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Autocrine Regulation of Human Preadipocyte Migration by Plasminogen Activator Inhibitor-1

Wyeth Research, Radnor, Pennsylvania 19087; and Department of Surgery, Downstate Medical Center (J.G.K.), Brooklyn, New York 11203

Address all correspondence and requests for reprints to: Dr. David L. Crandall, Wyeth Research, P.O. Box 42528, Philadelphia, Pennsylvania 19101. E-mail: crandad{at}war.wyeth.com

One of the initial stages of adipogenesis is migration of preadipocytes of mesenchymal origin into cell clusters to form primitive fat organs. The serine protease inhibitor plasminogen activator inhibitor-1 (PAI-1) is synthesized and released from human adipose tissue ex vivo and regulates smooth muscle and endothelial cell migration in vitro, but its role in adipose tissue is not known. We investigated the role of PAI-1 in cultures of human preadipocytes from men and women of various ages and body mass indexes. Human preadipocytes expressed the messenger ribonucleic acid for PAI-1 and released significant quantities of PAI-1 protein into the medium. As PAI-1 regulates motility through the interaction of vitronectin with its receptor, the integrin _Vß₃, we identified this receptor in human preadipocytes. Flow cytometric analysis indicated that human preadipocytes express the vitronectin receptor _Vß₃ in a similar pattern as human umbilical vein endothelial cells. Functional studies indicated that active, but not latent, PAI-1 inhibited preadipocyte attachment to vitronectin with an IC₅₀ of 13.3 nmol/L, and preincubation of vitronectin-coated Transwells with active PAI-1 prevented preadipocyte migration. Vitronectin was identified in homogenates of the stromal-vascular fraction of human adipose tissue, but was absent from human adipocytes and cultured preadipocytes. These data indicate that human preadipocyte migration is regulated through the endogenous expression of PAI-1 and _Vß₃ integrin, a novel autocrine mechanism for potentially regulating cell cluster formation in adipogenesis.

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