Uterine fibroids at single-cell resolution: unveiling cellular heterogeneity to improve understanding of pathogenesis and guide future therapies

Uterine leiomyomas or fibroids are benign tumors of the myometrium that affect approximately 70% of reproductive-age women. Fibroids continue to be the leading cause of hysterectomy, resulting in substantial healthcare costs. Genetic complexity and lack of cellular and molecular understanding of fibroids have posed considerable challenges to developing noninvasive treatment options. Over the years, research efforts have intensified to unravel the genetic and cellular diversities within fibroids to deepen our understanding of their origins and progression. Studies using immunostaining and flow cytometry have revealed cellular heterogeneity within these tumors. A correlation has been observed between genetic mutations in fibroids and their size, which is influenced by cellular composition, proliferation rates, and extracellular matrix accumulation. Fibroids with mediator complex subunit 12 (MED12) mutation are composed of smooth muscle cells and fibroblasts equally. In contrast, the fibroids with high-mobility group AT-hook 2 (HMGA2) translocation are 90% composed of smooth muscle cells. More recently, single-cell RNA sequencing in the myometrium and MED12 mutation carrying fibroids has identified further heterogeneity in smooth muscle cells and fibroblast cells, identifying 3 different smooth muscle cell populations and fibroblast cell populations. Although both myometrium and fibroids have similar cellular composition, these cells differs in their transcriptomic profile and have specialized roles, underscoring the complex cellular landscape contributing to fibroid pathogenesis. Furthermore, not all smooth muscle cells in MED12-mutant fibroid carry the MED12 mutation, suggesting that MED12-mutant fibroids might not be monoclonal in nature. This review describes the intricacies of fibroid biology revealed by single-cell RNA sequencing. These advances have identified new cellular targets for potential therapies, provided insights into treatment resistance, and laid the groundwork for more personalized approaches to fibroid management. As we continue to unravel the cellular and molecular complexity of fibroids, we anticipate that this knowledge will translate into more effective and less invasive treatments, ultimately improving outcomes for the millions of women affected by this condition.