Role of Stro1+/CD44+ stem cells in myometrial physiology and uterine remodeling during pregnancy†

Abstract

Regulation of myometrial functions during pregnancy has been considered the result of the integration of endocrine and mechanical signals. Nevertheless, uterine regeneration is poorly understood, and the cellular source within the gravid uterus is largely unexplored.In this study, we isolated and quantified the myometrial stem cells (MSC) population from pregnant female Eker rat uteri, by using Stro1/CD44 surface markers. We demonstrated that prior parity significantly increased the percentage of Stro1+/CD44+ MSC because of injured tissue response. Interestingly, we established that Stro1+/CD44+ MSC respond efficiently to physiological cues when they were treated in vitro under different dose-dependent pregnant rat serum.Previous studies reveal strong regulatory links between O2 availability and stem cell function. Based on these premises, cell proliferation assays showed that isolated Stro1+/CD44+ MSC possess a higher proliferative rate under hypoxic versus normoxic conditions. We also detected a total of 37 upregulated and 44 downregulated hypoxia-related genes, which were differentially expressed in Stro1+/CD44+ MSC, providing an alternative approach to infer into complex molecular mechanisms such as energy metabolism, inflammatory response, uterine expansion, and/or remodeling.Since these cells preferentially grow under low oxygen conditions, we propose that the increase of the rat uterus during pregnancy involves myometrial oxygen consumption, thereby enhancing MSC proliferation. Moreover, pregnancy-induced mechanical stretching results in hypoxic conditions, ultimately creating an environment that promotes stem cell proliferation and further uterine enlargement, which is essential for a successful pregnancy. In summary, all of these data support that rat Stro1+/CD44+ MSC contribute to uterine enlargement during pregnancy.

Cancer stem cells as a therapeutic target in 3D tumor models of human chondrosarcoma: An encouraging future for proline rich polypeptide‑1

“…To confirm the presence of CSCs, western blot analysis was used to identify the mesenchymal and cSc markers STro-1, cd44 and STaT3 (36,37). The results indicate the presence of these markers with comparable band densities and almost identical average ods between the three markers of interest (Fig.…”

The ontogeny of myometrial stem cells in OCT4-GFP transgenic mouse model

“…During pregnancy, the human uterus undergoes a 500- to 1000-fold increase in volume and a 24-fold increase in weight, which demonstrates the remarkable capacity of the myometrium to regenerate and remodel itself [ 3 ]. Although the regulation of myometrial functions during pregnancy and labor is mainly the result of the integration of endocrine and mechanical signals, it is reasonable to assume that the impressive myometrium regenerative ability must be tightly connected to a resident somatic stem cell population [ 3 , 18 ]. There is increasing evidence that adult stem cells not only reside in highly regenerative tissue like bone marrow [ 25 , 26 ], intestine, and epidermis [ 27 , 28 ] but are also found in most tissue where they function to maintain hemostasis by replacing cells lost by apoptosis [ 2 ].…”

“…Myometrial smooth muscle cells have receptors for progesterone and estrogen, and they could play an important role in upregulating the proliferation of Oct-4/CD44/Nanog myometrial stem cells in murine myometrium, especially during pregnancy, via paracrine pathway [ 18 ]. Here, we demonstrated that both ER and PR are indeed abundantly expressed in the murine myometrium at ages 1, 3, and 4 weeks.…”

“…This highly suggests that the low number of MSCs at 1 week of age is primarily due to lack of circulating estrogen and progesterone in these sexually immature mice [ 33 , 34 ]. We have previously demonstrated that human and rat myometrial stem cells under-expressed ER and PR [ 19 ]; thus, it is likely that surrounding differentiated myometrial cells promote MSC proliferation in a paracrine manner, similar to human and rat myometrium [ 18 ]. This model has indeed been validated by recent work from Dr. Bulun’s group [ 24 ].…”

“…Our group has recently identified two specific cell surface markers (CD44 & Stro1) as human [ 17 ] and rat [ 18 , 19 ] myometrial stem cell markers. CD44 is a generic name for a complex set of cell surface glycoproteins involved in cell proliferation, differentiation, and migration [ 20 ].…”