Abstract
BackgroundMammary stem cells are maintained within specific microenvironments and recruited throughout lifetime to reconstitute de novo the mammary gland. Mammary stem cells have been isolated through the identification of specific cell surface markers and in vivo transplantation into cleared mammary fat pads. Accumulating evidence showed that during the reformation of mammary stem cell niches by dispersed epithelial cells in the context of the intact epithelium-free mammary stroma, non-mammary epithelial cells may be sequestered and reprogrammed to perform mammary epithelial cell functions and to adopt mammary epithelial characteristics during reconstruction of mammary epithelium in regenerating mammary tissue in vivo.Methodology/Principal FindingsTo examine whether other types of progenitor cells are able to contribute to mammary branching morphogenesis, we examined the potential of murine embryonic stem (mES) cells, undergoing hematopoietic differentiation, to support mammary reconstitution in vivo. We observed that cells from day 14 embryoid bodies (EBs) under hematopoietic differentiation condition, but not supernatants derived from these cells, when transplanted into denuded mammary fat pads, were able to contribute to both the luminal and myoepithelial lineages in branching ductal structures resembling the ductal-alveolar architecture of the mammary tree. No teratomas were observed when these cells were transplanted in vivo.Conclusions/SignificanceOur data provide evidence for the dominance of the tissue-specific mammary stem cell niche and its role in directing mES cells, undergoing hematopoietic differentiation, to reprogram into mammary epithelial cells and to promote mammary epithelial morphogenesis. These studies should also provide insights into regeneration of damaged mammary gland and the role of the mammary microenvironment in reprogramming cell fate.
Highlights
Mammary gland development occurs mostly postnatally and is dependent on a complex interplay of systemic hormones and local growth factors [1,2,3]
These cells were tested for expression of the mammary gland cell-lineage specific markers CK5, cytokeratin 14 (CK14), WAP and bcasein. These cells were positive for CK5 and CK14, but negative for b-casein and for the specific mammary whey acidic protein (WAP) (Figure 1B). When these 3D mammary epithelial cells were examined for their potential to support mammary branching morphogenesis in vivo, these cells failed to differentiate in vivo along all three mammary gland cell lineages and were unable to structurally and functionally recapitulate the architecture of the mammary gland
Hematopoietic differentiation of murine Embryonic stem (ES) cells and their transplantation into denuded mammary fat pads we examined the potential of embryoid bodies (EBs) derived from green fluorescence protein (GFP)-E14 murine embryonic stem (mES) cells to reconstitute mammary epithelial morphogenesis
Summary
Mammary gland development occurs mostly postnatally and is dependent on a complex interplay of systemic hormones and local growth factors [1,2,3]. Generation of a functional mammary gland from a single mammary stem cell has been reported by two groups [4,5]. A discrete population of mouse mammary cells with cell-surface markers Lin2CD29hiCD24+ was found to be enriched for transplantable mammary stem cells [4]. It was reported that a single cell, CD452Ter1192CD312Sca1low CD24medCD49fhigh, marked with a LacZ transgene, was able to reconstitute a complete mammary gland in vivo. The transplanted cells contributed to both the luminal and myoepithelial lineages and generated functional lobulo-alveolar units during pregnancy [4,5]. Mammary stem cells have been isolated through the identification of specific cell surface markers and in vivo transplantation into cleared mammary fat pads. Accumulating evidence showed that during the reformation of mammary stem cell niches by dispersed epithelial cells in the context of the intact epithelium-free mammary stroma, non-mammary epithelial cells may be sequestered and reprogrammed to perform mammary epithelial cell functions and to adopt mammary epithelial characteristics during reconstruction of mammary epithelium in regenerating mammary tissue in vivo
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