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TISSUE-SPECIFIC STEM CELLS

The Contribution of Bone Marrow-Derived Cells to the Development of Renal Interstitial Fibrosis

^aMonash Immunology and Stem Cell Laboratories, Monash University, Melbourne, Victoria, Australia;
^bDepartment of Anatomy and Cell Biology, Monash University, Victoria, Australia

Key Words. Bone marrow-derived progenitor cells • Myofibroblasts • Endothelial cells • p38 mitogen-activated protein kinase • Smad Renal fibrosis

Correspondence: Sharon D. Ricardo, Ph.D., Monash Immunology and Stem Cell Laboratories (MISCL), Monash University, Clayton, Victoria 3800, Australia. Telephone: 61 3 9905 0671; Fax: 61 3 9905 0680; e-mail: Sharon.ricardo{at}med.monash.edu.au

Received March 7, 2006; accepted for publication November 28, 2006.
First published online in STEM CELLS EXPRESS   December 14, 2006.



Recent evidence suggests that bone marrow (BM)-derived cells may integrate into the kidney, giving rise to functional renal cell types, including endothelial and epithelial cells and myofibroblasts. BM-derived cells can contribute to repair of the renal peritubular capillary (PTC) network following acute ischemic injury. However, the cell fate and regulation of BM-derived cells during the progression of chronic renal disease remains unclear. Using chimeric mice transplanted with enhanced green fluorescent protein (EGFP)-expressing BM, we demonstrate that the number of BM-derived myofibroblasts coincided with the development of fibrosis in a mouse adriamycin (ADR)-induced nephrosis model of chronic, progressive renal fibrosis. Four weeks after ADR injection, increased numbers of BM-derived myofibroblasts were observed in the interstitium of ADR-injected mice. Six weeks after ADR injection, more than 30% of renal -smooth muscle actin (+) (-SMA+) interstitial myofibroblasts were derived from the BM. In addition, BM-derived cells were observed to express the endothelial cell marker CD31 and the myofibroblast marker -SMA. Blockade of p38 mitogen-activated protein kinase (MAPK) and transforming growth factor (TGF)-β1/Smad2 signaling was found to protect BM-derived PTC endothelial cells and inhibit the number of BM-derived von Willebrand factor (vWF)(+)/EGFP(+)/-SMA(+) cells, EGFP(+)/-SMA(+) cells, and total -SMA(+) cells in ADR-injected mice. Inhibition of the p38 MAPK and TGF-β1/Smad signaling pathways enhanced PTC repair by decreasing endothelial-myofibroblast transformation, leading to structural and functional renal recovery and the attenuation of renal interstitial fibrosis. Investigation of the signaling pathways that regulate the differentiation and survival of BM-derived cells in a progressive disease setting is vital for the successful development of cell-based therapies for renal repair.