Concentration-dependent inhibition of angiogenesis by mesenchymal stem cells.
Mesenchymal stem cells (MSCs), which potentially transdifferentiate into multiple cell types, are increasingly reported to be beneficial in models of organ system injury. However, the molecular mechanisms underlying interactions between MSCs and host cells, in particular endothelial cells (ECs), remain unclear. We show here in a matrigel angiogenesis assay that MSCs are capable of inhibiting capillary growth. After addition of MSCs to EC-derived capillaries in matrigel at EC:MSC ratio of 1:1, MSCs migrated toward the capillaries, intercalated between ECs, established Cx43-based intercellular gap junctional communication (GJC) with ECs, and increased production of reactive oxygen species (ROS). These events led to EC apoptosis and capillary degeneration. In an in vivo tumor model, direct MSC inoculation into subcutaneous melanomas induced apoptosis and abrogated tumor growth. Thus, our findings show for the first time that at high numbers, MSCs are potentially cytotoxic and that when injected locally in tumor tissue they might be effective antiangiogenesis agents suitable for cancer therapy.
Otsu
Keishi
K
Lung Biology Laboratory, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Das
Shonit
S
Houser
Sandra D
SD
Quadri
Sadiqa K
SK
Bhattacharya
Sunita
S
Bhattacharya
Jahar
J
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002450:Cell Communication; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D017629:Gap Junctions / Q000502:physiology; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D007797:Laminin / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000378:metabolism; D008297:Male; D008546:Melanoma, Experimental / Q000098:blood supply*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000628:therapy*; D011509:Proteoglycans / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D023822:Tissue Engineering
D020533:Angiogenesis Inhibitors; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D017382:Reactive Oxygen Species; C059485:matrigel; D003094:Collagen