Contribution of bone marrow-derived cells to in situ engineered tissue capsules in a rat model of chronic kidney disease

Tissue engineered blood vessels (TEBVs) hold great promise for clinical use in patients with end stage renal disease (ESRD) requiring vascular access for hemodialysis. A promising way to make TEBVs is to exploit foreign body response (FBR) of polymeric rods used as templates. However, since the FBR predominantly involves bone marrow (BM) derived cells and ESRD coincides with impaired function of BM, it is important to assess the generation of TEBVs in conditions of renal failure. To this end, we implanted polymer rods in the subcutis of rats after BM-transplantation with OFF-labeled BM cells in a model of chronic kidney disease (CKD). At 3 weeks after implantation, rods were encapsulated by tissue capsule (TC) composed of collagen, myofibroblasts and macrophages. On average, 13% of CD68(+) macrophages were GFP(+), indicating BM origin. Macrophage-to-myofibroblasts differentiation appeared to play an important role in TC formation as 26% of SMA(+)/GFP(+) myofibroblasts co-expressed the macrophage marker CD68. Three weeks after rod implantation, the cellular response changed towards tissue repair, characterized by 40% increase in CD68(+)/CD163(+) repair associated macrophages and 95% increase in TGF beta and IL10 gene expression as compared to TCs harvested at 1 week. These results show that both BM derived and tissue resident cells, contribute to TC formation, whereas macrophages serve as precursors of myofibroblasts in mature TCs. Finally, the presence of CKD did not significantly alter the process of TC formation, which holds the potential to support our approach for future clinical use in ESRD patients.