scholarly journals Distinct skeletal stem cell types orchestrate long bone skeletogenesis

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Thomas H Ambrosi ◽  
Rahul Sinha ◽  
Holly M Steininger ◽  
Malachia Y Hoover ◽  
Matthew P Murphy ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Bone Growth ◽  
Cell Types ◽  
Long Bone ◽  
Cell Populations ◽  
Limited Information ◽  
Hematopoietic Stem ◽  
Hematopoietic Stem Cell Niche ◽  
Skeletal Stem Cell

Skeletal stem and progenitor cell populations are crucial for bone physiology. Characterization of these cell types remains restricted to heterogenous bulk populations with limited information on whether they are unique or overlap with previously characterized cell types. Here we show, through comprehensive functional and single-cell transcriptomic analyses, that postnatal long bones of mice contain at least two types of bone progenitors with bona fide skeletal stem cell (SSC) characteristics. An early osteochondral SSC (ocSSC) facilitates long bone growth and repair, while a second type, a perivascular SSC (pvSSC), co-emerges with long bone marrow and contributes to shape the hematopoietic stem cell niche and regenerative demand. We establish that pvSSCs, but not ocSSCs, are the origin of bone marrow adipose tissue. Lastly, we also provide insight into residual SSC heterogeneity as well as potential crosstalk between the two spatially distinct cell populations. These findings comprehensively address previously unappreciated shortcomings of SSC research.

scholarly journals Combined Single-Cell and Spatial Transcriptomics to Deconvolute the Hematopoietic Stem Cell Niche

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 876-876
Author(s):  
Simon Haas ◽  
Chiara Baccin ◽  
Jude Al-Sabah ◽  
Lars Velten ◽  
Steinmetz Lars ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Single Cell ◽  
Hematopoietic Stem Cell ◽  
Transcriptional Profiling ◽  
Stem Cell Differentiation ◽  
Cell Types ◽  
Hematopoietic Stem ◽  
Stem Cell Maintenance ◽  
Hematopoietic Stem Cell Niche

Abstract Coordinated interaction of many cell types is required to facilitate hematopoietic and mesenchymal stem cell maintenance and differentiation in the bone marrow. However, the molecular factors and cell types involved in this complex interplay remain poorly understood. Here we developed a combined single cell and spatial transcriptomics approach to address this problem. Large-scale single-cell transcriptional profiling in conjunction with a multi-layered sorting approach allowed us to generate a complete and evenly sampled transcriptional map of all major bone and bone marrow populations. Our dataset covers all cell types or differentiation trajectories involved in mesenchymal and hematopoietic stem cell differentiation, osteogenesis, adipogenesis, myelopoiesis, erythropoiesis, lymphopoiesis, memory T cell formation as well as bone marrow neural innervation and vascularization at the single cell level. Using this data, we derive fundamental properties of the described cell types, clarify the cellular source of signals affecting stem cell differentiation processes and provide a systems view on putative intercellular interactions. Systematic spatial transcriptomics, using laser-capture microdissection of selected bone marrow niches followed by transcriptional profiling and bioinformatic cellular deconvolution, allowed us to confirm predicted interactions and map the cellular composition of distinct bone marrow niches. Our analyses highlight the importance of pre-adipogenic CXCL12 abundant reticular cells as key niche cells for stem cell maintenance, provides a holistic systems view of the hematopoietic stem cell niche and offers a novel approach to systematically deconvolute the molecular, cellular and spatial composition of complex tissues. Disclosures No relevant conflicts of interest to declare.

scholarly journals Hematopoietic Stem Cell Niche During Homeostasis, Malignancy, and Bone Marrow Transplantation

2021 ◽  
Vol 9 ◽  
Author(s):  
Yan Man ◽  
Xiangmei Yao ◽  
Tonghua Yang ◽  
Yajie Wang
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Hematological Malignancies ◽  
Hematopoietic Cells ◽  
Cell Types ◽  
Hematopoietic Stem ◽  
Hematopoietic Stem Cell Niche ◽  
Bm Niche

Self-renewal and multidirectional differentiation of hematopoietic stem cells (HSCs) are strictly regulated by numerous cellular components and cytokines in the bone marrow (BM) microenvironment. Several cell types that regulate HSC niche have been identified, including both non-hematopoietic cells and HSC-derived cells. Specific changes in the niche composition can result in hematological malignancies. Furthermore, processes such as homing, proliferation, and differentiation of HSCs are strongly controlled by the BM niche and have been reported to be related to the success of hematopoietic stem cell transplantation (HSCT). Single-cell sequencing and in vivo imaging are powerful techniques to study BM microenvironment in hematological malignancies and after HSCT. In this review, we discuss how different components of the BM niche, particularly non-hematopoietic and hematopoietic cells, regulate normal hematopoiesis, and changes in the BM niche in leukemia and after HSCT. We believe that this comprehensive review will provide clues for further research on improving HSCT efficiency and exploring potential therapeutic targets for leukemia.

scholarly journals Closer to Nature: The Role of MSCs in Recreating the Microenvironment of the Hematopoietic Stem Cell Niche in vitro

2022 ◽  
pp. 1-10
Author(s):  
Patrick Wuchter ◽  
Anke Diehlmann ◽  
Harald Klüter
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Niche ◽  
Model Systems ◽  
Bone Marrow Niche ◽  
Hematopoietic Stem ◽  
Hematopoietic Stem Cell Niche ◽  
Cell Niche

<b><i>Background:</i></b> The stem cell niche in human bone marrow provides scaffolds, cellular frameworks and essential soluble cues to support the stemness of hematopoietic stem and progenitor cells (HSPCs). To decipher this complex structure and the corresponding cellular interactions, a number of in vitro model systems have been developed. The cellular microenvironment is of key importance, and mesenchymal stromal cells (MSCs) represent one of the major cellular determinants of the niche. Regulation of the self-renewal and differentiation of HSPCs requires not only direct cellular contact and adhesion molecules, but also various cytokines and chemokines. The C-X-C chemokine receptor type 4/stromal cell-derived factor 1 axis plays a pivotal role in stem cell mobilization and homing. As we have learned in recent years, to realistically simulate the physiological in vivo situation, advanced model systems should be based on niche cells arranged in a three-dimensional (3D) structure. By providing a dynamic rather than static setup, microbioreactor systems offer a number of advantages. In addition, the role of low oxygen tension in the niche microenvironment and its impact on hematopoietic stem cells need to be taken into account and are discussed in this review. <b><i>Summary:</i></b> This review focuses on the role of MSCs as a part of the bone marrow niche, the interplay between MSCs and HSPCs and the most important regulatory factors that need to be considered when engineering artificial hematopoietic stem cell niche systems. <b><i>Conclusion:</i></b> Advanced 3D model systems using MSCs as niche cells and applying microbioreactor-based technology are capable of simulating the natural properties of the bone marrow niche more closely than ever before.

scholarly journals The identification of fibrosis-driving myofibroblast precursors reveals new therapeutic avenues in myelofibrosis

Blood ◽  
2018 ◽  
Vol 131 (19) ◽  
pp. 2111-2119 ◽  
Author(s):  
Rafael Kramann ◽  
Rebekka K. Schneider
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Stromal Cells ◽  
Stem Cell Niche ◽  
Solid Organ ◽  
Hematopoietic Stem ◽  
Gli Proteins ◽  
Hematopoietic Stem Cell Niche ◽  
Cell Niche ◽  
Organ Fibrosis

Abstract Myofibroblasts are fibrosis-driving cells and are well characterized in solid organ fibrosis, but their role and cellular origin in bone marrow fibrosis remains obscure. Recent work has demonstrated that Gli1+ and LepR+ mesenchymal stromal cells (MSCs) are progenitors of fibrosis-causing myofibroblasts in the bone marrow. Genetic ablation of Gli1+ MSCs or pharmacologic targeting of hedgehog (Hh)-Gli signaling ameliorated fibrosis in mouse models of myelofibrosis (MF). Moreover, pharmacologic or genetic intervention in platelet-derived growth factor receptor α (Pdgfrα) signaling in Lepr+ stromal cells suppressed their expansion and ameliorated MF. Improved understanding of cellular and molecular mechanisms in the hematopoietic stem cell niche that govern the transition of MSCs to myofibroblasts and myofibroblast expansion in MF has led to new paradigms in the pathogenesis and treatment of MF. Here, we highlight the central role of malignant hematopoietic clone-derived megakaryocytes in reprogramming the hematopoietic stem cell niche in MF with potential detrimental consequences for hematopoietic reconstitution after allogenic stem cell transplantation, so far the only therapeutic approach in MF considered to be curative. We and others have reported that targeting Hh-Gli signaling is a therapeutic strategy in solid organ fibrosis. Data indicate that targeting Gli proteins directly inhibits Gli1+ cell proliferation and myofibroblast differentiation, which results in reduced fibrosis severity and improved organ function. Although canonical Hh inhibition (eg, smoothened [Smo] inhibition) failed to improve pulmonary fibrosis, kidney fibrosis, or MF, the direct inhibition of Gli proteins ameliorated fibrosis. Therefore, targeting Gli proteins directly might be an interesting and novel therapeutic approach in MF.

scholarly journals P04.45 Periarteriolar glioblastoma stem cell niches express bone marrow hematopoietic stem cell niche proteins

2018 ◽  
Vol 20 (suppl_3) ◽  
pp. iii289-iii289
Author(s):  
V V V Hira ◽  
J R Wormer ◽  
H Kakar ◽  
B Breznik ◽  
B van der Swaan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Stem Cell Niche ◽  
Hematopoietic Stem ◽  
Glioblastoma Stem Cell ◽  
Hematopoietic Stem Cell Niche ◽  
Cell Niche ◽  
Stem Cell Niches

scholarly journals Author Correction: Adrenergic nerve degeneration in bone marrow drives aging of the hematopoietic stem cell niche

2019 ◽  
Vol 25 (4) ◽  
pp. 701-701 ◽  
Author(s):  
Maria Maryanovich ◽  
Ali H. Zahalka ◽  
Halley Pierce ◽  
Sandra Pinho ◽  
Fumio Nakahara ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Stem Cell Niche ◽  
Nerve Degeneration ◽  
Adrenergic Nerve ◽  
Hematopoietic Stem ◽  
Hematopoietic Stem Cell Niche ◽  
Cell Niche

scholarly journals Restoration and reversible expansion of the osteoblastic hematopoietic stem cell niche after marrow radioablation

Blood ◽  
2009 ◽  
Vol 114 (11) ◽  
pp. 2333-2343 ◽  
Author(s):  
Massimo Dominici ◽  
Valeria Rasini ◽  
Rita Bussolari ◽  
Xiaohua Chen ◽  
Ted J. Hofmann ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Growth Factor ◽  
Hematopoietic Stem Cell ◽  
Donor Cell ◽  
Subsequent Increase ◽  
Hematopoietic Stem ◽  
Hematopoietic Stem Cell Niche ◽  
Cell Engraftment ◽  
Cell Niche

Abstract Adequate recovery of hematopoietic stem cell (HSC) niches after cytotoxic conditioning regimens is essential to successful bone marrow transplantation. Yet, very little is known about the mechanisms that drive the restoration of these niches after bone marrow injury. Here we describe a profound disruption of the marrow microenvironment after lethal total body irradiation of mice that leads to the generation of osteoblasts restoring the HSC niche, followed by a transient, reversible expansion of this niche. Within 48 hours after irradiation, surviving host megakaryocytes were observed close to the endosteal surface of trabecular bone rather than in their normal parasinusoidal site concomitant with an increased stromal-derived factor-1 level. A subsequent increase in 2 megakaryocyte-derived growth factors, platelet-derived growth factor-β and basic fibroblast growth factor, induces a 2-fold expansion of the population of N-cadherin-/osteopontin-positive osteoblasts, relative to the homeostatic osteoblast population, and hence, increases the number of potential niches for HSC engraftment. After donor cell engraftment, this expanded microenvironment reverts to its homeostatic state. Our results demonstrate the rapid recovery of osteoblastic stem cell niches after marrow radioablation, provide critical insights into the associated mechanisms, and suggest novel means to manipulate the bone marrow microenvironment to promote HSC engraftment.

scholarly journals Making sense of hematopoietic stem cell niches

Blood ◽  
2015 ◽  
Vol 125 (17) ◽  
pp. 2621-2629 ◽  
Author(s):  
Philip E. Boulais ◽  
Paul S. Frenette
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Molecular Mechanisms ◽  
Mesenchymal Cell ◽  
Cell Populations ◽  
Specific Cell ◽  
Hematopoietic Stem ◽  
Hsc Niche ◽  
Differentiation And Proliferation

Abstract The hematopoietic stem cell (HSC) niche commonly refers to the pairing of hematopoietic and mesenchymal cell populations that regulate HSC self-renewal, differentiation, and proliferation. Anatomic localization of the niche is a dynamic unit from the developmental stage that allows proliferating HSCs to expand before they reach the bone marrow where they adopt a quiescent phenotype that protects their integrity and functions. Recent studies have sought to clarify the complexity behind the HSC niche by assessing the contributions of specific cell populations to HSC maintenance. In particular, perivascular microenvironments in the bone marrow confer distinct vascular niches that regulate HSC quiescence and the supply of lineage-committed progenitors. Here, we review recent data on the cellular constituents and molecular mechanisms involved in the communication between HSCs and putative niches.

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