Transcriptionally and Functionally Distinct Mesenchymal Subpopulations Are Generated from Human Pluripotent Stem Cells

Abstract

SummaryVarious mesenchymal cell types have been identified as critical components of the hematopoietic stem/progenitor cell (HSPC) niche. Although several groups have described the generation of mesenchyme from human pluripotent stem cells (hPSCs), the capacity of such cells to support hematopoiesis has not been reported. Here, we demonstrate that distinct mesenchymal subpopulations co-emerge from mesoderm during hPSC differentiation. Despite co-expression of common mesenchymal markers (CD73, CD105, CD90, and PDGFRβ), a subset of cells defined as CD146hiCD73hi expressed genes associated with the HSPC niche and supported the maintenance of functional HSPCs ex vivo, while CD146loCD73lo cells supported differentiation. Stromal support of HSPCs was contact dependent and mediated in part through high JAG1 expression and low WNT signaling. Molecular profiling revealed significant transcriptional similarity between hPSC-derived CD146++ and primary human CD146++ perivascular cells. The derivation of functionally diverse types of mesenchyme from hPSCs opens potential avenues to model the HSPC niche and develop PSC-based therapies.

The mesenchymoangioblast, mesodermal precursor for mesenchymal and endothelial cells

“…In seminal studies, Cheung et al, [21] generated SMCs from hPSCs through well-defined neural crest, lateral plate and paraxial mesoderm intermediates, and demonstrated that these cells recapitulate origin-specific proliferative and secretory responses to growth factors, cytokines and vasoactive agonists. Other studies by Chin et al, [78], revealed phenotypical and functional heterogeneity within hPSC-derived mesenchymal cells defined by typical PDGFRβ + CD90 + CD105 + CD44 + CD73 + MSC phenotype. CD146 high CD73 high PDGFR − subset within phenotypical MSC population expressed genes associated with hematopoietic stem cell (HSC) niche and supported HSC expansion in vitro .…”

Non–fibro-adipogenic pericytes from human embryonic stem cells attenuate degeneration of the chronically injured mouse muscle

“…Multiple protocols to differentiate hPSCs into mesenchymal stem-like cells (16) and perivascular cells (17)(18)(19) have been described. However, functional differentiation demonstrated that in most cases, hPSC mesodermal derivatives are heterogenous cell populations composed of a mixture of mesodermal progenitors that can be distinguished based on their differentiation potentials (e.g., osteo-/chondro-/ fibro-/adipogenic) and level of expression or lack of expression of characteristic sets of markers (20,21). Additionally, in vitro modifications evolve in long-term cultures, resulting in progressive cell maturation or acquirement of fibroblast-like characteristics (12).…”

Engineering Brain-Specific Pericytes from Human Pluripotent Stem Cells

“…110 In addition, the hPSCs were induced for mesoderm differentiation using OP9 stromal cell coculture or growth factors BMP4, VEGF, and FGF-2. 111 The derived cells coexpressed common mesenchymal markers (CD73, CD90, CD105, and PDGFRb), and a subset of CD146 hi CD73 hi population was identified. It was found that the derived cells provided stromal support of hematopoietic stem cells, which was contact dependent and mediated through high Notch signaling (e.g., Jagged 1) and low Wnt signaling.…”