Abstract
Stem-cell containing mammary basal epithelial cells exist in a quasi-mesenchymal transcriptional state characterized by simultaneous expression of typical epithelial genes and typical mesenchymal genes. Whether robust maintenance of such a transcriptional state is required for adult basal stem cells to fuel self-renewal and regeneration remains unclear. In this work, we utilized SMA-CreER to direct efficient basal cell-specific deletion of Ovol2, which encodes a transcription factor that inhibits epithelial-to-mesenchymal transition (EMT), in adult mammary gland. We identified a basal cell-intrinsic role of Ovol2 in promoting epithelial, and suppressing mesenchymal, molecular traits. Interestingly, Ovol2-deficient basal cells display minimal perturbations in their ability to support tissue homeostasis, colony formation, and transplant outgrowth. These findings underscore the ability of adult mammary basal cells to tolerate molecular perturbations associated with altered epithelia-mesenchymal plasticity without drastically compromising their self-renewal potential.
Highlights
The mouse mammary gland is a dynamic and regenerative organ that undergoes most of its development after birth, with dramatic structural and/or functional changes occurring during puberty, estrus cycle, pregnancy, lactation, and involution [1, 2]
We previously reported that deletion of Epithelial-to-mesenchymal transition (EMT)-suppressive transcription factor Ovol2 in the entire mammary epithelium halts ductal morphogenesis during pubertal development [27, 28]
Acute deletion of Ovol2 in cultured basal cells results in increased colony formation. These findings reveal a context-dependent role of Ovol2 in basal cell proliferation/self-renewal and the robustness of adult mammary basal cells in tolerating EMT-like gene expression perturbations
Summary
The mouse mammary gland is a dynamic and regenerative organ that undergoes most of its development after birth, with dramatic structural and/or functional changes occurring during puberty, estrus cycle, pregnancy, lactation, and involution [1, 2]. It has become increasingly clear that EMT in vivo is not a binary process, but rather encompasses a heterogeneous spectrum of diverse intermediate or hybrid cellular states that exist between epithelial and mesenchymal phenotypes. Mammary basal/myoepithelial cells express both epithelial and mesenchymal genes, and are in a “quasi-mesenchymal” transcriptional state that resembles intermediate cell states within the epithelialmesenchymal spectrum [17,18,19,20]. Expression of core EMT-inducing transcription factors is linked to the acquisition of stem cell traits [21,22,23,24,25,26]. How the “quasi-mesenchymal” transcriptional state is maintained in adult mammary tissue basal cells and whether aberrant epithelial-mesenchymal plasticity (EMP) alters stemness remain to be fully understood
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