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SCA-1 Expression Level Identifies Quiescent Hematopoietic Stem and Progenitor Cells.

ABSTRACT: Blood cell generation depends on continuous cellular output by the sequential hierarchy of hematopoietic stem cell (HSC) and progenitor populations that all contain quiescent and actively cycling cells. Hematopoietic stem and progenitor cells (HSPCs) express the surface molecule Stem cell antigen 1 (SCA-1/LY6A). Using histone 2B-red fluorescent fusion protein label retention and cell-cycle reporter mice, we demonstrate that high SCA-1 expression (SCA-1^hi) identifies not only quiescent HSCs but quiescent cells on all hierarchical levels within the lineage^-SCA-1⁺KIT⁺ (LSK) population. Each transplanted SCA-1^hi HSPC population also displayed self-renewal potential superior to that of the respective SCA-1^lo population. SCA-1 expression is inducible by type I interferon (IFN). We show, however, that quiescence and high self-renewal capacity of cells with brighter SCA-1 expression at steady state were independent of type I IFN signaling. We conclude that SCA-1 expression levels can be used to prospectively isolate functionally heterogeneous HSPC subpopulations.

SUBMITTER: Morcos MNF

PROVIDER: S-EPMC5469944 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:How inflammatory responses are mechanistically modulated by nicotinic acetylcholine receptors (nAChR), especially by receptors composed of alpha7 (?7) subunits, is poorly defined. This includes a precise definition of cells that express ?7 and how these impact on innate inflammatory responses. To this aim we used mice generated through homologous recombination that express an Ires-Cre-recombinase bi-cistronic extension of the endogenous ?7 gene that when crossed with a reporter mouse expressing Rosa26-LoxP (yellow fluorescent protein (YFP)) marks in the offspring those cells of the ?7 cell lineage (?7(lin+)). In the adult, on average 20-25 percent of the total CD45(+) myeloid and lymphoid cells of the bone marrow (BM), blood, spleen, lymph nodes, and Peyers patches are ?7(lin+), although variability between litter mates in this value is observed. This hematopoietic ?7(lin+) subpopulation is also found in Sca1(+)cKit(+) BM cells suggesting the ?7 lineage is established early during hematopoiesis and the ratio remains stable in the individual thereafter as measured for at least 18 months. Both ?7(lin+) and ?7(lin-) BM cells can reconstitute the immune system of naïve irradiated recipient mice and the ?7(lin+):?7(lin-) beginning ratio is stable in the recipient after reconstitution. Functionally the ?7(lin+):?7(lin-) lineages differ in response to LPS challenge. Most notable is the response to LPS as demonstrated by an enhanced production of IL-12/23(p40) by the ?7(lin+) cells. These studies demonstrate that ?7(lin+) identifies a novel subpopulation of bone marrow cells that include hematopoietic progenitor cells that can re-populate an animal's inflammatory/immune system. These findings suggest that ?7 exhibits a pleiotropic role in the hematopoietic system that includes both the direct modulation of pro-inflammatory cell composition and later in the adult the role of modulating pro-inflammatory responses that would impact upon an individual's lifelong response to inflammation and infection.

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SCA-1 Expression Level Identifies Quiescent Hematopoietic Stem and Progenitor Cells.

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