No metazoan cell survives on its own, absent the signals and support of its milieu. For multicellular life with specialized tissues to persist, organization is everything and so defining the ...association of position with cell state is critical to understanding how tissues function, maintain, and repair. This review focuses specifically on place for progenitor and stem cells. Especially emphasized are hematopoietic cells that balance free movement and stable position and where concepts of regulatory interrelationships have been shown with some precision. It reviews classical and emerging concepts of the niche, particularly considering how niche functions may participate in neoplastic disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Bone metastases are devastating complications of cancer. They are particularly common in prostate cancer (PCa), represent incurable disease, and are refractory to immunotherapy. We seek to define ...distinct features of the bone marrow (BM) microenvironment by analyzing single cells from bone metastatic prostate tumors, involved BM, uninvolved BM, and BM from cancer-free, orthopedic patients, and healthy individuals. Metastatic PCa is associated with multifaceted immune distortion, specifically exhaustion of distinct T cell subsets, appearance of macrophages with states specific to PCa bone metastases. The chemokine CCL20 is notably overexpressed by myeloid cells, as is its cognate CCR6 receptor on T cells. Disruption of the CCL20-CCR6 axis in mice with syngeneic PCa bone metastases restores T cell reactivity and significantly prolongs animal survival. Comparative high-resolution analysis of PCa bone metastases shows a targeted approach for relieving local immunosuppression for therapeutic effect.
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•An immune-suppressive microenvironment characterizes bone metastatic prostate cancer•Infiltrating T cells are exhausted and dysfunctional•Inflammatory monocytes and M2 polarized macrophages are enriched and overexpress CCL20•Disruption of the CCL20/CCR6 axes relieves T cell exhaustion and extends survival
Kfoury et al. identify an immune-suppressive microenvironment in human bone metastatic prostate cancer enriched in exhausted T cells and orchestrated by myeloid cells overexpressing CCL20. Pharmacological or genetic targeting of the CCL20/CCR6 axes in an animal model relieves the immune-suppressive state and extends the survival of metastatic tumor-bearing mice.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mesenchymal stromal cells (MSCs) are heterogeneous and primitive cells discovered first in the bone marrow (BM). They have putative roles in maintaining tissue homeostasis and are increasingly ...recognized as components of stem cell niches, which are best defined in the blood. The absence of in vivo MSC markers has limited our ability to track their behavior in vivo and draw comparisons with in vitro observations. Here we review the historical background of BM-MSCs, advances made in their prospective isolation, their developmental origin and contribution to maintaining subsets of hematopoietic cells, and how mesenchymal cells contribute to other stem cell niches.
Kfoury and Scadden discuss how mesenchymal stromal cells (MSCs) contribute to stem cell niches, with a focus on MSCs in the bone marrow (BM). They review the historical background of BM-MSCs, advances made in their prospective isolation, their developmental origins, and their contribution to maintaining subsets of hematopoietic cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Niches are local tissue microenvironments that maintain and regulate stem cells. Haematopoiesis provides a model for understanding mammalian stem cells and their niches, but the haematopoietic stem ...cell (HSC) niche remains incompletely defined and beset by competing models. Recent progress has been made in elucidating the location and cellular components of the HSC niche in the bone marrow. The niche is perivascular, created partly by mesenchymal stromal cells and endothelial cells and often, but not always, located near trabecular bone. Outstanding questions concern the cellular complexity of the niche, the role of the endosteum and functional heterogeneity among perivascular microenvironments.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Single-cell data provide a means to dissect the composition of complex tissues and specialized cellular environments. However, the analysis of such measurements is complicated by high levels of ...technical noise and intrinsic biological variability. We describe a probabilistic model of expression-magnitude distortions typical of single-cell RNA-sequencing measurements, which enables detection of differential expression signatures and identification of subpopulations of cells in a way that is more tolerant of noise.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Stromal cell populations that maintain hematopoietic stem and progenitor cells (HSPCs) are generally characterized in steady-state conditions. Here, we report a comprehensive atlas of bone marrow ...stromal cell subpopulations under homeostatic and stress conditions using mass cytometry (CyTOF)-based single-cell protein analysis. We identified 28 subsets of non-hematopoietic cells during homeostasis, 14 of which expressed hematopoietic regulatory factors. Irradiation-based conditioning for HSPC transplantation led to the loss of most of these populations, including the LeptinR+ and Nestin+ subsets. In contrast, a subset expressing Ecto-5′-nucleotidase (CD73) was retained and a specific CD73+NGFRhigh population expresses high levels of cytokines during homeostasis and stress. Genetic ablation of CD73 compromised HSPC transplantation in an acute setting without long-term changes in bone marrow HSPCs. Thus, this protein-based expression mapping reveals distinct sets of stromal cells in the bone marrow and how they change in clinically relevant stress settings to contribute to early stages of hematopoietic regeneration.
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•Single-cell mass cytometry defines 28 subsets of bone marrow stromal cells (BMSCs)•Cytokine profiling and persistence to radiation reveal BMSC niche candidates•LeptinR+ and Nestin+ putative niche cells are lost with radiation conditioning•CD73+ BMSCs contribute to HSPC engraftment and acute hematopoietic recovery
Severe et al. used single-cell mass cytometry to define 28 subsets of bone marrow stromal cells based on protein expression. Cytokine production and response to stress functionally selected niche candidates. While LeptinR+ and Nestin+ cells were lost with conditioning, CD73+ subpopulations contribute to HSPC engraftment and acute hematopoietic recovery.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mesenchymal cells contribute to the 'stroma' of most normal and malignant tissues, with specific mesenchymal cells participating in the regulatory niches of stem cells. By examining how mesenchymal ...osteolineage cells modulate haematopoiesis, here we show that deletion of Dicer1 specifically in mouse osteoprogenitors, but not in mature osteoblasts, disrupts the integrity of haematopoiesis. Myelodysplasia resulted and acute myelogenous leukaemia emerged that had acquired several genetic abnormalities while having intact Dicer1. Examining gene expression altered in osteoprogenitors as a result of Dicer1 deletion showed reduced expression of Sbds, the gene mutated in Schwachman-Bodian-Diamond syndrome-a human bone marrow failure and leukaemia pre-disposition condition. Deletion of Sbds in mouse osteoprogenitors induced bone marrow dysfunction with myelodysplasia. Therefore, perturbation of specific mesenchymal subsets of stromal cells can disorder differentiation, proliferation and apoptosis of heterologous cells, and disrupt tissue homeostasis. Furthermore, primary stromal dysfunction can result in secondary neoplastic disease, supporting the concept of niche-induced oncogenesis.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Stem-cell populations are established in 'niches'--specific anatomic locations that regulate how they participate in tissue generation, maintenance and repair. The niche saves stem cells from ...depletion, while protecting the host from over-exuberant stem-cell proliferation. It constitutes a basic unit of tissue physiology, integrating signals that mediate the balanced response of stem cells to the needs of organisms. Yet the niche may also induce pathologies by imposing aberrant function on stem cells or other targets. The interplay between stem cells and their niche creates the dynamic system necessary for sustaining tissues, and for the ultimate design of stem-cell therapeutics.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Stroma is a poorly defined non-parenchymal component of virtually every organ with key roles in organ development, homeostasis, and repair. Studies of the bone marrow stroma have defined individual ...populations in the stem cell niche regulating hematopoietic regeneration and capable of initiating leukemia. Here, we use single-cell RNA sequencing (scRNA-seq) to define a cellular taxonomy of the mouse bone marrow stroma and its perturbation by malignancy. We identified seventeen stromal subsets expressing distinct hematopoietic regulatory genes spanning new fibroblastic and osteoblastic subpopulations including distinct osteoblast differentiation trajectories. Emerging acute myeloid leukemia impaired mesenchymal osteogenic differentiation and reduced regulatory molecules necessary for normal hematopoiesis. These data suggest that tissue stroma responds to malignant cells by disadvantaging normal parenchymal cells. Our taxonomy of the stromal compartment provides a comprehensive bone marrow cell census and experimental support for cancer cell crosstalk with specific stromal elements to impair normal tissue function and thereby enable emergent cancer.
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•A single-cell bone marrow stromal cell atlas at steady-state and emergent leukemia•A portal for comparative cell and molecular analyses of bone marrow stromal cells•Distinction among putative niche cells and types of osteolineage differentiation•Leukemia remodeling of stroma to the disadvantage of normal hematopoietic cells
Molecular definition of the cell populations comprising bone marrow stroma is provided with single-cell resolution. Seventeen distinct cell subsets with new mesenchymal, pericyte, fibroblast, and endothelial subpopulations, new inferred osteolineage differentiation trajectories, and distinctions among Lepr, Nestin, and NG2-expressing HSC niche populations are defined. The changes imposed by an emergent AML indicate impaired stromal differentiation among mesenchymal cells and decreased expression of hematopoietic regulatory genes consistent with cancer cells indirectly impairing the normal hematopoietic cells with whom they must compete.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Using MRI techniques, we show here that normalization of tumor vessels in recurrent glioblastoma patients by daily administration of AZD2171—an oral tyrosine kinase inhibitor of VEGF receptors—has ...rapid onset, is prolonged but reversible, and has the significant clinical benefit of alleviating edema. Reversal of normalization began by 28 days, though some features persisted for as long as four months. Basic FGF, SDF1α, and viable circulating endothelial cells (CECs) increased when tumors escaped treatment, and circulating progenitor cells (CPCs) increased when tumors progressed after drug interruption. Our study provides insight into different mechanisms of action of this class of drugs in recurrent glioblastoma patients and suggests that the timing of combination therapy may be critical for optimizing activity against this tumor.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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