . MSCs are thought to balance the immune system and stop its over-activation.

Such a balance of the immune system is very important, as complete shutting down of the immune system will affect the infection fighting ability of patients. This article is protected by copyright. All rights reserved.

Although 

It has been shown that there are multiple mechanisms through which MSCs can exert their immunomodulatory effects. It was previously thought that MSCs promoted lung regeneration through engraftment and trans-differentiation. However, later studies 

conclusions cannot be drawn. In addition, the treated groups were given stem cells in conjunction with conventional therapy and therefore it is questionable if the effect of patients is due to administered stem cells. Proper randomization, larger sample size,

proper control groups with longer follow up in multi-center studies are therefore required to properly assess the effectiveness and safety of stem cell use for Covid-19.

Due to the promising results of preclinical studies stem cell-based therapeutics has a special interest for incurable diseases. However, these significant developments in the stem cell field also face the issues of immunogenicity and limited cell numbers. The clinical use of MSCs from autologous sources is the best approach in terms of safety and function, however, production of clinically relevant number of stem cells requires a substantial amount of time which in not always feasible in an emergency situation like the current Covid-19 emergency. As shown in Table 1 

Covid-19 is a new disease and there is limited information regarding its pathology and effective treatment. Due to current prevalence of the disease, the relevant information regarding infection and mortality rate changes each day and therefore the information regarding the total number of cases and the mortality rate described in this article may be changed in the near future. Currently only a few studies have evaluated the use of MSCs This article is protected by copyright. All rights reserved.

However, in the near future such options may be expanded as preventive remedy especially for elderly patients and patients who also have comorbidities. Due to limited available data, although the information regarding MSC based therapies is limited in this review article we have highlighted the arguments relevant to MSC use for Covid-19.

Stem cells seem to have significant potential to treat 

The author declares that there is no conflict of interest

No funding was received for this study or manuscript. 

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