HMGA2 overexpression induces plasticity in myometrial cells and a transcriptomic profile more similar to that of uterine fibroids

Abstract

ObjectiveTo study the possible role for HMGA2 overexpression in differentiated myometrial cells and its potential to induce a stem cell-like or dedifferentiating phenotype and drive fibroid development. DesignMyometrial cells were immortalized and transduced with an HMGA2 lentivirus to produce HMGA2hi cells. In vitro stem cell assays were conducted and RNA from HMGA2hi and control cells and fibroid-free myometrial (MyoN) and HMGA2 fibroid (HMGA2F) tissues were submitted for RNA-sequencing. SettingUniversity research laboratory SubjectsWomen undergoing hysterectomy for symptomatic uterine fibroids or other gynecological conditions. InterventionNot applicable. Main Outcome MeasuresIn-vitro stem-like properties from myometrium cell lines. RNA-sequencing and collagen production of HMGA2 overexpressing primary leiomyoma tissue and cell lines. ResultsHMGA2hi cells have enhanced self-renewal capacity, decreased proliferation, and have a greater ability to differentiate into other mesenchymal cell types. HMGA2hi cells exhibit a stem cell-like signature and share transcriptomic similarities with HMGA2F. Moreover, dysregulated extracellular matrix pathways are observed in both HMGA2hi cells and HMGA2F. ConclusionOur findings suggest that HMGA2 overexpression drives myometrial cells to dedifferentiate into a more plastic phenotype and provides evidence for an alternative mechanism for fibroid etiology, suggesting that fibroids may not only arise from a mutated stem cell but also from a mutated differentiated myometrial cell.