OSR1 and SIX2 Drive Divergent Transcriptional Programs in Human Kidney Cells: Implications for Regeneration and Tumorigenesis\

During human nephrogenesis, nephron progenitor cells generate approximately one million nephrons. We investigated the effects of ectopic expression of OSR1 and SIX2, both individually and in combination, in adult human kidney cells. OSR1 and SIX2 induced distinct reprogramming programs with differential functional outcomes. SIX2 overexpression maintained epithelial morphology while significantly enhancing proliferation and clonogenic efficiency. Transcriptionally, SIX2 established epithelialization and cell cycle networks, downregulating proximal tubule markers, while upregulating distal nephron markers and proliferation genes. In vivo, SIX2-expressing cells formed organized tubular structures with distinct luminal architecture. In contrast, OSR1 overexpression induced morphological changes and activated developmental morphogenetic pathways but did not enhance proliferation and showed minimal tubulogenic capacity. RNA sequencing analysis revealed coordinated changes in nephron segment-specific markers and activation of distinct transcriptional programs.\