Highlights d Growing human renal epithelial cells in 3D restores epithelial identity lost in 2D d These 3D nephrospheres (nSPHs) organize into renal tubular structures in vivo d By doing so, nSPHs engraft long term and improve renal function in CKD mice d In vivo repair involves anti-fibrotic effects and possible addition of nephron segments

Apoptosis culminates in the activation of caspase-3, which plays an important role in implementing the cell death program. Here, we reveal a non-apoptotic role of caspase-3 as a key regulator of cell proliferation and organ size. Caspase-3 is specifically activated in the proliferating cells of the sebaceous gland, but does not instruct cell elimination. Deletion or chemical inhibition of caspase-3 diminishes cell proliferation, decreases cell number and reduces sebaceous gland size in vivo. Exploring the underlying mechanism, we demonstrate that α-catenin is cleaved by caspase-3, thus facilitating the activation and nuclear translocation of yes-associated protein (YAP), a vital regulator of organ size. Accordingly, activation of caspase-3 leads to YAP-dependent organ size augmentation. Finally, we show that X-linked inhibitor of apoptosis protein (XIAP) serves as an endogenous feedback antagonist for the caspase-3/YAP signaling module. Taken together, we report here a molecular mechanism wherein the apoptotic machinery is refocused to regulate cell proliferation and orchestrate organ size.

Stem cells (SCs) play a pivotal role in fueling homeostasis and regeneration. While much focus has been given to self-renewal and differentiation pathways regulating SC fate, little is known regarding the specific mechanisms utilized for their elimination. Here, we report that the pro-apoptotic protein ARTS (a Septin4 isoform) is highly expressed in cells comprising the intestinal SC niche and that its deletion protects Lgr5+ and Paneth cells from undergoing apoptotic cell death. As a result, the Sept4/ARTS−/− crypt displays augmented proliferation and, in culture, generates massive cystic-like organoids due to enhanced Wnt/β-catenin signaling. Importantly, Sept4/ARTS−/− mice exhibit resistance against intestinal damage in a manner dependent upon Lgr5+ SCs. Finally, we show that ARTS interacts with XIAP in intestinal crypt cells and that deletion of XIAP can abrogate Sept4/ARTS−/−-dependent phenotypes. Our results indicate that intestinal SCs utilize specific apoptotic proteins for their elimination, representing a unique target for regenerative medicine.

Highlights d Deletion of Caspase-9 in hair follicle stem cells delays the apoptotic cascade d Apoptotic hair follicle stem cells release Wnt3 and instruct proliferation d A caspase-3/Dusp8/p38 module is responsible for Wnt3 induction in apoptotic cells d Casp-9 fl/fl mice display accelerated wound repair and de novo hair follicle neogenesis.

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