Mesenchymal Stem Cell-Based COVID-19 Therapy: Bioengineering Perspectives

Abstract

The novel pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). Mesenchymal stem cells (MSCs) are currently utilized in clinics for pulmonary inflammatory diseases, including acute respiratory distress syndrome and acute lung injury. Given that MSCs offer a promising treatment against COVID-19, they are being used against COVID-19 in more than 70 clinical trials with promising findings. Genetically engineered MSCs offer promising therapeutic options in pulmonary diseases. However, their potential has not been explored yet. In this review, we provide perspectives on the functionally modified MSCs that can be developed and harnessed for COVID-19 therapy. Options to manage the SARS-CoV-2 infection and its variants using various bioengineering tools to increase the therapeutic efficacy of MSCs are highlighted.

Keywords: ACE2; COVID-19; SARS-CoV-2; TMPRSS2; bioengineering; genetic engineering; mesenchymal stem cells.

Figure 1

Engineered versus naive MSC therapy against COVID-19. MSCs can be engineered to secrete anti-inflammatory cytokines and/or genetically silenced for pro-inflammatory cytokine release. Engineering MSCs may be capacitated to prevent infection and prolong MSC longevity/functionality within the patient. Abbreviations: ACE2, angiotensin-converting enzyme 2; TMPRSS2, transmembrane serine protease 2; IL-10, interleukin-10; IL-6, interleukin-6.

Figure 2

In vitro modeling and assessment of engineered MSC therapy against SARS-CoV-2. Co-culture of therapeutically engineered MSCs and bioimageable host cells (VERO E6 or HK-2 cells). Groups: includes MSC only, host cells only (VERO E6/HK-2) and their co-cultures (MSC+VERO E6/HK-2). All of these groups can be infected by SARS-CoV-2, while the control groups remain unaffected. MSCs in co-cultures with exposure to SARS-CoV-2 can be examined for their safety and therapeutic potential. For this, MSCs in co-culture can be evaluated for their (1) MSC-specific characteristics (expression of surface markers, capacity of mesodermal differentiation and plasticity abilities), (2) risks of cancerogenic phenotype (such as expressing cancer stem cell markers, forming tumorspheres in vitro, and teratomes in vivo, and vice versa) and (3) their survival rates in the infectious microenvironment. Additionally, the conditioned medium can be assayed for enhanced anti-inflammatory/immunomodulatory cytokine release (or any other proposed secretions) by the engineered MSCs. To confirm the infection, SARS-CoV-2 and relative cytopathic effects (CPE) in host cells (VERO E6/HK-2) can be detected. The viability can be measured in host cells which have been previously modified to express one of the luciferases. Likewise, fluorescence proteins can be integrated to the luciferase (during pDNA construction) and the cells in co-cultures can be distinguishable from MSCs under the microscope. Conversely, bioimageable MSCs (or both MSCs and host cells) can be established according to the experimental necessities. Options can be altered and such an infectious coculture system can mimic MSC residing in the infectious microenvironment and their interactions with the hosts. This may eventually provide an in vitro model for various evaluations.