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Embryonic stem cells and mammary luminal progenitors directly sense and respond to microbial products.

ABSTRACT: 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.

SUBMITTER: Lee SH

PROVIDER: S-EPMC4157827 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Embryonic stem cells and mammary luminal progenitors directly sense and respond to microbial products.

Lee Sung-Hyung SH Hong Bangxing B Sharabi Andrew A Huang Xue F XF Chen Si-Yi SY

Stem cells (Dayton, Ohio) 20090701 7

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, lead ...[more]

PMID: 19544467

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Project description:Studies have identified multi-potent stem cells in the adult mammary gland. More recent studies have suggested that the embryonic mammary gland may also contain stem/progenitor cells that contribute to initial ductal development. We were interested in determining whether embryonic cells might also directly contribute to long-lived stem cells that support homeostasis and development in the adult mammary gland.We used DNA-label retention to detect long label-retaining cells in the mammary gland. Mouse embryos were labeled with 5-ethynl-2'-deoxyuridine (EdU) between embryonic day 14.5 and embryonic day 18.5 and were subsequently sacrificed and examined for EdU retention at various intervals after birth. EdU retaining cells were co-stained for various lineage markers and identified after fluorescence activated cell sorting analysis of specific epithelial subsets. EdU-labeled mice were subjected to subsequent 5-bromo-2'-deoxyuridine administration to determine whether EdU-labeled cells could re-enter the cell cycle. Finally, EdU-labeled cells were grown under non-adherent conditions to assess their ability to form mammospheres.We demonstrate embryonically-derived, long label-retaining cells (eLLRCs) in the adult mammary gland. eLLRCs stain for basal markers and are enriched within the mammary stem cell population identified by cell sorting. eLLRCs are restricted to the primary ducts near the nipple region. Interestingly, long label retaining cells (labeled during puberty) are found just in front of the eLLRCs, near where the ends of the ducts had been at the time of DNA labeling in early puberty. A subset of eLLRCs becomes mitotically active during periods of mammary growth and in response to ovarian hormones. Finally, we show that eLLRCs are contained within primary and secondary mammospheres.Our findings suggest that a subset of proliferating embryonic cells subsequently becomes quiescent and contributes to the pool of long-lived mammary stem cells in the adult. eLLRCs can re-enter the cell cycle, produce both mammary lineages and self-renew. Thus, our studies have identified a putative stem/progenitor cell population of embryonic origin. Further study of these cells will contribute to an understanding of how quiescent stem cells are generated during development and how fetal exposures may alter future breast cancer risk in adults.

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Embryonic stem cells and mammary luminal progenitors directly sense and respond to microbial products.

Publications

Embryonic stem cells and mammary luminal progenitors directly sense and respond to microbial products.

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