CD34 and CD49f double-positive and lineage marker-negative cells isolated from human myometrium exhibit stem cell-like properties involved in pregnancy-induced uterine remodeling

Repeated and dramatic pregnancy-induced uterine enlargement and remodeling throughout reproductive life suggests the existence of uterine smooth muscle stem/progenitor cells. The aim of this study was to isolate and characterize stem/ progenitor-like cells from human myometrium through identification of specific surface markers. We here identify CD49f and CD34 as markers to permit selection of the stem/progenitor celllike population from human myometrium and show that human CD45^- CD31^- glycophorin A^- and CD49f⁺ CD34⁺ myometrial cells exhibit stem cell-like properties. These include side population phenotypes, an undifferentiated status, high colonyforming ability, multilineage differentiation into smooth muscle cells, osteoblasts, adipocytes, and chondrocytes, and in vivo myometrial tissue reconstitution following xenotransplantation. Furthermore, CD45^- CD31^- glycophorin A^- and CD49f⁺ CD34⁺ myometrial cells proliferate under hypoxic conditions in vitro and, compared with the untreated nonpregnant myometrium, show greater expansion in the estrogen-treated nonpregnant myometrium and further in the pregnant myometrium in mice upon xenotransplantation. These results suggest that the newly identified myometrial stem/progenitor-like cells influenced by hypoxia and sex steroids may participate in pregnancy-induced uterine enlargement and remodeling, providing novel insights into human myometrial physiology.