Abstract
BackgroundStem cells are precursors for all mammary epithelia, including ductal and alveolar epithelia, and myoepithelial cells. In vivo mammary epithelia reside in a tissue context and interact with their milieu via receptors such as integrins. Extracellular matrix receptors coordinate important cellular signalling platforms, of which integrins are the central architects. We have previously shown that integrins are required for mammary epithelial development and function, including survival, cell cycle, and polarity, as well as for the expression of mammary-specific genes. In the present study we looked at the role of integrins in mammary epithelial stem cell self-renewal.MethodsWe used an in vitro stem cell assay with primary mouse mammary epithelial cells isolated from genetically altered mice. This involved a 3D organoid assay, providing an opportunity to distinguish the stem cell- or luminal progenitor-driven organoids as structures with solid or hollow appearances, respectively.ResultsWe demonstrate that integrins are essential for the maintenance and self-renewal of mammary epithelial stem cells. Moreover integrins activate the Rac1 signalling pathway in stem cells, which leads to the stimulation of a Wnt pathway, resulting in expression of β-catenin target genes such as Axin2 and Lef1.ConclusionsIntegrin/Rac signalling has a role in specifying the activation of a canonical Wnt pathway that is required for mammary epithelial stem cell self-renewal.
Highlights
Stem cells are precursors for all mammary epithelia, including ductal and alveolar epithelia, and myoepithelial cells
To directly address the functional importance of β1-integrin signalling in bipotent cells, we examined their role using a 3D organoid assay for mammary stem cells [14]
Our findings reveal that the β1-integrin/Rac1 signalling axis regulates the maintenance and self-renewal of bipotent cells through Wnt signalling
Summary
Stem cells are precursors for all mammary epithelia, including ductal and alveolar epithelia, and myoepithelial cells. Involution is triggered to clear up all milk-secreting cells and return the gland to a non-pregnant state [4]. These extensive tissue-remodelling processes repeat with each oestrus cycle and pregnancy. The presence of mammary epithelial stem cells (MaSCs) is the driving force behind this high regenerative capacity [44]. Their existence and potency has been demonstrated by serial transplantation studies. Single-cell transplant experiments have identified MaSCs as β1-integrinhiCD24+ cells, α6-integrinhiCD24+ can be used to identify MaSCs [33, 36]
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