title: Mesenchymal stromal cells: inhibiting PDGF receptors or depleting fibronectin induces mesodermal progenitors with endothelial potential.
abstract: Realizing the full therapeutic potential of mesenchymal stromal/stem cells (MSCs) awaits improved understanding of mechanisms controlling their fate. Using MSCs cultured as spheroids to recapitulate a three-dimensional cellular environment, we show that perturbing the mesenchymal regulators, platelet-derived growth factor (PDGF) receptors or fibronectin, reverts MSCs toward mesodermal progenitors with endothelial potential that can potently induce neovascularization in vivo. MSCs within untreated spheroids retain their mesenchymal spindle shape with abundant smooth muscle α-actin filaments and fibronectin-rich matrix. Inhibiting PDGF receptors or depleting fibronectin induces rounding and depletes smooth muscle α-actin expression; these cells have characteristics of mesenchymoangioblasts, with enhanced expression of mesendoderm and endoderm transcription factors, prominent upregulation of E-cadherin, and Janus kinase signaling-dependent expression of Oct4A and Nanog. PDGF receptor-inhibited spheroids also upregulate endothelial markers platelet endothelial cell adhesion molecule 1 and vascular endothelial-cadherin and secrete many angiogenic factors, and in vivo they potently stimulate neovascularization, and their MSCs integrate within functional blood vessels that are perfused by the circulation. Thus, MSC potency and vascular induction are regulated by perturbing mesenchymal fate.
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, School of Materials, Faculty of Engineering and Physical Sciences, University of Manchester, Manchester, Lancashire, United Kingdom; Faculty of Life Sciences, School of Materials, Faculty of Engineering and Physical Sciences, University of Manchester, Manchester, Lancashire, United Kingdom.
authors.forename: S G
authors.initials: SG
authors.lastname: Ball
authors.forename: J J
authors.initials: JJ
authors.lastname: Worthington
authors.forename: A E
authors.initials: AE
authors.lastname: Canfield
authors.forename: C L R
authors.initials: CL
authors.lastname: Merry
authors.forename: C M
authors.initials: CM
authors.lastname: Kielty
mesh_terms: D000328:Adult; D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D000818:Animals; D003094:Collagen / Q000494:pharmacology; D004338:Drug Combinations; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000172:deficiency / Q000378:metabolism*; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000494:pharmacology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008648:Mesoderm / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D000071317:Nanog Homeobox Protein; D018919:Neovascularization, Physiologic / Q000187:drug effects; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D011509:Proteoglycans / Q000494:pharmacology; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D055815:Young Adult
chemical_list: D043925:Angiogenesis Inducing Agents; D004338:Drug Combinations; D005353:Fibronectins; D018398:Homeodomain Proteins; D007797:Laminin; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen; D017479:Receptors, Platelet-Derived Growth Factor
keywords: Endothelial; Fibronectin; Mesenchymal stromal cells; Neovascularization; Platelet-derived growth factor receptor; Spheroids
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