Volume 11, Number 2; 462-464, April 2020

http://dx.doi.org/10.14336/AD.2020.0301

Editorial

Mesenchymal Stem Cell Infusion Shows Promise for

Combating Coronavirus (COVID-19)- Induced
Pneumonia
Ashok K. Shetty*

Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M University
College of Medicine, College Station, Texas, USA
[Received March 1, 2020; Revised March 1, 2020; Accepted March 1, 2020]

ABSTRACT: A new study published by the journal Aging & Disease reported that intravenous administration
of clinical-grade human mesenchymal stem cells (MSCs) into patients with coronavirus disease 2019 (COVID-
19) resulted in improved functional outcomes (Leng et al., Aging Dis, 11:216-228, 2020). This study demonstrated
that intravenous infusion of MSCs is a safe and effective approach for treating patients with COVID-19
pneumonia, including elderly patients displaying severe pneumonia. COVID-19 is a severe acute respiratory
illness caused by a new coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Currently, treating COVID-19 patients, particularly those afflicted with severe pneumonia, is challenging as no
specific drugs or vaccines against SARS-CoV-2 are available. Therefore, MSC therapy inhibiting the
overactivation of the immune system and promoting endogenous repair by improving the lung microenvironment
after the SARS-CoV-2 infection found in this study is striking. Additional studies in a larger cohort of patients
are needed to validate this therapeutic intervention further, however.

A new study published by the journal “Aging & Disease” of new cases and significant mortality worldwide [3].
by a team led by Dr. Zhao reports that intravenous Coronaviruses are commonly found in people and
administration of clinical-grade human mesenchymal multiple species of animals. Sometimes, animal
stem cells (MSCs) into seven patients with Coronavirus coronaviruses infect people and spread from person to
Disease 2019 (COVID-19) resulted in improved person [4]. SARS-CoV-2, one such example, causes mild
functional outcomes and facilitated recovery [1]. COVID- to severe symptoms, which include fever, cough, and
19 is a severe acute respiratory illness caused by a new shortness of breath, but severe cases (~2%) have been
coronavirus named severe acute respiratory syndrome observed to result in death [1-3].
coronavirus 2 (SARS-CoV-2) [2-3]. This new corona- The pathogenesis of SARS-CoV-2 has been
virus has elicited a pandemic of respiratory ailment since suggested to include the recognition of the angiotensin I
December 2019. It first appeared in Wuhan, China, but converting enzyme 2 receptor (ACE2) by its spike protein,
has now disseminated to multiple countries in the world, and priming of its spike protein by the cellular
including the United States [2-3]. Even with painstaking transmembrane protease, serine 2 (TMPRSS2) facilitating
global restraint and confinement efforts, the prevalence of host cell entry and spread [1,5-6]. Severe respiratory
COVID-19 continues to climb, with an increasing number illness is a significant symptom of SARS-CoV-2 infection

*Correspondence should be addressed to: Dr. Ashok K. Shetty, Institute for Regenerative Medicine, Texas A&M Health
Science Center, College of Medicine, College Station, TX 77843, USA. E-mail: [email protected]
Copyright: © 2020 Shetty AK. This is an open-access article distributed under the terms of the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
ISSN: 2152-5250 462
Shetty AK. MSC and COVID-19 pneumonia

because the ACE2 receptor is widely expressed in the lung of paracrine factors, which interact with immune cells
alveolar type II cells and capillary endothelial cells. resulting eventually in immunomodulation [10-13]. The
Besides, alveolar cells express TMPRSS2 [1,7]. Infection mechanisms underlying the improvements after MSC
of the lung by this virus leads to a cytokine storm with infusion in COVID-19 patients also appeared to be the
elevated levels of multiple proinflammatory cytokines, robust antiinflammatory activity of MSCs. Such
which causes edema, air exchange dysfunction, acute processes were evident from multiple beneficial
respiratory distress, secondary infection, which may result outcomes, which include an increased number of
in death [1]. ACE2 expression is also seen in other tissues peripheral lymphocytes, the decline in the C-reactive
such as the heart, liver, kidney, and digestive organs. Such protein, and waning of overactivated cytokine-secreting
expression pattern explains why infected ICU patients are immune cells (CXCR3+CD4+ T cells, CXCR3+CD8+ T
afflicted with not only acute respiratory distress syndrome cells, and CXCR3+ NK cells) by 3-6 days in the
but also other complications such as myocardial injury, circulating blood [1]. Moreover, a group of
arrhythmia, acute kidney injury, shock, and death from CD14+CD11c+CD11bmid regulatory dendritic cell (DC)
multiple organ dysfunction syndromes [1,8]. The World population increased after MSC treatment. Also, in
Health Organization has proclaimed this epidemic as a comparison to the placebo group, the patients receiving
global public health emergency [3]. Currently, treating MSCs displayed a decreased level of tumor necrosis
COVID-19 patients, particularly those afflicted with factor-alpha, a major pro-inflammatory cytokine, with
severe pneumonia, is challenging as no specific drugs or concurrent elevation in the concentration of the
vaccines against SARS-CoV-2 are available [9]. antiinflammatory protein interleukin-10 [1]. Furthermore,
Therefore, identifying a safe and effective treatment for 10 x RNA-sequencing uncovered that infused MSCs were
severely affected COVID-19 patients is critical for saving negative for ACE2 and TMPRSS2, which implied that
lives. MSCs were free from COVID-19 infection. Besides,
In the study by Dr. Zhao and collaborators, seven multiple antiinflammatory and trophic factors were highly
patients with COVID-19 pneumonia displayed improved expressed in MSCs. Also, the Kyoto Encyclopedia of
functional outcomes and recovered after an intravenous Genes and Genomes (KEGG) analysis suggested that
administration of clinical-grade human MSCs [1]. The MSCs were involved in antiviral pathways [1].
chosen patients were positive for SARS-CoV-2, with one Remarkably, the study by Dr. Zhao and colleagues
displaying critically severe type, 4 exhibiting severe showed that intravenous MSC infusion could reduce the
types, and the other 2 showing common types of the overactivation of the immune system and support repair
syndrome. An additional three patients with severe types by modulating the lung microenvironment after SARS-
were enrolled for placebo control. Before MSC infusion, CoV-2 infection even in elderly patients. Intravenous
all patients displayed high fever, shortness of breath, low infusion of MSCs typically leads to their accumulation in
oxygen saturation, and pneumonia. The patients received the lungs, where they secrete multiple paracrine factors
1 million MSCs per kilogram body weight when their [16]. Such factors likely played a significant role in
symptoms were getting worse and were observed closely protecting or rejuvenating alveolar epithelial cells,
for 14 days. Notably, the study found that virtually all counteracting fibrosis, and improving lung function. MSC
symptoms subsided by 2-4 days after receiving MSC infusion would likely be particularly beneficial to elderly
infusion with no apparent adverse effects. Chest CT individuals infected with SARS-CoV-2, both with and
imaging demonstrated that chest pneumonia infiltration without co-morbidities, as this population is more
was significantly subsided. Also, the majority of patients susceptible to SARS-CoV-2 induced pneumonia,
showed negative results for the SARS-CoV-2 nucleic acid resulting in severe respiratory distress and death because
test over a week or two after MSC infusion. The overall of immunosenescence [17-20]. In summary, this study
improvement was quite extraordinary for an elderly showed that intravenous infusion of MSCs is a safe and
patient in a critical condition after the infection [1]. efficient approach for treating patients with COVID-19
MSCs have been employed extensively in cell pneumonia, including in elderly patients displaying
therapy, which includes a plethora of preclinical research severe pneumonia. Additional studies in a larger cohort of
investigations as well as a significant number of clinical patients are needed to validate this therapeutic
trials [10-13]. Safety and efficacy have been shown in intervention further, however.
many clinical trials. The notable examples include the
immune-mediated inflammatory diseases, such as graft- Acknowledgments
versus-host disease and systemic lupus erythematosus
[14-15]. Improved function after MSC infusions in The author is supported by grants from the National
multiple disease conditions has been mostly attributed to Institute of Neurological Disorders and Stroke
immunomodulatory effects, as these cells secrete a variety

Aging and Disease • Volume 11, Number 2, April 2020 463

Shetty AK. MSC and COVID-19 pneumonia

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