Mesenchymal Stromal Cells: Inhibiting PDGF Receptors or Depleting Fibronectin Induces Mesodermal Progenitors with Endothelial Potential
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, platele...
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| Veröffentlicht in: | Stem cells (Dayton, Ohio) Ohio), 2014-03, Vol.32 (3), p.694-705 |
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| creator | Ball, S. G. Worthington, J. J. Canfield, A. E. Merry, C. L. R. Kielty, C. M. |
| description | 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. Stem Cells 2014;32:694–705 |
| doi_str_mv | 10.1002/stem.1538 |
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G. ; Worthington, J. J. ; Canfield, A. E. ; Merry, C. L. R. ; Kielty, C. M.</creator><creatorcontrib>Ball, S. G. ; Worthington, J. J. ; Canfield, A. E. ; Merry, C. L. R. ; Kielty, C. M.</creatorcontrib><description>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. Stem Cells 2014;32:694–705</description><identifier>ISSN: 1066-5099</identifier><identifier>EISSN: 1549-4918</identifier><identifier>DOI: 10.1002/stem.1538</identifier><identifier>PMID: 24022915</identifier><language>eng</language><publisher>United States: Oxford University Press</publisher><subject>Adult ; Angiogenesis ; Angiogenesis Inducing Agents - metabolism ; Animals ; Cell adhesion & migration ; Collagen - pharmacology ; Drug Combinations ; Endothelial ; Endothelial Cells - cytology ; Endothelial Cells - drug effects ; Endothelial Cells - metabolism ; Female ; Fibronectin ; Fibronectins - deficiency ; Fibronectins - metabolism ; Gene Expression Profiling ; Homeodomain Proteins - metabolism ; Humans ; Laminin - pharmacology ; Male ; Mesenchymal Stem Cells - cytology ; Mesenchymal Stem Cells - drug effects ; Mesenchymal Stem Cells - metabolism ; Mesenchymal stromal cells ; Mesoderm - cytology ; Mice ; Mice, Inbred C57BL ; Nanog Homeobox Protein ; Neovascularization ; Neovascularization, Physiologic - drug effects ; Octamer Transcription Factor-3 - metabolism ; Platelet‐derived growth factor receptor ; Proteoglycans - pharmacology ; Receptors, Platelet-Derived Growth Factor - antagonists & inhibitors ; Receptors, Platelet-Derived Growth Factor - metabolism ; Signal Transduction - drug effects ; Smooth muscle ; Spheroids ; Spheroids, Cellular - cytology ; Spheroids, Cellular - drug effects ; Spheroids, Cellular - metabolism ; Stem cells ; Tissue-Specific Stem Cells ; Up-Regulation - drug effects ; Young Adult</subject><ispartof>Stem cells (Dayton, Ohio), 2014-03, Vol.32 (3), p.694-705</ispartof><rights>AlphaMed Press</rights><rights>AlphaMed Press.</rights><rights>2013 AlphaMed Press</rights><rights>AlphaMed Press 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4768-8a4cedc1926934c156995b4992d8429f0cd0f0be521372da5cf1e65ad9fdad743</citedby><cites>FETCH-LOGICAL-c4768-8a4cedc1926934c156995b4992d8429f0cd0f0be521372da5cf1e65ad9fdad743</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24022915$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ball, S. G.</creatorcontrib><creatorcontrib>Worthington, J. J.</creatorcontrib><creatorcontrib>Canfield, A. E.</creatorcontrib><creatorcontrib>Merry, C. L. R.</creatorcontrib><creatorcontrib>Kielty, C. M.</creatorcontrib><title>Mesenchymal Stromal Cells: Inhibiting PDGF Receptors or Depleting Fibronectin Induces Mesodermal Progenitors with Endothelial Potential</title><title>Stem cells (Dayton, Ohio)</title><addtitle>Stem Cells</addtitle><description>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. Stem Cells 2014;32:694–705</description><subject>Adult</subject><subject>Angiogenesis</subject><subject>Angiogenesis Inducing Agents - metabolism</subject><subject>Animals</subject><subject>Cell adhesion & migration</subject><subject>Collagen - pharmacology</subject><subject>Drug Combinations</subject><subject>Endothelial</subject><subject>Endothelial Cells - cytology</subject><subject>Endothelial Cells - drug effects</subject><subject>Endothelial Cells - metabolism</subject><subject>Female</subject><subject>Fibronectin</subject><subject>Fibronectins - deficiency</subject><subject>Fibronectins - metabolism</subject><subject>Gene Expression Profiling</subject><subject>Homeodomain Proteins - metabolism</subject><subject>Humans</subject><subject>Laminin - pharmacology</subject><subject>Male</subject><subject>Mesenchymal Stem Cells - cytology</subject><subject>Mesenchymal Stem Cells - drug effects</subject><subject>Mesenchymal Stem Cells - metabolism</subject><subject>Mesenchymal stromal cells</subject><subject>Mesoderm - cytology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Nanog Homeobox Protein</subject><subject>Neovascularization</subject><subject>Neovascularization, Physiologic - drug effects</subject><subject>Octamer Transcription Factor-3 - metabolism</subject><subject>Platelet‐derived growth factor receptor</subject><subject>Proteoglycans - pharmacology</subject><subject>Receptors, Platelet-Derived Growth Factor - antagonists & inhibitors</subject><subject>Receptors, Platelet-Derived Growth Factor - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>Smooth muscle</subject><subject>Spheroids</subject><subject>Spheroids, Cellular - cytology</subject><subject>Spheroids, Cellular - drug effects</subject><subject>Spheroids, Cellular - metabolism</subject><subject>Stem cells</subject><subject>Tissue-Specific Stem Cells</subject><subject>Up-Regulation - drug effects</subject><subject>Young Adult</subject><issn>1066-5099</issn><issn>1549-4918</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><recordid>eNp1kc1u1DAQgCMEoj9w4AVQJC5wSGs7dmJzQELb3VKpFRUtZ8uxJxtXib3YCdU-QV8bZ7dUgMRpxppvPo89WfYGoxOMEDmNIwwnmJX8WXaIGRUFFZg_TzmqqoIhIQ6yoxjvEMKUcf4yOyAUESIwO8weriCC0912UH1-MwY_xwX0ffyYX7jONna0bp1fn52v8m-gYTP6EHMf8jPY9LCrrWwTvAOdDqnFTBpinqzeQJhl18Gvwdld370du3zpjB876O1c9CO4MWWvshet6iO8fozH2ffV8nbxpbj8en6x-HxZaFpXvOCKajAaC1KJkmrMKiFYQ4UghlMiWqQNalEDjOCyJkYx3WKomDKiNcrUtDzOPu29m6kZkindHlQvN8EOKmylV1b-XXG2k2v_U9KyrlFdJcH7R0HwPyaIoxxs1OnDlAM_RYkZYiUllIuEvvsHvfNTcOl5EqeRS05ZhRP1YU_p4GMM0D4Ng5Gc1yvn9cp5vYl9--f0T-TvfSbgdA_c2x62_zfJm9vl1U75C-JdssQ</recordid><startdate>201403</startdate><enddate>201403</enddate><creator>Ball, S. G.</creator><creator>Worthington, J. J.</creator><creator>Canfield, A. E.</creator><creator>Merry, C. L. R.</creator><creator>Kielty, C. M.</creator><general>Oxford University Press</general><general>BlackWell Publishing Ltd</general><scope>24P</scope><scope>WIN</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>201403</creationdate><title>Mesenchymal Stromal Cells: Inhibiting PDGF Receptors or Depleting Fibronectin Induces Mesodermal Progenitors with Endothelial Potential</title><author>Ball, S. G. ; Worthington, J. J. ; Canfield, A. E. ; Merry, C. L. R. ; Kielty, C. 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G.</au><au>Worthington, J. J.</au><au>Canfield, A. E.</au><au>Merry, C. L. R.</au><au>Kielty, C. M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mesenchymal Stromal Cells: Inhibiting PDGF Receptors or Depleting Fibronectin Induces Mesodermal Progenitors with Endothelial Potential</atitle><jtitle>Stem cells (Dayton, Ohio)</jtitle><addtitle>Stem Cells</addtitle><date>2014-03</date><risdate>2014</risdate><volume>32</volume><issue>3</issue><spage>694</spage><epage>705</epage><pages>694-705</pages><issn>1066-5099</issn><eissn>1549-4918</eissn><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. Stem Cells 2014;32:694–705</abstract><cop>United States</cop><pub>Oxford University Press</pub><pmid>24022915</pmid><doi>10.1002/stem.1538</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Oxford University Press Journals All Titles (1996-Current); EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Adult Angiogenesis Angiogenesis Inducing Agents - metabolism Animals Cell adhesion & migration Collagen - pharmacology Drug Combinations Endothelial Endothelial Cells - cytology Endothelial Cells - drug effects Endothelial Cells - metabolism Female Fibronectin Fibronectins - deficiency Fibronectins - metabolism Gene Expression Profiling Homeodomain Proteins - metabolism Humans Laminin - pharmacology Male Mesenchymal Stem Cells - cytology Mesenchymal Stem Cells - drug effects Mesenchymal Stem Cells - metabolism Mesenchymal stromal cells Mesoderm - cytology Mice Mice, Inbred C57BL Nanog Homeobox Protein Neovascularization Neovascularization, Physiologic - drug effects Octamer Transcription Factor-3 - metabolism Platelet‐derived growth factor receptor Proteoglycans - pharmacology Receptors, Platelet-Derived Growth Factor - antagonists & inhibitors Receptors, Platelet-Derived Growth Factor - metabolism Signal Transduction - drug effects Smooth muscle Spheroids Spheroids, Cellular - cytology Spheroids, Cellular - drug effects Spheroids, Cellular - metabolism Stem cells Tissue-Specific Stem Cells Up-Regulation - drug effects Young Adult |
| title | Mesenchymal Stromal Cells: Inhibiting PDGF Receptors or Depleting Fibronectin Induces Mesodermal Progenitors with Endothelial Potential |
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