State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China.
Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin, China.
Aging Cell. 2021 Feb;20(2):e13304. doi: 10.1111/acel.13304. Epub 2021 Jan 14.
Stem cell transplantation has been generally considered as promising therapeutics in preserving or recovering functions of lost, damaged, or aging tissues. Transplantation of primordial germ cells (PGCs) or oogonia stem cells (OSCs) can reconstitute ovarian functions that yet sustain for only short period of time, limiting potential application of stem cells in preservation of fertility and endocrine function. Here, we show that mTOR inhibition by INK128 extends the follicular and endocrine functions of the reconstituted ovaries in aging and premature aging mice following transplantation of PGCs/OSCs. Follicular development and endocrine functions of the reconstituted ovaries by transplanting PGCs into kidney capsule of the recipient mice were maintained by INK128 treatment for more than 12 weeks, in contrast to the controls for only about 4 weeks without receiving the mTOR inhibitors. Comparatively, rapamycin also can prolong the ovarian functions but for limited time. Furthermore, our data reveal that INK128 promotes mitochondrial function in addition to its known function in suppression of immune response and inflammation. Taken together, germline stem cell transplantation in combination with mTOR inhibition by INK128 improves and extends the reconstituted ovarian and endocrine functions in reproductive aging and premature aging mice.
干细胞移植被普遍认为是一种有前途的治疗方法，可以保留或恢复失去、受损或衰老组织的功能。原始生殖细胞（PGCs）或卵原干细胞（OSCs）的移植可以重建卵巢功能，但只能维持很短的时间，限制了干细胞在保留生育和内分泌功能方面的潜在应用。在这里，我们表明，INK128 通过抑制 mTOR 延长了 PGCs/OSCs 移植后衰老和早衰小鼠重建卵巢的卵泡和内分泌功能。INK128 处理可维持通过将 PGCs 移植到受体小鼠肾囊中来重建卵巢的卵泡发育和内分泌功能超过 12 周，而对照组没有接受 mTOR 抑制剂则只能维持约 4 周。相比之下，雷帕霉素也可以延长卵巢功能，但时间有限。此外，我们的数据表明，INK128 除了已知的抑制免疫反应和炎症的功能外，还可以促进线粒体功能。总之，生殖干细胞移植与 INK128 抑制 mTOR 相结合，可改善和延长生殖衰老和早衰小鼠重建卵巢和内分泌功能。
