Kidney stem/progenitor cells as a potent source for kidney-targeted cell therapy

End stage kidney disease (ESKD) is the result of a permanent failure of the kidneys. Kidney failure is caused by the irreversible loss of nephrons, the structural and functional units of the kidney. Although the final patterned and segmented nephrons contain numerous functionally distinct cell types, lineage tracing showed that all these cell types are derived from a SIX2+ progenitor’s population at the kidney cap mesenchyme (CM). The expression of SIX2 is essential for self-renew to maintain the CM, and its cessation signals to the initiation of nephron commitment via a mesenchyme-to-epithelial transition. However, the SIX2+ kidney progenitors are exhausted in the mature kidney as human nephrogenesis ends at the 36th week of gestation. We have found a novel source of kidney stem/progenitor cells (nKSPCs) derived from urine of neonates born prematurely, when the SIX2+ progenitors were still present. nKSPCs express SIX2 and various other CM progenitor markers and they show high capacity to differentiate towards functional mature kidney epithelial cells. Additionally, our recent data show that nKSPCs have immunomodulatory capacity and can efficiently suppress T cells proliferation. Upon 6 hours of perfusion in normothermic machine perfusion (NMP), nKSPCs could be traced in a human kidney, which showed early reduced inflammatory response and re-activation of nephrogenesis genes, suggesting initiation of a regenerative process. We hypothesize that nKSPCs are the ideal source for kidney-targeted cell therapy, providing immunomodulation and regeneration to kidney tissue. We aim to elucidate, in vitro, the complete immunomodulatory profile of nKSPCs, and their engraftment/regenerative potential using co-culture methodologies. Moreover, we will use the innovative pre-clinical platform of NMP to assess ex-vivo the potential of nKSPCs to immunomodulate and regenerate human kidney allografts during preservation. Once successful, nKSPCs will represent a potent source of cells, which can be used for cell therapy as a new approach to treat kidney diseases and revolutionize kidney regenerative medicine.