Abstract
SummaryThe gap in knowledge of the molecular mechanisms underlying differentiation of human pluripotent stem cells (hPSCs) into the mesenchymal cell lineages hinders the application of hPSCs for cell-based therapy. In this study, we identified a critical role of muscle segment homeobox 2 (MSX2) in initiating and accelerating the molecular program that leads to mesenchymal stem/stromal cell (MSC) differentiation from hPSCs. Genetic deletion of MSX2 impairs hPSC differentiation into MSCs. When aided with a cocktail of soluble molecules, MSX2 ectopic expression induces hPSCs to form nearly homogeneous and fully functional MSCs. Mechanistically, MSX2 induces hPSCs to form neural crest cells, an intermediate cell stage preceding MSCs, and further differentiation by regulating TWIST1 and PRAME. Furthermore, we found that MSX2 is also required for hPSC differentiation into MSCs through mesendoderm and trophoblast. Our findings provide novel mechanistic insights into lineage specification of hPSCs to MSCs and effective strategies for applications of stem cells for regenerative medicine.
Highlights
Mesenchymal stem/stromal cells (MSCs) are promising sources for cell-based therapies due to their self-renewal capacity, multi-lineage differentiation potential, and immunomodulatory properties (Friedenstein et al, 1968; Nombela-Arrieta et al, 2011)
muscle segment homeobox 2 (MSX2) Initiates Mesenchymal Differentiation in human pluripotent stem cells (hPSCs) We recently reported that MSX2 mediates the entry of hPSCs into mesendoderm during early fate specification (Wu et al, 2015)
From the RNA sequencing (RNA-seq) data of hPSCs with MSX2 ectopic expression, we found rapid upregulation of multiple mesenchyme development and mesenchymal cell differentiation-associated genes in cells 48 hr and 72 hr after MSX2 overexpression, even under pluripotency-supporting conditions (Figures 1A and S1A)
Summary
Mesenchymal stem/stromal cells (MSCs) are promising sources for cell-based therapies due to their self-renewal capacity, multi-lineage differentiation potential, and immunomodulatory properties (Friedenstein et al, 1968; Nombela-Arrieta et al, 2011). Bone marrowderived MSCs (BM-MSCs) are the most commonly used source for MSCs in clinical trials (Ankrum and Karp, 2010). These cell sources have some limitations, including limited cell proliferative capacity, declined therapeutic potency after in vitro expansion, donor-dependent variability in quality, and the risk of pathogen transmission (Wang et al, 2016). There is an urgent need to find alternative inexhaustible sources of MSCs
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