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MSCs Relevant for ARDS Therapy Display Resistance to SARS‐CoV‐2 Infection

Review of “Human mesenchymal stromal cells do not express ACE2 and TMPRSS2 and are not permissive to SARS-CoV-2 infection” from STEM CELLS Translational Medicine by Stuart P. Atkinson

Preclinical and early clinical evidence supports mesenchymal stem cell (MSC) therapy as a potentially effective treatment option for patients suffering from acute respiratory distress syndrome (ARDS) [1, 2]; therefore, this strategy has been considered for the treatment of patients with severe forms of Coronavirus disease (COVID-19) caused by infection with severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) [3].  However, can SARS‐CoV‐2 infect MSCs to potentially reduce efficacy and induce deleterious effects?

Whether human MSCs constitutively express angiotensin‐converting enzyme 2 (ACE2) [4], the primary host cell receptor for SARS‐CoV‐2 entry, and/or transmembrane serine protease II (TMPRSS2) [4], which is used for Spike envelope protein priming, remains relatively unclear [3]. For these reasons, researchers led by Massimiliano Gnecchi (University of Pavia and Fondazione IRCCS Policlinico San Matteo) and Maria A. Avanzi (Fondazione IRCCS Policlinico San Matteo, Pavia, Italy) sought to define the expression profile of ACE2 and TMPRSS2 in human MSCs of various adult and fetal origins and explore their permissivity to SARS‐CoV‐2 infection.

As reported in STEM CELLS Translational Medicine recently [5], Avanzi et al. evaluated MSCs derived from the amniotic membrane of the placenta, umbilical cord tissue, umbilical cord blood, bone marrow, and adipose tissue with a variety of assays, finding that these cells failed to express ACE2 and TMPRSS2. Direct exposure of these MSC types to SARS‐CoV‐2 infection also failed to elicit any cytopathic effect, suggesting that SARS‐CoV‐2 cannot infect MSCs through other host factors/receptors. Furthermore, MSC-conditioned medium did not contain viral particles after infections, which discounts MSC infection without lysis.

Overall, these findings provide robust evidence that MSCs are not permissive to SARS‐CoV‐2 infection and support MSC therapy as a safe means to modulate the immune hyper‐activation in severe COVID‐19 patients and inhibit severe long‐term pulmonary sequelae such as ARDS.

For more on how MSCs represent a safe and potentially effective treatment for ARDS in severe COVID‐19 patients, stay tuned to the Stem Cells Portal!


  1. Hoogduijn MJ and Lombardo E, Mesenchymal Stromal Cells Anno 2019: Dawn of the Therapeutic Era? Concise Review. STEM CELLS Translational Medicine 2019;8:1126-1134.
  2. Khoury M, Cuenca J, Cruz FF, et al., Current status of cell-based therapies for respiratory virus infections: applicability to COVID-19. European Respiratory Journal 2020;55:2000858.
  3. Leng Z, Zhu R, Hou W, et al., Transplantation of ACE2(-) Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia. Aging and Disease 2020;11:216-228.
  4. Hoffmann M, Kleine-Weber H, Schroeder S, et al., SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 2020;181:271-280.e8.
  5. Avanzini MA, Mura M, Percivalle E, et al., Human mesenchymal stromal cells do not express ACE2 and TMPRSS2 and are not permissive to SARS-CoV-2 infection. STEM CELLS Translational Medicine 2021;10:636-642.