Potencial terapêutico de células tronco pluripotentes induzidas e células progenitoras renais na insuficiência renal crônica experimental

Abstract

Chronic Kideny Disease (CKD) is characterized by progressive and irreversible loss of renal function and its treatment leads to a significant health public expendure on the maintenance of patients in dialysis. Therapy with stem cells, especially, renal progenitor cells (RPCs) and human induced pluripotent stem cells (hiPSCs), represents a promising strategy for CKD. Objectives: To genetically modify cells from human peripheral blood, in order to reprogram them into hiPSC; to treat hiPSC with mitomycin C (MMC), to reduce their tumorigenic potential; to induce the differentiation of hiPSCs into RPCs; and to evaluate the effects of both cells in the treatment of experimental CKD. Material and Method: Reprogramming of peripheral blood cells was carried out by using epissomal vectors. The hiPSCs generated were then differentiated into RPCs, through a nephrogenic cocktail induction in culture, and both cells were characterized by immunofluorescence and qRT-PCR. The MMC-treated hiPSCs and the RPCs were transplanted into a 5/6 CKD animal model. The treated groups were compared to controls, and evaluated 45 days after cell transplantation, through histological, immunohistochemical and renal function analysis. Results: The hiPSCs were generated from peripheral blood cells and then differentiated into RPCs, which showed specific markers of renal progenitor cells (PAX2, SIX2, SALL1, WT1) and podocytes (SYNPO and NPHS1). After cell transplantation, both cells were effective in preventing CKD-associated body weight loss. Creatinine clearance was preserved and the number of macrophages was reduced in the renal tissue of the hiPSCs treated group, when compared to control group. The positive staining for α-smooth muscle actin was attenuated in both treated groups. Likewise, both cells reduced tubulointerstitial damage and glomerulosclerosis in the renal tissue of treated animals. Conclusion: Cell therapy with hiPSCs and RPCs represents a promising strategy for CKD treatment.