key: cord-0820033-ax360gz9
authors: Desterke, Christophe; Griscelli, Frank; Imeri, Jusuf; Marcoux, Paul; Lemonnier, Thomas; Latsis, Theodoros; Turhan, Ali G.; Bennaceur‐Griscelli, Annelise
title: Molecular investigation of adequate sources of mesenchymal stem cells for cell therapy of COVID‐19‐associated organ failure
date: 2020-11-25
journal: Stem Cells Transl Med
DOI: 10.1002/sctm.20-0189
sha: 0410c3738fa70d8bad0dc5c93adb1cfd5628ca17
doc_id: 820033
cord_uid: ax360gz9

The use of mesenchymal stem cells (MSC) derived from several sources as a major anti‐inflammation strategy has been suggested in the recent outbreak of Coronavirus‐19 (COVID‐19). As the virus enters the target cells through the receptor ACE2, it is important to determine if the MSC population transfused to patients could also be a target for the virus entry. We report here that ACE2 is highly expressed in adult bone marrow, adipose tissue or umbilical cord‐derived MSC. On the other hand, placenta‐derived MSC express low levels of ACE2 but only in early passages of cultures. MSC derived from human embryonic stem cell (hESC) or human induced pluripotent stem cells (hIPSC) express also very low levels of ACE2. The transcriptome analysis of the MSCs with lowest expression of ACE2 in fetal‐like MSCs is found to be associated in particularly with an anti‐inflammatory signature. These results are of major interest for designing future clinical MSC‐based stem cell therapies for severe COVID‐19 infections.

The use of mesenchymal stem cells (MSC) derived from several sources as a major anti-inflammation strategy has been suggested in the recent outbreak of Coronavirus-19 (COVID-19). As the virus enters the target cells through the receptor ACE2, it is important to determine if the MSC population transfused to patients could also be a target for the virus entry. We report here that ACE2 is highly expressed in adult bone marrow, adipose tissue or umbilical cord-derived MSC. On the other hand, placenta-derived MSC express low levels of ACE2 but only in early passages of cultures. 

The outbreak of the new coronavirus, designed as COVID-19, is now spread from China to Europe, United States, and to the rest of the world, representing a major health problem for the humanity. 1 The bat SARS-like coronavirus COVID-19, uses the angiotensin converting enzyme receptor 2 (ACE2) to enter the cells. 2 ACE2 is highly distributed in all adult cells, including lung, heart, kidney, liver and endothelial cells that are then highly susceptible to infection by COVID-19, which uses its S protein to this purpose. The high expression of ACE2 by lung alveolar cells (AT2) is one of the reasons of the major tropism of the COVID-19 for lung infection. In a subgroup of patients, COVID-19 infection induces a strong cytokine storm and a severe disease with a macrophage activation syndrome (MAS) leading to a rapid progression to acute respiratory distress syndrome (ARDS), multiorgan failure and death. 3 COVID-19 associated pneumonia is associated with lung damage and infiltration of activated pro-inflammatory M1 macrophages associated with low IFN-γ production by CD4 + Tcells, as part of the virally induced immunosuppression and lymphopenia. Preliminary data suggest that severity COVID-19-associated disease may be to the loss antiviral defense mechanism, which activates a secondary cytokine storm as "second wave" of more tissue aggressive immunity leading to increased tissue damage. This nontype-1 interferon pathway implies the secretion of myeloid/macrophage derived-cytokines including exacerbated production of IL-6, IL- Interestingly, culture conditions can also impact ACE2 expression levels as after late passages (3-5 passages), both UC and placentaderived MSC were found to express higher levels of ACE2 (P = .006951, Supporting Information Figure S1 ). We then analyzed ACE2 expression levels in the human embryonic stem cell (hESC) line H1 and the MSC derived from this cell line as reported by Barberi et al. 8 As seen in Figure 1B , although pluripotent H1 cells express very high levels of ACE2, its MSC-derivatives express very low levels (P = .0143, Figure 1D ). To determine if IPSC and their MSC-derivatives exhibit the same pattern, we used an IPSC cell line derived from bone marrow of a donor and their corresponding MSC after differentiation. As can be seen in Figure 1E F I G U R E 1 Regulation of ACE2 expression and immune signature human MSCs derived from distinct tissues. A, Expression of ACE2 in MSCs generated from distinct tissues. (p:Kruskal-Wallis P-value test); B, Circos plot of genes whose expression are correlated to ACE2 expression in human MSCs (dataset GSE108511) and identified by text mining to an immunological function (Pubmed Results). C, Heatmap expression of ACE2 signature associated with an immunity gene in human MSCs; D, Boxplot of ACE2 expression in embryonic stem cell-derived MSCs compared with undifferentiated embryonic stem cells (GSE2248, p:Kruskal-Wallis P-value test). E, Real-time reverse transcription-PCR mRNA analysis of iPSCs (PB33) and MSC-derived from the same iPSCs (passage 6). AD, adipose tissue; BM, bone marrow; CB, cord blood; PL, placenta M2 anti-inflammatory polarization via TNF-α-mediated-activation of cyclooxygenase-2 (COX-2) and TNF-stimulated gene-6 (TSG-9). 9 Therapeutic effects of MSC may thus arise from the regulation of multiple macrophage functions by targeting various cytokines simultaneously, implying that these immune-balancing effects enable fetallike MSCs to be a promising therapeutic option for COVID-19induced cytokine storm. However, currently there are no sufficient clinical data about the potential clinical efficacy of MSC to treat all patients with several COVID-19 disease and clinical trials using either placental or hESC/IPSC-derived MSCs are urgently needed.

A novel coronavirus from patients with pneumonia in China

Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Amniotic fluid-derived mesenchymal stem cells prevent fibrosis and preserve renal function in a preclinical porcine model of kidney transplantation

Human mesenchymal stem cells derived from induced pluripotent stem cells down-regulate NKcell cytolytic machinery

Transplantation of mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia

Improvement of therapeutic effects of mesenchymal stem cells in myocardial infarction through genetic suppression of microRNA-142

Derivation of multipotent mesenchymal precursors from human embryonic stem cells

Human umbilical cord blood-stem cells direct macrophage polarization and block inflammasome activation to alleviate rheumatoid arthritis

Molecular investigation of adequate sources of mesenchymal stem cells for cell therapy of COVID-19-associated organ failure

The authors declared no potential conflicts of interest. 

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Ali G. Turhan https://orcid.org/0000-0002-4861-0137