Tissue-Specific Stem Cells in the Myometrium and Tumor-Initiating Cells in Leiomyoma1

Abstract

Tissue-specific (or somatic) stem cells constitute a subset of cells residing in normal adult tissues. By undergoing asymmetric division, they retain their ability to self-renew while producing daughter cells that go on to differentiate and play a role in tissue regeneration and repair. The human uterus consists primarily of endometrium and myometrium (the smooth muscle layer) that rapidly enlarges through its tremendous regenerative and remodeling capacity to accommodate the developing fetus. Such uterine enlargement and remodeling can take place repeatedly and cyclically over the course of a woman's reproductive life. These unique properties of the uterus suggest the existence of endometrial and myometrial stem cell systems. In addition, like somatic cells, tumor stem cells or tumor-initiating cells, a subset of cells within a tumor, retain the ability to reconstitute tumors. Uterine smooth muscle cells are thought to be the origin of leiomyomas that are the most common type of gynecologic tumor. Recent work has identified, isolated, and characterized putative stem/progenitor cells in the myometrium and in leiomyomas. Here, we review current studies of myometrial and leiomyoma stem/progenitor cells and provide a new paradigm for understanding myometrial physiology and pathology and how these cells might contribute to uterine remodeling during pregnancy and the formation of leiomyomas. The role of the WNT/CTNNB1 pathway in the pathogenesis of leiomyoma is also discussed.

The Krüppel-like factors in female reproductive system pathologies

“…By regulating adult stem cell signaling pathways (e.g., Wnt, Notch), KLFs may similarly control the regenerative capacity of endometrial and myometrial stem/progenitor cells. In this regard, endometriosis (Sassoon & Taylor 2008) and leiomyoma (Ono et al ., 2014) are increasingly considered to be a consequence of deregulated stem cell expansion. Indeed, endometrial epithelial stem/progenitor cells have been characterized from eutopic endometrium of women with endometriosis (Li et al ., 2014), ovarian endometriotic cysts (Chan et al, 2011), endometrial carcinoma tissues (Hubbard et al, 2009) and uterine leiomyoma (Ono et al, 2012).…”

Endocrine-disrupting chemicals and uterine fibroids

“…Tissue-specific stem cells have been identified in a variety of tissues and organs (99). The presence of a myometrial stem cell (MSC) population in the uterus was first shown in 2007 in mouse myometrium and non-pregnant human myometrium, using 5-bromo-2′-deoxyuridine and sorting of a side population, respectively (89,100).…”

“…One principal difference between MSCs and TICs at the DNA level is that MED12 mutations are found only in UF TICs, but not normal myometrium or MSCs (90). TICs derived from UFs have stem cell characteristics, and are proliferative, give rise to tumors in vivo (90,95) and comprise~1% of UF cells, (99). Similar to MSCs, TICs express low levels of ER and PR, although they are paradoxically dependent on estrogen/progesterone for growth (90,102).…”

Developmental Environmental Exposure Alters the Epigenetic Features of Myometrial Stem Cells

“…17 UF growth and progression depend on a specialized subpopulation of tumor cells, termed tumor initiating cells (TICs). 3,23 Thus, TICs represent a critical therapeutic target, but the molecular mechanisms that regulate them are poorly understood.…”

“…Although the role of MSCs in development of UFs is extremely important, 23,32,33 the molecular mechanism underlying developmental exposure to EDCs and other toxins at MSCs levels has not been characterized before. 15 By ribonucleic acid (RNA)- sequencing analysis, we recently identified some key genes including estrogen responsive genes (ERGs) that are differentially regulated in MSCs early-life exposed to diethylstilbestrol (DES) verse control (VEH).…”