Human mesenchymal stem cells inhibit endothelial proliferation and angiogenesis via cell-cell contact through modulation of the VE-Cadherin/β-catenin signaling pathway.
Over the past 10 years, a great deal has been learned about the fundamental biology and therapeutic application of bone marrow-derived human mesenchymal stem cells (MSCs). Intravenous administration of these cells is the preferred route for therapeutic delivery of MSCs. Vascular endothelial cells (ECs) are the first cell type that MSCs encounter following IV administration. However, little is known about the biological consequences of interactions between MSCs and ECs, and if any therapeutic benefit results from this interaction. We show that MSCs exert potent stabilizing effects on ECs using an in vitro coculture system. Such effects include decreased EC proliferation and the reduction of EC vascular network formation in matrigel. Interestingly, these effects appear to require EC-MSC contact and result in enhanced colocalization of VE-Cadherin and β-catenin at the cell membrane. Disruption of the VE-Cadherin/β-catenin interaction abrogates the observed effects. As a functional in vivo correlate, we show that intravenously administered MSCs strongly inhibit angiogenesis in a matrigel plug assay. Taken together, these results identify a novel mechanism of action of MSCs that involves a contact-dependent EC interaction. These findings are relevant to intravenous use of MSCs and provide insight into further optimizing therapeutic strategies involving MSCs.
Blood Systems Research Institute, San Francisco, California 94118, USA.
Tyler
T
Menge
Michael
M
Gerber
Kathryn
K
Wataha
William
W
Reid
Sushovan
S
Guha
Charles S
CS
Cox
Pramod
P
Dash
Marvin S
MS
Reitz
Aarif Y
AY
Khakoo
Shibani
S
Pati
D022005:Adherens Junctions / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism*; D002450:Cell Communication; D049109:Cell Proliferation; D018920:Coculture Techniques; D003094:Collagen; D004338:Drug Combinations; D059585:G1 Phase Cell Cycle Checkpoints; D061307:Human Umbilical Vein Endothelial Cells / Q000502:physiology*; D006801:Humans; D007797:Laminin; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D018919:Neovascularization, Physiologic; D011509:Proteoglycans; D060449:Wnt Signaling Pathway; D060509:Wnt3A Protein / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D003094:Collagen; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D060509:Wnt3A Protein; D051176:beta Catenin; D000099152:Cadherin 5; C555510:WNT3A protein, human; C059485:matrigel