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Nephron progenitor cell therapy to mitigate CKD following AKI would be a breakthrough discovery that aligns with the KUH mission of kidney repair and regeneration. Cell therapy represents a paradigm-shift in the treatment of tubular AKI, the most common cause of AKI, whose present management is supportive care due to the lack of FDA-approved treatments. Derived from human pluripotent stem cells (hPSCs), nephron progenitor cells (NPCs) may enhance adaptive repair that preserves kidney architecture while limiting maladaptive repair in which fibrosis permanently replaces nephrons. We have previously developed and validated a kidney organoid model of the AKI to CKD transition, predicated on tubular conversion from adaptive to maladaptive repair, which serves as a human testing platform for limiting CKD following AKI. Although nephron formation ceases by birth in humans, hPSC-derived NPCs are an unlimited cell source for either post-natal neonephrogenesis or for nephron repair after injury. Here we propose a high-risk/high-reward strategy using our organoid AKI to CKD model to determine whether NPC cell therapy causes i) preservation of pre-existing injured tubules, ii) integration into injured tubules, iii) formation of new nephrons, or any combination thereof. Towards future hypothesis-based research, the results of the proposed confocal microscopy, RNAseq profiling, and mesoscale discovery will be correlated to the degree of tubular preservation, integration, and neonephrogenesis to determine nephroprotective mechanisms by which NPC-based cell therapy may promote kidney repair and regeneration.
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