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Type IV Collagen Induces Podocytic Features in Bone Marrow Stromal Stem Cells In Vitro

Julie Perry^*, Stephanie Tam^*, Keqin Zheng^*, Yoshikazu Sado, Howard Dobson, Barbara Jefferson, Robert Jacobs and Paul S. Thorner^*,||

^* Division of Pathology, Hospital for Sick Children, Toronto, Ontario, Canada; Division of Immunology, Shigei Medical Research Institute, Okayama, Japan; Departments of; Clinical Studies; Pathobiology, University of Guelph, Guelph, Ontario, Canada; and ^|| Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

Address correspondence to: Dr. Paul Scott Thorner, Division of Pathology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. Phone: 416-813-5108; Fax: 416-813-5974; E-mail: thorner{at}sickkids.on.ca

Received for publication June 10, 2005. Accepted for publication September 28, 2005.

Bone marrow–derived stromal stem cells (BMSC) can differentiate along a variety of mesenchymal lines, including mesangial cells. For determining whether BMSC can be induced to differentiate along podocytic lines in vitro, canine BMSC were cultured on plastic, type I collagen, and NC1 hexamers of type IV collagen from normal and Alport canine glomerular basement membrane. Results were compared with a mouse podocyte cell line. In the case of the podocyte line, differentiation occurred on all three matrices as indicated by the expression of synaptopodin and CD2-associated protein (CD2AP) and organization of myosin heavy chain IIA into a linear pattern. BMSC proliferated equally well on all matrices, but cells that were grown on type IV collagen NC1 hexamers became larger and stellate. Evidence for podocytic differentiation occurred on all three collagen matrices as indicated by the redistribution of myosin IIA to a linear pattern and expression of synaptopodin, CD2AP, and -actinin. A punctate distribution of CD2AP was seen only in cells that were grown on normal and Alport glomerular basement membrane NC1 hexamers. Differentiated podocytes expressed the 1, 2, and 5 chains of type IV collagen but at higher levels in cells that were grown on NC1 hexamers. Similar results were obtained in BMSC for the 1 and 2 chains only. The 3, 4, and 6 chains were never detected in the podocyte line or BMSC. These results indicate that BMSC undergo a degree of podocytic differentiation in vitro and greater when grown on type IV collagen NC1 hexamers than type I collagen. Alport and normal NC1 hexamers seem equally permissive to BMSC growth and differentiation, suggesting that these processes are not influenced specifically by the 3/4/5 network. BMSC may be useful in the development of stem cell–based reconstitution of glomeruli that are damaged by disease and for gene therapy of genetic glomerular diseases such as Alport syndrome.

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