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Stem cells are normally maintained in a quiescent state and proliferate only under certain conditions; however, little is known about the biological stimuli that initiate the proliferation and differentiation of stem cells. In this study, we found that functional Toll‐like receptors (TLRs) are expressed on mouse embryonic stem (ES) cells and that TLR ligands stimulate ES cell proliferation and promote their hematopoietic differentiation. TLR ligands activate TLR‐mediated signaling pathways, leading to the altered expression of numerous genes in ES cells. Moreover, TLR ligands efficiently stimulate the proliferation and expansion of adult stem cells and progenitors of nonhematopoietic tissues, such as mammary glands and intestine as well. We further found that mammary luminal progenitor cells (Lin − CD29 + CD61 + ) express TLR4‐MD2 complex and actively proliferate, resulting in the enhanced growth of mammospheres in response to TLR ligands. Thus, mouse ES cells and adult tissue‐specific stem cells/progenitors directly sense and respond to microbial products, which function as a class of foreign, but biological stimuli for stem cell/progenitor proliferation. This finding expands the biological role of TLRs and has implications in understanding stem cell biology, tissue repair/homeostasis, and the role of infection and inflammation in malignant transformation. STEM CELLS 2009;27:1604–1615

Embryonic Stem Cells and Mammary Luminal Progenitors Directly Sense and Respond to Microbial Products