Apoptotic cells represent a dynamic stem cell niche governing proliferation and tissue regeneration
Apoptotic cells represent a dynamic stem cell niche governing proliferation and tissue regeneration
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DOI：
10.1016/j.devcel.2021.06.008
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发表时间：
2021-07-12
影响因子：
11.8
通讯作者：
Fuchs, Yaron
中科院分区：
文献类型：
--
作者：
Ankawa, Roi;Goldberger, Nitzan;Fuchs, Yaron
干细胞在体内平衡和修复中起着关键作用。虽然许多研究都集中在SC自我更新和分化，很少有人知道有关的分子机制调节SC消除和补偿损失。在这里，我们报告说，在毛囊干细胞（HFSCs）中的Caspase-9缺失减弱了凋亡级联反应，导致显着的时间延迟。令人惊讶的是，缺乏Casp 9的HFSC积累高水平的裂解的半胱天冬酶-3，并且由于必需的半胱天冬酶-3/半胱天冬酶-9前馈环而被不适当地清除。这些SC保持在促分裂接合状态，通过持续释放Wnt 3和指示增殖而充当促有丝分裂信号中心。研究潜在的机制，我们揭示了一个caspase-3/Dusp 8/p38模块负责Wnt 3诱导，这在正常和Casp 9缺失的HFSC中都起作用。值得注意的是，Casp 9缺失的小鼠显示出加速的伤口修复和从头毛囊再生。综上所述，我们证明凋亡细胞代表了一个动态的SC生态位，从中发出的信号驱动SC增殖和组织再生
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