Park Joung-Sun, Jeon Ho-Jun, Pyo Jung-Hoon, Kim Young-Shin, Yoo Mi-Ae
Department of Molecular Biology, Pusan National University, Busan 46241, Republic of Korea.
Aging (Albany NY). 2018 Mar 7;10(3):322-338. doi: 10.18632/aging.101390.
Stem cell dysfunction is closely linked to tissue and organismal aging and age-related diseases, and heavily influenced by the niche cells' environment. The DNA damage response (DDR) is a key pathway for tissue degeneration and organismal aging; however, the precise protective role of DDR in stem cell/niche aging is unclear. The midgut is an excellent model to study the biology of stem cell/niche aging because of its easy genetic manipulation and its short lifespan. Here, we showed that deficiency of DDR in enterocytes (ECs) accelerates intestinal stem cell (ISC) aging. We generated flies with knockdown of , , , , , , and , which decrease the DDR system in ECs. EC-specific DDR depletion induced EC death, accelerated the aging of ISCs, as evidenced by ISC hyperproliferation, DNA damage accumulation, and increased centrosome amplification, and affected the adult fly's survival. Our data indicated a distinct effect of DDR depletion in stem or niche cells on tissue-resident stem cell proliferation. Our findings provide evidence of the essential role of DDR in protecting EC against ISC aging, thus providing a better understanding of the molecular mechanisms of stem cell/niche aging.
干细胞功能障碍与组织和机体衰老以及年龄相关疾病密切相关，并受到生态位细胞环境的严重影响。DNA损伤反应（DDR）是组织退化和机体衰老的关键途径；然而，DDR在干细胞/生态位衰老中的精确保护作用尚不清楚。中肠是研究干细胞/生态位衰老生物学的理想模型，因为它易于进行基因操作且寿命较短。在此，我们表明肠上皮细胞（ECs）中DDR的缺陷会加速肠道干细胞（ISC）衰老。我们构建了敲低、、、、、和的果蝇，这些基因会降低ECs中的DDR系统。EC特异性DDR缺失诱导EC死亡，加速ISC衰老，表现为ISC过度增殖、DNA损伤积累和中心体扩增增加，并影响成年果蝇的存活。我们的数据表明，干细胞或生态位细胞中DDR缺失对组织驻留干细胞增殖有明显影响。我们的研究结果提供了DDR在保护EC免受ISC衰老方面的重要作用的证据，从而更好地理解干细胞/生态位衰老的分子机制。
