Human mesenchymal stem cells (MSCs) are multilineage somatic progenitor/stem cells that have been shown to possess immunomodulatory properties in recent years. Initially met with much skepticism, MSC immunomodulation has now been well reproduced across tissue sources and species to be clinically relevant. This has opened up the use of these versatile cells for application as 3rd party/allogeneic use in cell replacement/tissue regeneration, as well as for immune- and inflammation-mediated disease entities. Most surprisingly, use of MSCs for in immune-/inflammation-mediated diseases appears to yield more efficacy than for regenerative medicine, since engraftment of the exogenous cell does not appear necessary. In this review, we focus on this non-traditional clinical use of a tissue-specific stem cell, and highlight important findings and trends in this exciting area of stem cell therapy.

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.

Skeletal muscle (SkM) comprise *40% of human body weight. Injury or damage to this important tissue can result in physical disability, and in severe cases is difficult for its endogenous stem cell-the satellite cellto reverse effectively. Mesenchymal stem cells (MSC) are postnatal progenitor/stem cells that possess multilineage mesodermal differentiation capacity, including toward SkM. Adult bone marrow (BM) is the beststudied source of MSCs; however, aging also decreases BMMSC numbers and can adversely affect differentiation capacity. Therefore, we asked whether human sources of developmentally early stage mesenchymal stem cells (hDE-MSCs) isolated from embryonic stem cells, fetal bone, and term placenta could be cellular sources for SkM repair. Under standard muscle-inducing conditions, hDE-MPCs differentiate toward a SkM lineage rather than cardiomyocytic or smooth muscle lineages, as evidenced by increased expression of SkM-associated markers and in vitro myotube formation. In vivo transplantation revealed that SkM-differentiated hDE-MSCs can efficiently incorporate into host SkM tissue in a mouse model of SkM injury. In contrast, adult BMMSCs do not express SkM-associated genes after in vitro SkM differentiation nor engraft in vivo. Further investigation of possible factors responsible for this difference in SkM differentiation potential revealed that, compared with adult BMMSCs, hDE-MSCs expressed higher levels of serum response factor (SRF), a transcription factor critical for SkM lineage commitment. Moreover, knockdown of SRF in hDE-MSCs resulted in decreased expression of SkM-related genes after in vitro differentiation and decreased in vivo engraftment. Our results implicate SRF as a key factor in age-related SkM differentiation capacity of MSCs, and demonstrate that hDEMSCs are possible candidates for SkM repair.