Stem Cell Biology Department, ICMR-National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai, 400 012, India.
Stem Cell Res Ther. 2022 Feb 5;13(1):60. doi: 10.1186/s13287-022-02703-8.
True identity and specific set of markers to enrich endometrial stem cells still remains elusive. Present study was undertaken to further substantiate that very small embryonic-like stem cells (VSELs) are the true and elusive stem cells in adult mice endometrium.
This was achieved by undertaking three sets of experiments. Firstly, SSEA-1+ and Oct-4 + positive VSELs, sorted from GFP mice, were transplanted into the uterine horns of wild-type Swiss mice and GFP uptake was studied within the same estrus cycle. Secondly, uterine lumen was scratched surgically and OCT-4 expressing stem/progenitor cells were studied at the site of injury after 24-72 h. Thirdly, OCT-4 expression was studied in the endometrium and myometrium of adult mice after neonatal exposure to estradiol (20 µg/pup/day on days 5-7 after birth).
GFP + ve VSELs expressing SSEA-1 and Oct-4 engrafted and differentiated into the epithelial cells lining the lumen as well as the glands during the estrus stage when maximum remodeling occurs. Mechanical scratching activated tissue-resident, nuclear OCT-4 positive VSELs and slightly bigger 'progenitors' endometrial stem cells (EnSCs, cytoplasmic OCT-4) which underwent clonal expansion and further differentiated into luminal and glandular epithelial cells. Neonatal exposure to endocrine disruption resulted in increased numbers of OCT-4 positive VSELs/EnSCs in adult endometrium.
Results support the presence of functionally active VSELs in adult endometrium. VSELs self-renew and give rise to EnSCs that further differentiate into epithelial cells under normal physiological conditions. Also, VSELs are vulnerable to endocrine insults. To conclude VSELs are true and elusive uterine stem cells that maintain life-long uterine homeostasis and their dysregulation may result in various pathologies.
子宫内膜干细胞的确切身份和特定标志物仍难以确定。本研究旨在进一步证实，非常小的胚胎样干细胞（VSELs）是成年小鼠子宫内膜中真正且难以捉摸的干细胞。
通过进行三组实验来实现这一目标。首先，从 GFP 小鼠中分离出 SSEA-1+和 Oct-4+阳性的 VSELs，并将其移植到野生型瑞士小鼠的子宫角中，在同一发情周期内研究 GFP 的摄取情况。其次，通过手术刮伤子宫腔，并在 24-72 小时后研究损伤部位表达 OCT-4 的干细胞/祖细胞。第三，在新生鼠暴露于雌二醇后（出生后第 5-7 天每天每只幼鼠 20µg），研究成年小鼠子宫内膜和子宫肌层中的 OCT-4 表达。
GFP+ve VSELs 表达 SSEA-1 和 Oct-4，在发情期时，当发生最大重塑时，它们可以植入并分化为腔衬上皮细胞和腺体。机械刮擦激活了组织驻留的、核 OCT-4 阳性的 VSELs 和稍大的“祖细胞”子宫内膜干细胞（EnSCs，细胞质 OCT-4），它们经历克隆扩增并进一步分化为腔上皮细胞和腺体上皮细胞。新生鼠暴露于内分泌干扰物会导致成年子宫内膜中 OCT-4 阳性 VSELs/EnSCs 的数量增加。
结果支持成年子宫内膜中存在功能活跃的 VSELs。VSELs 自我更新，并在正常生理条件下产生 EnSCs，进一步分化为上皮细胞。此外，VSELs 易受内分泌干扰。综上所述，VSELs 是真正且难以捉摸的子宫干细胞，它们维持着子宫的终身内稳态，其失调可能导致各种病理。
