Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China.
Laboratory for Aging and Stem Cell Research, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
PLoS Genet. 2021 Jul 6;17(7):e1009649. doi: 10.1371/journal.pgen.1009649. eCollection 2021 Jul.
The differentiation efficiency of adult stem cells undergoes a significant decline in aged animals, which is closely related to the decline in organ function and age-associated diseases. However, the underlying mechanisms that ultimately lead to this observed decline of the differentiation efficiency of stem cells remain largely unclear. This study investigated Drosophila midguts and identified an obvious upregulation of caudal (cad), which encodes a homeobox transcription factor. This factor is traditionally known as a central regulator of embryonic anterior-posterior body axis patterning. This study reports that depletion of cad in intestinal stem/progenitor cells promotes quiescent intestinal stem cells (ISCs) to become activate and produce enterocytes in the midgut under normal gut homeostasis conditions. However, overexpression of cad results in the failure of ISC differentiation and intestinal epithelial regeneration after injury. Moreover, this study suggests that cad prevents intestinal stem/progenitor cell differentiation by modulating the Janus kinase/signal transducers and activators of the transcription pathway and Sox21a-GATAe signaling cascade. Importantly, the reduction of cad expression in intestinal stem/progenitor cells restrained age-associated gut hyperplasia in Drosophila. This study identified a function of the homeobox gene cad in the modulation of adult stem cell differentiation and suggested a potential gene target for the treatment of age-related diseases induced by age-related stem cell dysfunction.
成体干细胞的分化效率在老年动物中显著下降，这与器官功能下降和与年龄相关的疾病密切相关。然而，导致干细胞分化效率观察到的下降的潜在机制在很大程度上仍不清楚。本研究调查了果蝇的中肠，发现尾基因（cad）明显上调，该基因编码一个同源盒转录因子。该因子传统上被认为是胚胎前后体轴模式形成的中央调节因子。本研究报告称，在正常肠道稳态条件下，cad 在肠干细胞/祖细胞中的耗竭会促进静止的肠干细胞（ISCs）激活并产生中肠的肠细胞。然而，cad 的过表达导致 ISC 分化失败和损伤后肠道上皮再生。此外，本研究表明，cad 通过调节 Janus 激酶/信号转导和转录激活因子和 Sox21a-GATAe 信号级联来阻止肠干细胞/祖细胞的分化。重要的是，肠干细胞/祖细胞中 cad 表达的减少抑制了果蝇与年龄相关的肠道过度增生。本研究鉴定了同源盒基因 cad 在调节成体干细胞分化中的作用，并为治疗与年龄相关的干细胞功能障碍引起的与年龄相关的疾病提供了一个潜在的基因靶点。
