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

¹ Monash Immunology and Stem Cell Laboratories (MISCL), Monash University, Melbourne, Victoria, Australia
² Monash Immunology and Stem Cell Laboratories (MISCL), Monash University, Melbourne, Victoria, Australia; Department of Anatomy and Cell Biology, Monash University, Victoria, Australia
³ Department of Anatomy and Cell Biology, Monash University, Victoria, Australia

^* To whom correspondence should be addressed. E-mail: sharon.ricardo{at}med.monash.edu.au.

	Abstract

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 MAPK and TGF-1/Smad2 signaling was found to protect BM-derived PTC endothelial cells and inhibit the number of BM-derived vWF(+)/EGFP(+)/-SMA(+) cells, EGFP(+)/-SMA(+) cells and total -SMA(+) cells in ADR-injected mice. Inhibition of the p38 MAPK and TGF-1/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.