Human Myometrial and Uterine Fibroid Stem Cell-Derived Organoids for Intervening the Pathophysiology of Uterine Fibroid

Abstract

Uterine fibroids (UFs) (leiomyomas or myomas) are the most common clonal neoplasms of the uterus in women of reproductive age worldwide. UFs originate from myometrium consist of smooth muscle and fibroblast components, in addition to a substantial amount of fibrous extracellular matrix which all contribute to the pathogenetic process. Current treatments are primarily limited to surgical and interventional. Here, we have established a novel and promising organoid model from both normal and patient myometrial stem cells (MMSCs). MMSCs embedded in Matrigel in stem cell media swiftly formed organoids which successfully proliferate and self-organized into complex structures developing a sustainable organoid culture that maintain their capacity to differentiate into the different cell types recapitulating their tissue of origin and shows responsiveness to the reproductive hormones (estrogen and progesterone). Gene expression analysis and structural features indicated the early onset of uterine fibrosis led to the accumulation of extracellular matrix suggesting the potential use of this model in better understanding of the pathophysiology associated with UFs and inventing novel therapeutics for the treatment of UFs.

Unraveling the Molecular Landscape of Uterine Fibroids, Insights intoHMGA2and Stem Cell Involvement

“…Transcriptomic analysis of HMGA2hi cells further revealed increased stemness, as evidenced by a significant increase in the expression of another mesenchymal marker, CSPG4 (26), along with enrichment for two stem-related pathways. Several studies have demonstrated the capability of myometrial and fibroid stem/progenitor cells to differentiate into various cell types (26,32,36). However, to our knowledge, no previous reports have investigated whether myometrium and fibroid cells depleted for stem/progenitor cells retain the ability to differentiate into other cell types.…”

Progesterone Signaling and Uterine Fibroid Pathogenesis; Molecular Mechanisms and Potential Therapeutics

“…MMSCs formed organoids and showed responsiveness to the core regulatory hormone estrogen with an overall increase in size. Interestingly, MMSC and UFSC developed organoids showed a differential gene expression profile in response to progesterone treatment in terms of progesterone-responsive genes expression [ 67 ].…”

Gene Expression Profile of Uterine Leiomyoma from Women Exposed to Different Air Pollution Levels in Metropolitan Cities of Sao Paulo, Brazil

“…An increasing amount of evidence supports the hypothesis that LM arises from abnormal stem cells in the myometrial smooth muscle compartment of the uterus [18,19]. Such cells seem to originate from a point mutation in key genes and may present complex histologic features that interfere directly with the diagnosis [20].…”

“…Such cells seem to originate from a point mutation in key genes and may present complex histologic features that interfere directly with the diagnosis [20]. Endocrine disruptors and racial or ethnic factors may contribute to genetic alterations in myometrial stem cells [18][19][20][21]. Additionally, these cells are more frequent in Afro-descendant women with LMs than in Caucasians without them [21].…”