title: Adult mouse myometrial label-retaining cells divide in response to gonadotropin stimulation.
abstract: Conditional deletion of beta-catenin in the Müllerian duct mesenchyme results in a degenerative uterus characterized by replacement of the myometrial smooth muscle with adipose tissue. We hypothesized that the mouse myometrium houses somatic smooth muscle progenitor cells that are hormonally responsive and necessary for remodeling and regeneration during estrous cycling and pregnancy. We surmise that the phenotype observed in beta-catenin conditionally deleted mice is the result of dysregulation of these progenitor cells. The objective of this study was to identify the mouse myometrial smooth muscle progenitor cell and its niche, define the surface marker phenotype, and show a functional response of these cells to normal myometrial cycling. Uteri were labeled with 5-bromo-2'-deoxyuridine (BrdU) and chased for up to 14 weeks. Myometrial label-retaining cells (LRCs) were observed in the myometrium and stroma throughout the chase period. After 12 weeks, phenotypic analysis of the LRCs by immunofluorescence demonstrated that the majority of LRCs colocalized with alpha-smooth muscle actin, estrogen receptor-alpha, and beta-catenin. Flow cytometry of myometrial cells identified a myometrial Hoechst 33342 effluxing "side population" that expresses MISRII-Cre-driven YFP. Functional response of LRCs was investigated by human chorionic gonadotropin stimulation of week 12 chase mice and demonstrated sequential proliferation of LRCs in the endometrial stroma, followed by the myometrium. These results suggest that conventional myometrial regeneration and repair is executed by hormonally responsive stem or progenitor cells derived from the Müllerian duct mesenchyme. Disclosure of potential conflicts of interest is found at the end of this article.
authors.affiliation: Pediatric Surgical Research Laboratories, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Paul P
authors.initials: PP
authors.lastname: Szotek
authors.forename: Henry L
authors.initials: HL
authors.lastname: Chang
authors.forename: LiHua
authors.initials: L
authors.lastname: Zhang
authors.forename: Frederic
authors.initials: F
authors.lastname: Preffer
authors.forename: David
authors.initials: D
authors.lastname: Dombkowski
authors.forename: Patricia K
authors.initials: PK
authors.lastname: Donahoe
authors.forename: Jose
authors.initials: J
authors.lastname: Teixeira
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects; D000375:Aging / Q000502:physiology*; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006063:Chorionic Gonadotropin / Q000494:pharmacology*; D005260:Female; D006801:Humans; D019426:Integrases / Q000378:metabolism; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects; D009215:Myometrium / Q000166:cytology* / Q000187:drug effects*; D010641:Phenotype; D018000:Receptors, Peptide / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects; D051176:beta Catenin / Q000172:deficiency
chemical_list: D001426:Bacterial Proteins; D006063:Chorionic Gonadotropin; D008164:Luminescent Proteins; D018000:Receptors, Peptide; D018125:Receptors, Transforming Growth Factor beta; C084621:anti-Mullerian hormone receptor; D051176:beta Catenin; C054562:yellow fluorescent protein, Bacteria; C045073:Cre recombinase; D019426:Integrases; D001973:Bromodeoxyuridine