Endometrial Injury Increases Side Population Cells in the Uterine Endometrium: A Decisive Role of Estrogen

Abstract

Normal endometrial growth is essential for embryonic implantation and maintenance of pregnancy. The uterine endometrium contains stem cells that are involved in tissue regeneration. Side population cells (SP cells) are an emerging cell population that may be responsible for the regeneration process of uterine endometrium. In this study, we investigated the changes in the distribution of SP cells using a mouse model of uterine endometrial injury that was induced by peritoneal injection of lipopolysaccharide (LPS). The uterine horns were collected 0, 6, 12, and 18 hours after LPS injection. ATP-binding cassette and sub-family G member 2 (Abcg2) is highly expressed on the cellular membrane of some stem and progenitor cells, and was used as a marker for SP cells. Immunohistochemistry demonstrated that Abcg2-positive cells were increased around the uterine endometrial glands from 6 to 12 h after LPS injection. The percentage of Abcg2-positive cells was calculated using flow cytometry. The percentage of stromal SP cells was significantly higher at 6 h after LPS injection, compared with the value before the injection (3.01 ± 0.41% vs. 1.63 ± 0.31%, P < 0.05). To evaluate the influence of ovarian hormones, we implanted pellets containing 17β-estradiol (0.1 mg), progesterone (10 mg), or a combination of 17β-estradiol and progesterone in the bilaterally ovariectomized mice. Ovariectomy abolished the increase in SP cells, which was restored by estradiol, but not by progesterone or the combination treatment. In conclusion, estrogen is required for the increase of SP cells, thereby leading to the regeneration of the uterine endometrium.

Effects of endometrial stem cell transplantation combined with estrogen in the repair of endometrial injury

“…Estrogen is able to increase the number of cells during endometrial injury and promote the regeneration of the uterine endometrium (23)(24)(25). In the present study, the level of E2 was significantly increased in the serum of rats with IUA compared with that in the controls, suggesting an effect of estrogen in the repair of intrauterine adhesions.…”

Endometrial scratching to improve pregnancy rate in couples with unexplained subfertility: A randomized controlled trial

“…The questions regarding the underlying mechanism of the procedure action remain unanswered, however some hypotheses have been made to explain its beneficial effect. It was hypothesized that the local injury to the endometrium in a cycle might induce proper decidualization for implantation competency . Li and Hao suggested that endometrial injury increases the expression of estradiol receptor in endometrial stroma causing changes in endometrial maturation .…”

Expression of SOX2, NANOG and OCT4 in a mouse model of lipopolysaccharide-induced acute uterine injury and intrauterine adhesions

“…Single or repeated biopsy of the thin endometrium induce an injury response that stimulates resident endometrial stem/progenitor cells to initiate a regenerative response and restore endometrial tissue homeostasis [2]. Human endometrial Side Population (SP) cells, a component of putative progenitor/stem cells, rapidly accumulated in mice endometrium during acute uterine injury induced by lipopolysaccharide (LPS) [8]. Though the acute inflammatory response may be beneficial to the endometrium, in IUA the inflammation is self-perpetuating and persists for a long period and can trigger abnormal endometrial functions to facilitate the formation of fibrosis and adhesion.…”