Differentiation of Mesenchymal Stem Cells from Human Induced Pluripotent Stem Cells Results in Downregulation of c-Myc and DNA Replication Pathways with Immunomodulation Toward CD4 and CD8 Cells

Abstract

Multilineage tissue-source mesenchymal stem cells (MSCs) possess strong immunomodulatory properties and are excellent therapeutic agents, but require constant isolation from donors to combat replicative senescence. The differentiation of human induced pluripotent stem cells (iPSCs) into MSCs offers a renewable source of MSCs; however, reports on their immunomodulatory capacity have been discrepant. Using MSCs differentiated from iPSCs reprogrammed using diverse cell types and protocols, and in comparison to human embryonic stem cell (ESC)-MSCs and bone marrow (BM)-MSCs, we performed transcriptome analyses and assessed for functional immunomodulatory properties. Differentiation of MSCs from iPSCs results in decreased c-Myc expression and its downstream pathway along with a concomitant downregulation in the DNA replication pathway. All four lines of iPSC-MSCs can significantly suppress in vitro activated human peripheral blood mononuclear cell (PBMC) proliferation to a similar degree as ESC-MSCs and BM-MSCs, and modulate CD4 T lymphocyte fate from a type 1 helper T cell (Th1) and IL-17A-expressing (Th17) cell fate to a regulatory T cell (Treg) phenotype. Moreover, iPSC-MSCs significantly suppress cytotoxic CD8 T proliferation, activation, and differentiation into type 1 cytotoxic T (Tc1) and IL-17-expressing CD8 T (Tc17) cells. Coculture of activated PBMCs with human iPSC-MSCs results in an overall shift of secreted cytokine profile from a pro-inflammatory environment to a more immunotolerant milieu. iPSC-MSC immunomodulation was also validated in vivo in a mouse model of induced inflammation. These findings support that iPSC-MSCs possess low oncogenicity and strong immunomodulatory properties regardless of cell-of-origin or reprogramming method and are good potential candidates for therapeutic use. Stem Cells 2018;36:903-914.

Amelioration of Endoplasmic Reticulum Stress by Mesenchymal Stem Cells via Hepatocyte Growth Factor/c-Met Signaling in Obesity-Associated Kidney Injury

“…Mechanistically, this effect is mediated through diminished UPR activation, downregulation of Bip , chop , inflammatory genes Il6 , chemokines Cxcl1 and Cxcl2 , and pro‐apoptotic signals ( Bax/Bcl2 ratio) with reversal of Bcl2 gene expression, decreased activation of NF‐κB, JNK kinase and TUNEL‐positive renal cells. Our finding of equivalent efficacy between iPS‐MSCs and BM‐MSCs in ameliorating HFD‐induced kidney injury is in agreement with that observed in other disease models .…”

“…Pharmacological attempts targeting ER stress are still premature . iPS‐MSCs may be a superior alternative to BM‐MSCs for MSC‐based therapy . Here, we showed that both iPS‐MSCs and BM‐MSCs partially reversed renal pathology and albuminuria through suppression of renal ER stress induced by lipotoxicity.…”

“…Pharmacological attempts targeting ER stress are still premature [5]. iPS-MSCs may be a superior alternative to BM-MSCs for MSC-based therapy [13]. Here, we showed that both iPS-MSCs and BM-MSCs partially reversed renal pathology and Although an expanding body of the literature has shown the renotropic function of HGF [18,19,23,24], its mechanism of action remains largely unknown.…”

Regulation of the mitochondrial reactive oxygen species: Strategies to control mesenchymal stem cell fates ex vivo and in vivo

“…Various conditions including ageing, long‐term culture and H 2 O 2 , adverse oxygen content, high glucose, proinflammatory cytokines and other toxic factors, abnormally up‐regulated ROS production can harm MSC activities . On the other hand, although MSCs play critical roles on immunomodulatory properties for therapy in various diseases, the constant isolation from donors also bring out unrecoverable injury …”

“…22,[29][30][31][32][33] On the other hand, although MSCs play critical roles on immunomodulatory properties for therapy in various diseases, the constant isolation from donors also bring out unrecoverable injury. 34…”