Endothelial and perivascular cells maintain haematopoietic stem cells. Nature

Howard Hughes Medical Institute, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Nature (Impact Factor: 41.46). 01/2012; 481(7382):457-62. DOI: 10.1038/nature10783
Source: PubMed


Several cell types have been proposed to create niches for haematopoietic stem cells (HSCs). However, the expression patterns of HSC maintenance factors have not been systematically studied and no such factor has been conditionally deleted from any candidate niche cell. Thus, the cellular sources of these factors are undetermined. Stem cell factor (SCF; also known as KITL) is a key niche component that maintains HSCs. Here, using Scf(gfp) knock-in mice, we found that Scf was primarily expressed by perivascular cells throughout the bone marrow. HSC frequency and function were not affected when Scf was conditionally deleted from haematopoietic cells, osteoblasts, nestin-cre- or nestin-creER-expressing cells. However, HSCs were depleted from bone marrow when Scf was deleted from endothelial cells or leptin receptor (Lepr)-expressing perivascular stromal cells. Most HSCs were lost when Scf was deleted from both endothelial and Lepr-expressing perivascular cells. Thus, HSCs reside in a perivascular niche in which multiple cell types express factors that promote HSC maintenance.

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Available from: Grigori Enikolopov,
    • "In the perivascular niche multiple cell types express factors that promote HSC maintenance (Ding et al., 2012). Nestin-expressing tissue-resident multipotent stem cells are mobilized to newly formed endothelia and differentiate into pericytes (Klein et al., 2014). "
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    ABSTRACT: An innate osteogenic potential of the Schneiderian membrane (SM) is progressively assessed in studies ranging from non-human species to human subjects. It has relevance for endosteal placement and osseointegration. Nestin-expressing osteogenic progenitor cells are allegedly involved in bone formation and remodelling. Nestin phenotype was not assessed previously in human SM. We therefore aimed to fill that particular gap in the literature. Bioptic samples of human adult SM were obtained during surgery from eight adult patients, operated for non-malignant pathologies. Immunohistochemistry on paraffin-embedded tissue samples used primary antibodies against nestin, CD45, CD146, cytokeratin 7 (CK7) and alpha-smooth muscle actin (α-SMA). Nestin expression was consistently found in endothelial cells, and was scarcely encountered in pericytes, putative stromal stem/progenitor cells, as well as in glandular epithelial cells. Moreover, woven bone formation in the periosteal layer of the SM can also be regarded as evidence of the osteogenic potential of this membrane. Nestin and CD45 expression in cells of the primary bone supports the osteogenic potential of SM nestin-expressing cells and a possible involvement of hematopoietic stem cells in maxillary sinus floor remodelling. CD146, a known inducer of epithelial-mesenchymal transition (EMT), was expressed in epithelia, as was CK7. Isolated stromal cells were found expressing CD146, CK7 and α-SMA, suggesting that regenerative processes happening in the SM may also involve processes of EMT which generate stem/progenitor cells. This study provides additional evidence for the regenerative potential of the Schneiderian membrane and identifies potential roles for cells of its stem niche in osteogenesis. This article is protected by copyright. All rights reserved.
    The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology 09/2015; DOI:10.1002/ar.23276 · 1.54 Impact Factor
    • "Moreover, Nestin-GFP and Nestin-CFPnuc lines can be crossed to efficiently visualize both the soma and the nuclei of stem and progenitor cells (Fig. 1C). In Nestin-mCherry animals (Ding et al. 2012; G Enikolopov , unpubl.), stem and progenitor cells are marked by red fluorescence; this becomes important for generating multiallelic reporter lines, in which an FP of a different color marks the progeny of stem cells (e.g., NestinmCherry/Nestin-Cre-ER/ZEG mice) or other types of stem cells (e.g., Nestin-mCherry/ Sox2-GFP mice). Together, this set of matching lines expands the palette of available colors and the range of possible experiments. "
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    ABSTRACT: Stem and progenitor cells of the developing and adult brain can be effectively identified and manipulated using reporter genes, introduced into transgenic reporter mouse lines or recombinant viruses. Such reporters rely on an ever-increasing variety of fluorescent proteins and a continuously expanding list of regulatory elements and of mouse lines engineered for cell- or time-specific recombination. An important extension of stem-cell-based genetic strategies is an opportunity to explore the properties of newly generated neurons and their contribution to synaptic plasticity. Here, we review available strategies for marking and quantifying various classes of stem and progenitor cells in the adult brain, genetically tracing their progeny, and studying the properties of stem cells and new neurons. We compare various experimental approaches to labeling and investigating stem cells and their progeny and discuss caveats and limitations inherent to each approach. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
    Cold Spring Harbor perspectives in biology 08/2015; 7(8). DOI:10.1101/cshperspect.a018804 · 8.68 Impact Factor
    • "In 2012 Ding et al. identified perivascular HSC-supporting stromal cells using the expression of the HSC maintenance factor stem cell factor (Scf; also known as kitl). This cell population overlapped only with Nestin–GFP lo cells, and not with Nestin–GFP hi cells [20]. However, Kunisaki et al. proposed NG2+ Nestin–GFP hi cells as components of an arteriolar HSC–BMSC niche. "
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    ABSTRACT: Recent discoveries have significantly expanded our previous knowledge about the role of bone marrow mesenchymal stem cells (BMSCs) in hematopoiesis. BMSCs and their derivatives modulate blood production and immunity at different levels but a prominent role has emerged for BMSCs in the regulation of hematopoietic stem and progenitor cells (HSPCs). Additionally, BMSC-like cells regulate B and T cell lymphopoiesis and also probably myelopoiesis. Furthermore, BMSCs might also exhibit key regulatory properties in non-physiological conditions. BMSCs in extramedullary sites might provide a permissive microenviroment to allow for transient hematopoiesis. BMSCs might be also involved in the manifestation and/or the development of hematopoietic diseases, as steming from their emerging roles in the progression of hematological malignancies. Here we review some key molecular pathways, adhesion molecules and ligand/receptor interactions that mediate the crosstalk between BMSCs and hematopoietic stem cells (HSCs) in health and disease. The development of novel markers to visualize and isolate individual cells will help to dissect the stromal-hematopoietic interplay. Copyright © 2015. Published by Elsevier B.V.
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