Human mesenchymal stromal cells do not express ACE2 and TMPRSS2 and are not permissive to SARS-CoV-2 infection

Abstract

Anti‐inflammatory and immune‐modulatory therapies have been proposed for the treatment of COVID‐19 and its most serious complications. Among others, the use of mesenchymal stromal cells (MSCs) is under investigation given their well‐documented anti‐inflammatory and immunomodulatory properties. However, some critical issues regarding the possibility that MSCs could be infected by the virus have been raised. Angiotensin‐converting enzyme 2 (ACE2) and type II transmembrane serine protease (TMPRSS2) are the main host cell factors for the Severe Acute Respiratory Syndrome‐Coronavirus 2 (SARS‐CoV‐2) entry but so far it is unclear if human MSCs express or do not these two proteins. To elucidate these important aspects, we evaluated if human MSCs from both fetal and adult tissues constitutively express ACE2 and TMPRSS2 and, most importantly, if they can be infected by SARS‐CoV‐2. We evaluated human MSCs derived from amnios, cord blood, cord tissue, adipose tissue and bone marrow. ACE2 and TMPRSS2 were expressed by the SARS‐CoV‐2‐permissive human pulmonary Calu‐3 cell line but not by all the MSCs tested. MSCs were then exposed to SARS‐CoV‐2 wild strain without evidence of cytopathic effect. Moreover, we also excluded that the MSCs could be infected without showing lytic effects since their conditioned medium after SARS‐CoV‐2 exposure did not contain viral particles. Our data, demonstrating that MSCs derived from different human tissues are not permissive to SARS‐CoV‐2 infection, support the safety of MSCs as potential therapy for COVID‐19. © AlphaMed Press 2020 Significance statement Human mesenchymal stromal cells (hMSCs) are currently under investigation for the treatment of COVID‐19. However, the potential safety profile of hMSCs in this context has never been defined since none has described if they express ACE2 and TMPRSS2, the main host cell factors for SARS‐CoV‐2 entry, and if they can be infected by SARS‐CoV‐2. We provide the first evidence that ACE2 and TMPRSS2 are not expressed in hMSCs derived from both adult and fetal human tissues and, most importantly, that hMSCs are not permissive to SARS‐CoV‐2 infection. These results support the safety of MSCs as potential therapy for COVID‐19.

Dodging COVID-19 infection: low expression and localization of ACE2 and TMPRSS2 in multiple donor-derived lines of human umbilical cord-derived mesenchymal stem cells

“…By having used hUC-MSC lots derived from multiple donors, we have established that there is no ACE2 expression in hUC-MSCs, while TMPRSS2 expression could be donor-dependent. This provides a reasonable basis to support the evasion of infection by hUC-MSCs, making them an effective, non-vector, option for COVID-19 treatment, thereby supporting the findings of Avanzini et al [ 53 ] and Leng et al [ 32 ].…”

Current Status of Cell-Based Therapies for COVID-19: Evidence From Mesenchymal Stromal Cells in Sepsis and ARDS

“…In parallel with proper ventilation management, dexamethasone, antiviral agents, convalescent plasma, and IL-1/6 inhibitors, MSCs are also considered a promising candidate therapy for COVID-19-related ARDS (4,119). It was reported that MSCs from the bone marrow, amniotic fluid, and adipose tissue were all resistant to SARS-CoV-2 infection due to the low expressions of angiotensin-converting enzyme 2 (ACE-2) and transmembrane protease serine subtype 2 (TMPRSS2) on the cell surface under both steady-state and inflammatory conditions (120,121), which supported the potential applicability of MSCs for COVID-19 treatment (Figure 1).…”

Treatment of COVID-19 by Stage: Any Space Left for Mesenchymal Stem Cell Therapy?

“…Noteworthy, another advantage of MSCs is that they do not express the ACE-2 receptor and the priming enzyme that allow SARS-CoV-2 engagement and entry [ 118 ]. Cultured MSCs from different tissues were exposed to SARS-CoV-2 wild strain without evidence of cytopathic effects; moreover, under in vitro challenges with the virus, the conditioned medium did not contain viral particles [ 118 ].…”

“…Noteworthy, another advantage of MSCs is that they do not express the ACE-2 receptor and the priming enzyme that allow SARS-CoV-2 engagement and entry [ 118 ]. Cultured MSCs from different tissues were exposed to SARS-CoV-2 wild strain without evidence of cytopathic effects; moreover, under in vitro challenges with the virus, the conditioned medium did not contain viral particles [ 118 ]. The lack of ACE2 and TMPRSS expression was also interpreted as a key element for the reported clinical success of an MSC therapy trial, described in more detail below, in seven patients with COVID-19 pneumonia [ 119 ].…”