The bone marrow niche for haematopoietic stem cells

Morrison, Sean J.; Scadden, David T.

doi:10.1038/nature12984

Cited by 1,933 publications

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“…In summary, our data demonstrate a stem cell extrinsic contribution to HSC aging (Medyouf et al , 2014; Morrison & Scadden, 2014) and indicate a critical role for reduced stroma‐derived OPN in promoting aging‐associated phenotypes on HSCs. We further identified thrombin‐cleaved OPN as a novel treatment for ameliorating segments of hematopoietic stem cell aging.…”

Section: Discussionsupporting

confidence: 58%

Osteopontin attenuates aging‐associated phenotypes of hematopoietic stem cells

et al. 2017

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Upon aging, hematopoietic stem cells (HSCs) undergo changes in function and structure, including skewing to myeloid lineages, lower reconstitution potential and loss of protein polarity. While stem cell intrinsic mechanisms are known to contribute to HSC aging, little is known on whether age‐related changes in the bone marrow niche regulate HSC aging. Upon aging, the expression of osteopontin (OPN) in the murine bone marrow stroma is reduced. Exposure of young HSCs to an OPN knockout niche results in a decrease in engraftment, an increase in long‐term HSC frequency and loss of stem cell polarity. Exposure of aged HSCs to thrombin‐cleaved OPN attenuates aging of old HSCs, resulting in increased engraftment, decreased HSC frequency, increased stem cell polarity and a restored balance of lymphoid and myeloid cells in peripheral blood. Thus, our data suggest a critical role for reduced stroma‐derived OPN for HSC aging and identify thrombin‐cleaved OPN as a novel niche informed therapeutic approach for ameliorating HSC phenotypes associated with aging.

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Section: Discussionsupporting

confidence: 58%

Osteopontin attenuates aging‐associated phenotypes of hematopoietic stem cells

et al. 2017

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“…Just as the quest for the identification of HSCs has historically been the driving force for the dissection of the hematopoietic system, much of what has been learned on BM microarchitecture has been gleaned from formative studies in search of the HSC niche. 69 Indeed, significant progress has been achieved. However, beyond the precise nature of HSC niches, much is still to be learned on the spatiotemporal dynamics of hematopoiesis.…”

Section: Outlook and Future Challengesmentioning

confidence: 99%

Quantification and three-dimensional microanatomical organization of the bone marrow

Nombela‐Arrieta

Manz

2017

Blood Advances

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Bone marrow (BM) constitutes one of the largest organs in mice and humans, continuously generating, in a highly regulated manner, red blood cells, platelets, and white blood cells that together form the majority of cells of the body. In this review, we provide a quantitative overview of BM cellular composition, we summarize emerging knowledge on its structural organization and cellular niches, and we argue for the need of multidimensional approaches such as recently developed imaging techniques to uncover the complex spatial logic that underlies BM function in health and disease.Since Neumann and Bizzozero independently proposed in 1868 that the origin of blood cells was to be found in soft tissues contained inside bone cavities, the bone marrow (BM) has continued to fascinate scientists and clinicians alike. 1,2 Yet more than a century later, our understanding of how the hematopoietic, immune, and bone-forming tasks of the BM are tightly controlled and integrated in the context of one common anatomical space is still incomplete. Methodological approaches and advances to study BM tissuesEarly studies on BM cellular composition and microarchitecture date back to the 19th century when the first biopsies of marrow content were performed in living individuals. 3 Microscopic observation of BM smears and examination of histological sections became the standard technique, which is still used to this day to study, diagnose, and classify hematologic disorders. The realization in the post-World War II era that transplantation of BM cells from healthy individuals could rescue the lethal effects of high-dose irradiation on hematopoiesis galvanized scientific interest in BM and lead to the development of methods to detect and measure hematopoietic stem and progenitor cell (HSPC) activity, absolute cellularity, lineage-specific half-lives, and kinetics of cell production in the BM of humans and in laboratory animals. 4,5 Gradual improvements in light and electron microscopy further refined the understanding of the quantitative composition and ultrastructural features of BM tissues. 6 The biggest leap in the fields of immunology and hematology came with the advent of recombinant antibody technology and flow cytometry in the 1960s. These breakthroughs permitted the identification, quantification, and isolation of diverse populations from highly heterogeneous cell suspensions through detection of phenotypic traits. 5 Indeed, to this day, flow cytometry remains the technological mainstay for the study and dissection of the hematopoietic system.Immunolabeling methods were further adopted in modern fluorescence-based microscopy to discriminate cellular phenotypes in tissue sections and study cellular organization in the BM. In recent years, confocal microscopy has become the most popular modality to define spatial relationships and study developmental-stage specific localization patterns, with a keen interest of many groups in the dissection of HSPC niches. 7 In addition, intravital multiphoton microscopy is employed to obtain dyna...

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“…Recent evidence also reveals that perivascular Nestin + mesenchymal progenitor cells form a supportive niche for HSCs [3,7,8]. In addition, studies from Dr. Morrison suggest that HSCs mainly reside in the perivascular niches whereas the early lymphoid progenitor cells prefer to locate at endosteal niches [9,10].Correspondence: Dr. Xizhi Guo e-mail: xzguo2005@sjtu.edu.cn; zjyao@sjtu.edu.cnCompelling evidence reveals that Wnt signaling is an important regulator for HSCs integrity and function. Wnt proteins, which consist of 19 members in mammals, could be transduced through canonical or noncanonical signaling pathways [11].…”

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confidence: 99%

Ablation of Wntless in endosteal niches impairs lymphopoiesis rather than HSCs maintenance

et al. 2015

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Osteoblasts and perivascular stromal cells constitute essential niches for HSC selfrenewal and maintenance in the bone marrow. Wnt signaling is important to maintain HSC integrity. However, the paracrine role of Wnt proteins in osteoblasts-supported HSC maintenance and differentiation remains unclear. Here, we investigated hematopoiesis in mice with Wntless (Wls) deficiency in osteoblasts or Nestin-positive mesenchymal progenitor cells, which presumptively block Wnt secretion in osteoblasts. We detected defective B-cell lymphopoiesis and abnormal T-cell infiltration in the bone marrow of Wls mutant mice. Notably, no impact on HSC frequency and repopulation in the bone marrow was observed with the loss of osteoblastic Wls. Our findings revealed a supportive role of Wnts in osteoblasts-regulated B-cell lymphopoiesis. They also suggest a preferential niche role of osteoblastic Wnts for lymphoid cells rather than HSCs, providing new clues for the molecular nature of distinct niches occupied by different hematopoietic cells.Keywords: B cell r HSC maintenance r Osteoblast r T-cell infiltration r Wntless Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionHSCs that periodically generate all hematopoietic lineages are mostly stored in vascular or endosteal niches in the bone marrow [1]. Vascular niches consist of sinusoidal endothelium cells [2][3][4] whereas endosteal niches are mainly composed of osteoblasts [5,6]. These niche cells are important to regulate HSCs self-renewal and maintenance. Recent evidence also reveals that perivascular Nestin + mesenchymal progenitor cells form a supportive niche for HSCs [3,7,8]. In addition, studies from Dr. Morrison suggest that HSCs mainly reside in the perivascular niches whereas the early lymphoid progenitor cells prefer to locate at endosteal niches [9,10].Correspondence: Dr. Xizhi Guo e-mail: xzguo2005@sjtu.edu.cn; zjyao@sjtu.edu.cnCompelling evidence reveals that Wnt signaling is an important regulator for HSCs integrity and function. Wnt proteins, which consist of 19 members in mammals, could be transduced through canonical or noncanonical signaling pathways [11]. β-Catenin is the key and obligatory mediator of canonical Wnt signaling. Stabilized β-catenin expression expands the pool of HSCs and leads to deficiency in HSCs repopulation capacity [12,13]. Conversely, deletion of β-catenin or Wnt3a leads to defective HSCs long-term maintenance [14,15]. Nevertheless, several lines of evidence also indicate that β-catenin is dispensable for HSCs maintenance [16,17]. On the other hand, inhibition of environmental canonical Wnt signaling in osteoblasts impairs HSCs self-renewal and quiescence [18]. Collectively, canonical Wnt signaling is revealed to * These authors contributed equally to this work. regulate HSCs self-renewal in a dosage-dependent manner [19]. In addition, noncanonical Wnt signaling is also reported to sustain HSCs maintenance and aging [20,21]. Osteoblasts also support B-cell commitment an...

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The bone marrow niche for haematopoietic stem cells

Cited by 1,933 publications

References 122 publications

Osteopontin attenuates aging‐associated phenotypes of hematopoietic stem cells

Osteopontin attenuates aging‐associated phenotypes of hematopoietic stem cells

Quantification and three-dimensional microanatomical organization of the bone marrow

Ablation of Wntless in endosteal niches impairs lymphopoiesis rather than HSCs maintenance

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