Apoptotic cells represent a dynamic stem cell niche governing proliferation and tissue regeneration

Stem cells (SCs) play a key role in homeostasis and repair. While many studies have focused on SC selfrenewal and differentiation, little is known regarding the molecular mechanism regulating SC elimination and compensation upon loss. Here, we report that Caspase-9 deletion in hair follicle SCs (HFSCs) attenuates the apoptotic cascade, resulting in significant temporal delays. Surprisingly, Casp9-deficient HFSCs accumulate high levels of cleaved caspase-3 and are improperly cleared due to an essential caspase-3/caspase-9 feedforward loop. These SCs are retained in an apoptotic-engaged state, serving as mitogenic signaling centers by continuously releasing Wnt3 and instructing proliferation. Investigating the underlying mechanism, we reveal a caspase-3/Dusp8/p38 module responsible for Wnt3 induction, which operates in both normal and Casp9-deleted HFSCs. Notably, Casp9-deleted mice display accelerated wound repair and de novo hair follicle regeneration. Taken together, we demonstrate that apoptotic cells represent a dynamic SC niche, from which emanating signals drive SC proliferation and tissue regeneration

Automated summary

The study shows that deletion of Caspase-9 in hair follicle stem cells attenuates the apoptotic cascade, resulting in significant temporal delays. These Casp9-deficient stem cells accumulate high levels of cleaved caspase-3 and are improperly cleared due to a caspase-3/caspase-9 feedforward loop. The apoptotic cells represent a dynamic stem cell niche that drives stem cell proliferation and tissue regeneration by continuously releasing Wnt3.