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WIREs Dev Biol
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Mammary stem cells, where art thou?

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Abstract Tremendous progress has been made in the field of stem cell biology. This is in part due to the emergence of various vertebrate organs, including the mammary gland, as an amenable model system for adult stem cell studies and remarkable technical advances in single cell technology and modern genetic lineage tracing. In the current review, we summarize the recent progress in mammary gland stem cell biology at both the adult and embryonic stages. We discuss current challenges and controversies, and potentially new and exciting directions for future research. This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Tissue Stem Cells and Niches Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cell Differentiation and Reversion Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration
Stages of mammary gland development based on epithelial morphogenesis. Diagram illustrating primordial, branching, and alveolar stages of mammary epithelial development. Note that stem cell differentiation into both basal and luminal cells occurs at the primordial stage concurrent with the onset of branching morphogenesis. From birth to the adult stage at around 10 weeks, the stromal fat‐pad is filled by epithelial branching, which is at its fastest pace after puberty, or around 3 weeks after birth in mice. Alveologenesis starts at pregnancy and is at its peak during late gestation. Mammary gland involution, by which the epithelial tree is remodeled back to the virgin‐like state is omitted for the sake of simplicity. LN, lymph node
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A new representation of stem cell lineage differentiation. (a) Pseudotime analysis of single cells from adult mammary gland based on single cell RNA‐sequencing data shows that basal and luminal cells are a continuum of cell population with varying differentiation states. The presence of “basal/luminal‐committed” cells allows the construction of a differentiation trajectory that greatly resembles the lineage tree based on genetic tracing experiment. (b) Traditional view of lineage development showing that stem and differentiated cell populations are homogeneous. (c) New representation of mammary gland lineage development showing that MaSCs are primed at an early stage (denoted by curved lines) for a certain lineage. This model also emphasizes cellular heterogeneity of different populations that were once thought to be homogeneous
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Cell fate is dynamic, flexible, reversible and context dependent. (a) Stem cell differentiation according to the Waddington's Canal Model. See main text for a detailed description. (b) “Terminally” differentiated cells can be reprogrammed back to pluripotency, as indicated by the iPSC technology. Potency cannot be equated to energy potential as proposed by the Waddington's Canal Model
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Cellular processes during transplantation‐based mammary gland regeneration. (a) Mammary gland regeneration from organoid epithelium. Note that basal and luminal epithelia are already present and regeneration occurs mostly by epithelial branching. (b) Mammary gland regeneration from transplanted basal cells. Note that luminal cell generation from mammary repopulating cells, which are a rare population enriched by certain surface markers as described in the main text in the basal cell compartment, precedes epithelial branching. This cell differentiation process is presumably similar to that during embryonic development, in which MaSCs first express both basal and luminal marker genes, denoted here as cells expressing both K8 and K14, before differentiating into basal or luminal cells that are K8+ or K14+, respectively
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Adult Stem Cells, Tissue Renewal, and Regeneration > Tissue Stem Cells and Niches
Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cell Differentiation and Reversion
Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration