hUC-MSCs Attenuate Acute Graft-Versus-Host Disease through Chi3l1 Repression of Th17 Differentiation

Abstract

Mesenchymal stem cells (MSCs) have already demonstrated definitive evidence of their clinical benefits in acute graft-versus-host disease (aGvHD) and other inflammatory diseases. However, the comprehensive mechanism of MSCs’ immunomodulation properties has not been elucidated. To reveal their potential immunosuppressive molecules, we used RNA sequencing to analyze gene expression in different tissue-derived MSCs, including human bone marrow, umbilical cord, amniotic membrane, and placenta, and found that chitinase-3-like protein 1 (Chi3l1) was highly expressed in human umbilical cord mesenchymal stem cells (hUC-MSCs). We found that hUC-MSCs treated with interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) exhibited increased expression of Chi3l1 and concurrently repressed T-helper 17 cell (Th17) differentiation through inhibition of signal transducer and activator of transcription 3 (STAT3) activation. Furthermore, Chi3l1 knockdown hUC-MSCs exhibited impaired therapeutic efficacy in aGvHD mice with an increased inflammatory response by promoting Th17 cell differentiation, including an increase in IL-17A in the spleen, intestine, and serum. Collectively, these results reveal a new immunosuppressive molecule, Chi3l1, in hUC-MSCs in the treatment of aGvHD that regulates Th17 differentiation and inhibits STAT3 activation. These novel insights into the mechanisms of hUC-MSC immunoregulation may lead to the consistent production of hUC-MSCs with strong immunosuppressive functions and thus improved clinical utility.

Different priming strategies improve distinct therapeutic capabilities of mesenchymal stromal/stem cells: Potential implications for their clinical use

“…In this study the authors showed that, though the priming treatment induced the increase of CCL2 and MHCI/II expression in IFN-γ-primed MSCs, it inhibited manifestations of autoimmune encephalomyelitis while keeping their immunogenicity low. The use of IFN-γ- or TNF-α-primed MSCs has also been shown to attenuate symptoms of GVHD[ 101 , 103 ]. In these cases, in the first study it was shown that therapeutic effects of MSCs were mediated by overproduction of IDO induced through the IFN-γ-JAK-STAT1 pathway[ 101 ].…”

Human umbilical cord mesenchymal stem cell-derived TGFBI attenuates streptozotocin-induced type 1 diabetes mellitus by inhibiting T-cell proliferation

“…According to our previous RNA sequencing results for different sources of MSCs, including MSCs derived from human umbilical cord, amniotic membrane, placenta, and bone marrow [ 13 ], we found that TGFBI, an extracellular matrix protein induced by TGF-β signaling, was highly expressed in human umbilical cord-derived hMSCs (hUC-MSCs) (Supplemental Fig. 1).…”

“…In addition, different sources of mesenchymal stem/stromal cells have distinct characteristics [ 11 , 12 ]. To identify the immune functional properties from different sources of MSCs, RNA sequencing was performed on MSCs isolated and cultured from umbilical cord, amniotic membrane, placenta, and bone marrow [ 13 ]. Our data showed that transforming growth factor beta-induced gene (TGFBI) was highly expressed in MSCs obtained from human umbilical cord.…”

Mesenchymal stem cell‐derived exosomes in preeclampsia: A next‐generation therapeutic tool

“…By increasing the generation of IL-10 and PGE2 and decreasing that of IL-17, IL-22, and IFN-y, MSCs prevent the differentiation of Th17. 75,76 T A B L E 2 MSCs-derived exosomes in animal models with deregulated immune response. their cytokine composition and raises the possibility that BM-MSCs may impact Th17 lymphocytes' biological functions.…”

“…It has been demonstrated that MSCs influence T‐cells and other members of the adaptive immune system through paracrine secretion. By increasing the generation of IL‐10 and PGE2 and decreasing that of IL‐17, IL‐22, and IFN‐y, MSCs prevent the differentiation of Th17 75,76 . Studies combining bone marrow (BM)‐MSCs with T cells in cocultivation have shown that cytokine priming of BM‐MSCs affects their cytokine composition and raises the possibility that BM‐MSCs may impact Th17 lymphocytes' biological functions 77 .…”