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Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - Mesenchymal stromal cells
T2 - inhibiting PDGF receptors or depleting fibronectin induces mesodermal progenitors with endothelial potential
AU - Ball, S. G.
AU - Worthington, John J.
AU - Canfield, A. E.
AU - Merry, C. L. R.
AU - Kielty, C. M.
N1 - © AlphaMed Press This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
PY - 2014/3
Y1 - 2014/3
N2 - 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.
AB - 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.
KW - Adult
KW - Angiogenesis Inducing Agents
KW - Animals
KW - Collagen
KW - Drug Combinations
KW - Endothelial Cells
KW - Female
KW - Fibronectins
KW - Gene Expression Profiling
KW - Homeodomain Proteins
KW - Humans
KW - Laminin
KW - Male
KW - Mesenchymal Stromal Cells
KW - Mesoderm
KW - Mice
KW - Mice, Inbred C57BL
KW - Neovascularization, Physiologic
KW - Octamer Transcription Factor-3
KW - Proteoglycans
KW - Receptors, Platelet-Derived Growth Factor
KW - Signal Transduction
KW - Spheroids, Cellular
KW - Up-Regulation
KW - Young Adult
U2 - 10.1002/stem.1538
DO - 10.1002/stem.1538
M3 - Journal article
C2 - 24022915
VL - 32
SP - 694
EP - 705
JO - Stem Cells
JF - Stem Cells
SN - 1066-5099
IS - 3
ER -