The Essential Functions of Adipo-osteogenic Progenitors as the Hematopoietic Stem and Progenitor Cell Niche

Omatsu, Yoshiki; Sugiyama, Tatsuki; Kohara, Hiroshi; Kondoh, Gen; Fujii, Nobutaka; Kohno, Kenji; Nagasawa, Takashi

doi:10.1016/j.immuni.2010.08.017

Cited by 724 publications

(749 citation statements)

References 52 publications

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“…Within the perivascular region, a large proportion of stromal cells express high levels of Cxcl12, which plays a crucial role in maintaining HSC function. So far, three stromal cell populations characterized by high Cxcl12 expression have been identified: (1) Cxcl12‐abundant reticular (CAR) cells 25, 26; (2) nestin (Nes) + MSCs (Nes‐MSCs) 27; and (3) leptin receptor (LepR) + stromal cells (Figure 1) 28, 29. It is likely that there is considerable overlap between these populations.…”

Section: Stromal Cell Populations In the Bm Microenvironment (The Hscmentioning

confidence: 99%

Understanding deregulated cellular and molecular dynamics in the haematopoietic stem cell niche to develop novel therapeutics for bone marrow fibrosis

Gleitz

Kramann

Schneider

2018

The Journal of Pathology

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Bone marrow fibrosis is the continuous replacement of blood‐forming cells in the bone marrow with excessive scar tissue, leading to failure of the body to produce blood cells and ultimately to death. Myofibroblasts are fibrosis‐driving cells and are well characterized in solid organ fibrosis, but their role and cellular origin in bone marrow fibrosis have remained obscure. Recent work has demonstrated that Gli1+ and leptin receptor+ mesenchymal stromal cells are progenitors of fibrosis‐causing myofibroblasts in the bone marrow. Genetic ablation or pharmacological inhibition of Gli1+ mesenchymal stromal cells ameliorated fibrosis in mouse models of myelofibrosis. Conditional deletion of the platelet‐derived growth factor (PDGF) receptor‐α (PDGFRA) gene (Pdgfra) and inhibition of PDGFRA by imatinib in leptin receptor+ stromal cells suppressed their expansion and ameliorated bone marrow fibrosis. Understanding the cellular and molecular mechanisms in the haematopoietic stem cell niche that govern the mesenchymal stromal cell‐to‐myofibroblast transition and myofibroblast expansion will be critical to understand the pathogenesis of bone marrow fibrosis in both malignant and non‐malignant conditions, and will guide the development of novel therapeutics. In this review, we summarize recent discoveries of mesenchymal stromal cells as part of the haematopoietic niche and as myofibroblast precursors, and discuss potential therapeutic strategies in the specific targeting of fibrotic transformation in bone marrow fibrosis. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Section: Stromal Cell Populations In the Bm Microenvironment (The Hscmentioning

confidence: 99%

Understanding deregulated cellular and molecular dynamics in the haematopoietic stem cell niche to develop novel therapeutics for bone marrow fibrosis

Gleitz

Kramann

Schneider

2018

The Journal of Pathology

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“…FAP þ cells of skeletal muscle are the major local source of follistatin, which is required to maintain muscle mass by inhibiting myostatin and activin A signaling in this tissue. In the bone marrow, FAP þ cells express CXCL12, IL-7, and KitL, identifying them as "CXCL12-associated reticular" cells (42). Experimental ablation of FAP þ cells from the skeletal muscle and bone marrow causes loss of muscle mass and a reduction of B-lymphopoiesis and erythropoiesis, respectively.…”

Section: Studies Of the Fap þ Stromal Cell In Normal Tissuesmentioning

confidence: 99%

The Carcinoma-Associated Fibroblast Expressing Fibroblast Activation Protein and Escape from Immune Surveillance

Fearon

2014

Cancer Immunology Research

228

158

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The fibroblastic element of the tumor microenvironment has been of great interest to cancer biologists but less so to cancer immunologists. Yet, the sharing of a common mesenchymal cell type in the stroma of tumors and at sites of chronic inflammatory lesions, some of which have an autoimmune basis, has been a strong hint that this cellular component of the tumor microenvironment may have an immunologic function. Recent studies have confirmed this possibility. These fibroblast-like cells, which are termed carcinoma-associated fibroblasts (CAF), can be identified by their expression of the membrane protein, fibroblast activation protein-a (FAP). The conditional depletion of the FAP þ CAF permits immune control not only of an artificial, transplanted tumor, but also of an autochthonous model of pancreatic ductal adenocarcinoma (PDA) that replicates the molecular, histologic, clinical, and immunologic characteristics of the human disease. Immune suppression by the FAP þ CAF is mediated by CXCL12, the chemokine that binds to cancer cells and excludes T cells by a mechanism that depends on signaling by the CXCL12 receptor CXCR4. Inhibition of CXCR4 leads to the elimination of cancer cells by enabling the rapid, intratumoral accumulation of preexisting, PDAspecific CD8 þ T cells, and reveals the antitumor efficacy of the T-cell checkpoint antagonist anti-PD-L1. Recent studies have also shown that the FAP þ CAF is related to FAP-expressing stromal cells of normal tissues, demonstrating that cancers recruit a member of an essential stromal cell lineage that is involved not only in wound repair but also in normal tissue homeostasis. These findings extend the concept introduced by cancer biologists that the fibroblastic component of tumors has a critical role in the adaptation of the cancer to the host.

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“…Adiponectin enhances HSC proliferation in vitro and when expanded can more efficiently reconstitute lethally irradiated hosts through AdipoR1-mediated signaling [19]. CXCL12-abundant reticular cells are adipo-osteogenic progenitors that produce large amount of CXCL12 and SCF, which are required for the proliferation and maintenance of HSCs [20].…”

Section: Introductionmentioning

confidence: 99%

Adipocytic Cells Augment the Support of Primitive Hematopoietic Cells In Vitro But Have No Effect in the Bone Marrow Niche Under Homeostatic Conditions

Spindler

Tseng

Zhou

et al. 2014

Stem Cells and Development

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Mesenchymal stem cells (MSCs), as well as osteoblastic cells derived from these MSCs, have been shown to be key components of the hematopoietic stem cell (HSC) niche. In this study, we wished to examine whether other cell types that are known to differentiate from MSCs similarly regulate the stem cell niche, namely cells of the adipocyte lineage. Recent studies have examined the role that adipocytes play in the biology of the HSCs in different bone locations and in transplantation settings; however, none have examined their role under homeostatic conditions. We compared the ability of adipocytic and nonadipocytic cell lines to support primitive hematopoietic cells in vitro. Preadipocytic cell lines demonstrated enhanced support of hematopoietic cells. Similarly, primary bone marrow (BM) cells treated with troglitazone, a drug that enhances adipogenesis, also demonstrated augmented support over control-treated stromal cells. We further examined the effects of increased adipocyte number in vivo under homeostatic conditions using troglitazone treatment and found that these alterations had no effect on HSC frequency. Taken together, we demonstrate that cells of the adipocyte lineage promote the ability of stromal cells to support primitive hematopoietic cells in vitro, yet alterations of adipocyte number and volume in vivo have no effect. These data suggest that adipocytes are not a component of the adult BM HSC niche under homeostatic conditions.

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The Essential Functions of Adipo-osteogenic Progenitors as the Hematopoietic Stem and Progenitor Cell Niche

Cited by 724 publications

References 52 publications

Understanding deregulated cellular and molecular dynamics in the haematopoietic stem cell niche to develop novel therapeutics for bone marrow fibrosis

Understanding deregulated cellular and molecular dynamics in the haematopoietic stem cell niche to develop novel therapeutics for bone marrow fibrosis

The Carcinoma-Associated Fibroblast Expressing Fibroblast Activation Protein and Escape from Immune Surveillance

Adipocytic Cells Augment the Support of Primitive Hematopoietic Cells In Vitro But Have No Effect in the Bone Marrow Niche Under Homeostatic Conditions

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