Asymmetric cell division of mammary stem cells

Somatic stem cells are distinguished by their capacity to regenerate themselves and also to produce daughter cells that will differentiate. Self-renewal is achieved through the process of asymmetric cell division which helps to sustain tissue morphogenesis as well as maintain homeostasis. Asymmetric cell division results in the development of two daughter cells with different fates after a single mitosis. Only one daughter cell maintains “stemness” while the other differentiates and achieves a non-stem cell fate. Stem cells also have the capacity to undergo symmetric division of cells that results in the development of two daughter cells which are identical. Symmetric division results in the expansion of the stem cell population. Imbalances and deregulations in these processes can result in diseases such as cancer. Adult mammary stem cells (MaSCs) are a group of cells that play a critical role in the expansion of the mammary gland during puberty and any subsequent pregnancies. Furthermore, given the relatively long lifespans and their capability to undergo self-renewal, adult stem cells have been suggested as ideal candidates for transformation events that lead to the development of cancer. With the possibility that MaSCs can act as the source cells for distinct breast cancer types; understanding their regulation is an important field of research. In this review, we discuss asymmetric cell division in breast/mammary stem cells and implications on further research. We focus on the background history of asymmetric cell division, asymmetric cell division monitoring techniques, identified molecular mechanisms of asymmetric stem cell division, and the role asymmetric cell division may play in breast cancer.

AP-2γ is Required for Maintenance of Pluripotent Mammary Stem Cells

SUMMARYMammary gland ductal morphogenesis depends on the differentiation of mammary stem cells (MaSCs) into basal and luminal lineages. The AP-2γ transcription factor, encoded by Tfap2c, has a central role in mammary gland development but its effect in mammary lineages and specifically MaSCs is largely unknown. Herein, we utilized an inducible, conditional knockout of Tfap2c to elucidate the role of AP-2γ in maintenance and differentiation of MaSCs. Loss of AP-2γ in the basal epithelium profoundly altered the transcriptomes and decreased the number of cells within several clusters of mammary epithelial cells, including adult MaSCs and luminal progenitors.AP-2γ regulated the expression of genes known to be required for mammary development including C/EBPβ, IκBα, and Rspo1. As a result, AP-2γ-deficient mice exhibited repressed mammary gland ductal outgrowth and inhibition of regenerative capacity. The findings demonstrate that AP-2γ is required for maintenance of pluripotent MaSCs and their ability to develop mammary gland structures.HighlightsAP-2γ-deficient mice exhibited repressed ductal outgrowth and regenerative capacityLoss of AP-2γ reduced the number of mammary stem and luminal progenitor cellsAP-2γ target genes, including C/EBPβ, IκBα, and Rspo1, regulate mammary developmentAP-2γ is required for maintenance of pluripotent mammary stem cellseTOC blurbGu, Cho and colleagues utilized a conditional knockout of Tfap2c to examine transcriptional effects of AP-2γ on mammary stem cells. Single cell analysis demonstrated that AP-2γ-deficient mice have decreased numbers of mammary stem cells and alteration of genes required for mammary development including C/EBPβ, IκBα, and Rspo1. They demonstrate that AP-2γ is necessary for maintenance of pluripotent mammary stem cells.

Interleukin-8 Dedifferentiates Primary Human Luminal Cells to Multipotent Stem Cells

ABSTRACT During aging, cellular plasticity and senescence play important roles in tissue regeneration and the pathogenesis of different diseases, including cancer. We have recently shown that senescent breast luminal cells can activate their adjacent stromal fibroblasts. In the present report, we present clear evidence that these senescence-related active fibroblasts can dedifferentiate proliferating primary human luminal cells to multipotent stem cells in an interleukin-8 (IL-8)-dependent manner. This was confirmed using recombinant IL-8, while the truncated protein was not active. This IL-8-related dedifferentiation of luminal cells was mediated through the STAT3-dependent downregulation of p16INK4A and the microRNA miR-141. Importantly, these in vitro-generated mammary stem cells exhibited high molecular and cellular similarities to human mammary stem cells. They have also shown a long-term mammary gland-reconstituting ability and the capacity to produce milk postdelivery. Thereby, these IL-8-generated mammary stem cells could be of great value for autologous cell therapy procedures and also for biomedical research as well as drug development.