Zell-basierte Ansätze zur Therapie der renalen Fibrose

Almost all progressive renal diseases lead to chronic kidney disease (CKD) and development of renal fibrosis. With a prevalence of more than 10% worldwide new therapeutic options are urgently needed. Today's only option for patients with end stage renal disease (ESRD) is renal replacement therapy (dialysis and kidney transplantation). Mesenchymal stem cell (MSC) transplantation could represent such a new therapy since it has the potential for organ repair. Nevertheless, some factors might lessen the regenerative potential of MSCs, e.g. donor age or systemic disease. In addition, first reports showed both antifibrotic as well as profibrotic effects after MSC therapy in different organs. In the present study the effect of bone marrow MSC transplantation into rats with 5/6 nephrectomy (remnant kidney RK) was investigated. Repeated MSC applications failed to improve renal function or kidney fibrosis. Next we analyzed the effects of CKD on bone marrow MSC function. Bone marrow MSCs were isolated from CKD rats (remnant kidney (CKD-RK-MSC) and adenine induced nephropathy (CKD-AD-MSC)) and compared to healthy MSC. We found signs of premature senescence in vitro: reduced proliferation capacity, spontaneous adipogenesis and accummulation of actin stress fibers and senescence-associated-beta-galactosidase. The in vivo functionality of CKD-MSCs was tested in rats with acute anti-Thy1.1-nephritis, where healthy MSCs have been shown to be beneficial. Rats received healthy MSCs, CKD-RK-MSC, CKD-AD-MSC or medium by injection into the left renal artery. Kidneys receiving healthy MSCs exhibited accelerated healing of glomerular lesions, whereas CKD-RK-MSC or CKD-AD-MSC or medium exerted no benefit. Another histological analysis showed that CKD can also influence a newly identified intrarenal cell population, which might have progenitor qualities. Taken together this study shows that CKD can influence the phenotype and function of bone marrow MSC and intrarenal cells. CKD-MSC show signs of premature senescence which might account ...