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

Chee Jia Chin; Suwen Li; Mirko Corselli; David Casero; Yuhua Zhu; Chong Bin He; Reef Hardy; Bruno Péault; Gay M Crooks

doi:10.1016/j.stemcr.2017.12.005

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

Stem Cell Reports. 2018 Feb 13;10(2):436-446. doi: 10.1016/j.stemcr.2017.12.005. Epub 2018 Jan 4.

Authors

Chee Jia Chin¹, Suwen Li¹, Mirko Corselli², David Casero¹, Yuhua Zhu¹, Chong Bin He¹, Reef Hardy³, Bruno Péault⁴, Gay M Crooks⁵

Affiliations

¹ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine (DGSOM), University of California (UCLA), Los Angeles, CA 90095, USA.
² Becton Dickinson, San Diego, CA 92121, USA.
³ Department of Orthopedics, DGSOM, UCLA, Los Angeles, CA 90095, USA; Orthopedic Hospital Research Center, UCLA, Los Angeles, CA 90095, USA; Broad Stem Cell Research Center (BSCRC), UCLA, Los Angeles, CA 90095, USA; Department of Medicine, University of Indiana, Indianapolis, IN 46202, USA.
⁴ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine (DGSOM), University of California (UCLA), Los Angeles, CA 90095, USA; Department of Orthopedics, DGSOM, UCLA, Los Angeles, CA 90095, USA; Orthopedic Hospital Research Center, UCLA, Los Angeles, CA 90095, USA; Broad Stem Cell Research Center (BSCRC), UCLA, Los Angeles, CA 90095, USA; Center for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK.
⁵ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine (DGSOM), University of California (UCLA), Los Angeles, CA 90095, USA; Broad Stem Cell Research Center (BSCRC), UCLA, Los Angeles, CA 90095, USA; Department of Pediatrics, DGSOM, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center (JCCC), UCLA, Los Angeles, CA 90095, USA. Electronic address: gcrooks@mednet.ucla.edu.

Abstract

Various 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 CD146^hiCD73^hi expressed genes associated with the HSPC niche and supported the maintenance of functional HSPCs ex vivo, while CD146^loCD73^lo 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.

Keywords: directed differentiation; hematopoietic stem cell niche; mesenchyme; mesoderm; pericyte biology; pluripotent stem cell.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

CD146 Antigen / genetics
Cell Differentiation / genetics*
Cell Lineage / genetics
Gene Expression Regulation, Developmental / genetics
Hematopoiesis / genetics
Humans
Mesenchymal Stem Cells / cytology*
Mesenchymal Stem Cells / metabolism
Mesoderm / cytology*
Mesoderm / growth & development
Mesoderm / metabolism
Pluripotent Stem Cells / cytology*
Pluripotent Stem Cells / metabolism
Stem Cell Niche / genetics
Wnt Signaling Pathway / genetics

Substances

CD146 Antigen
MCAM protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding