Identification of Label-Retaining Perivascular Cells in a Mouse Model of Endometrial Decidualization, Breakdown, and Repair1

Abstract

The human endometrium is incredibly dynamic, undergoing monthly cycles of growth and regression during a woman's reproductive life. Endometrial repair at the cessation of menstruation is critical for reestablishment of a functional endometrium receptive for embryo implantation; however, little is understood about the mechanisms behind this rapid and highly efficient process. This study utilized a functional mouse model of endometrial breakdown and repair to assess changes in endometrial vasculature that accompany these dynamic processes. Given that adult endometrial stem/progenitor cells identified in human and mouse endometrium are likely contributors to the remarkable regenerative capacity of endometrium, we also assessed label-retaining cells (LRC) as candidate stromal stem/progenitor cells and examined their relationship with endometrial vasculature. Newborn mouse pups were pulse-labeled with bromodeoxyuridine (BrdU) and chased for 5 wk before decidualization, endometrial breakdown, and repair were induced by hormonal manipulation. Mean vessel density did not change significantly throughout breakdown and repair; however, significantly elevated endothelial cell proliferation was observed in decidual tissue. Stromal LRC were identified throughout breakdown and repair, with significantly fewer observed during endometrial repair than before decidualization. A significantly higher percentage of LRC were associated with vasculature during repair than before decidualization, and a proportion were undergoing proliferation, indicative of their functional capacity. This study is the first to examine the endometrial vasculature and candidate stromal stem/progenitor cells in a functional mouse model of endometrial breakdown and repair and provides functional evidence suggesting that perivascular LRC may contribute to endometrial stromal expansion during the extensive remodeling associated with this process.

Label-Retaining Stromal Cells in Mouse Endometrium Awaken for Expansion and Repair After Parturition

“…A functional response of endometrial epithelial LRCs upon endometrial repair was also observed in an induced decidualization, breakdown, and repair mouse model [25,26]. Nonetheless, the role of endometrial LRCs in the remodeling processes during pregnancy and postpartum remains largely unknown.…”

“…In an artificial mouse endometrial repair model, LRSC near vasculatures proliferate upon tissue breakdown [25]. On the other hand, LRCs enriched at the distal oviduct and the endocervical transition zone did not respond to endometrial regeneration events [37].…”

“…Several evidences suggest that endometrial repair can trigger recruitment of endometrial stem/progenitor cells from the bone marrow through vasculature [25,38]. Hence, we examined three markers (CD44, CD90, and Sca-1), which have been reported to be expressed on mesenchymal stem-like cells in the female reproductive system, including the human endometrium [39], myometrium [14], menstrual blood [40], and mammary glands [41].…”

Mesenchymal-to-Epithelial Transition Contributes to Endometrial Regeneration Following Natural and Artificial Decidualization

“…Furthermore, label-retaining techniques have been used to identify slow-cycling, quiescent epithelial, and stromal cells in the female reproductive tract as potential stem cells [26,27,46]. Pericytes in both murine [47] and human [48] endometrium are proposed as a source of mesenchymal stem/ progenitor cells. Several of the aforementioned studies indicate the likelihood that stem/progenitor cells exist at the stromal-myometrial border.…”

The Endometrium as a Source of Mesenchymal Stem Cells for Regenerative Medicine1

“…The LRCs were located in the uterine stroma, and 0.32% of them expressed the stem cell marker c-KIT, while 0.19% of them expressed the pluripotency marker POU5F1 (OCT-4) [35]. Other studies investigated the LRCs in the context of their proliferation potential under the influence of estrogen and their contribution to endometrial decidualization, breakdown, and repair [37,38]. The quiescent nature of LRCs and their proliferation potential identified them as potential stem/progenitor cells in the endometrium.…”