scholarly journals Spatial transcriptome profiling by MERFISH reveals fetal liver hematopoietic stem cell niche architecture

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yanfang Lu ◽  
Miao Liu ◽  
Jennifer Yang ◽  
Sherman M. Weissman ◽  
Xinghua Pan ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Spatial Organization ◽  
Fetal Liver ◽  
Transcriptome Profiling ◽  
Cell Types ◽  
Systematic Investigation ◽  
Hematopoietic Stem ◽  
Hematopoietic Stem Cell Niche ◽  
Hsc Niche

AbstractThe hematopoietic stem cell (HSC) niche has been extensively studied in bone marrow, yet a more systematic investigation into the microenvironment regulation of hematopoiesis in fetal liver is necessary. Here we investigate the spatial organization and transcriptional profile of individual cells in both wild type (WT) and Tet2−/− fetal livers, by multiplexed error robust fluorescence in situ hybridization. We find that specific pairs of fetal liver cell types are preferentially positioned next to each other. Ligand-receptor signaling molecule pairs such as Kitl and Kit are enriched in neighboring cell types. The majority of HSCs are in direct contact with endothelial cells (ECs) in both WT and Tet2−/− fetal livers. Loss of Tet2 increases the number of HSCs, and upregulates Wnt and Notch signaling genes in the HSC niche. Two subtypes of ECs, arterial ECs and sinusoidal ECs, and other cell types contribute distinct signaling molecules to the HSC niche. Collectively, this study provides a comprehensive picture and bioinformatic foundation for HSC spatial regulation in fetal liver.

Osteopontin, a key component of the hematopoietic stem cell niche and regulator of primitive hematopoietic progenitor cells

Blood ◽  
2005 ◽  
Vol 106 (4) ◽  
pp. 1232-1239 ◽  
Author(s):  
Susan K. Nilsson ◽  
Hayley M. Johnston ◽  
Genevieve A. Whitty ◽  
Brenda Williams ◽  
Ryan J. Webb ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Negative Regulator ◽  
Hematopoietic Stem ◽  
Hematopoietic Stem Cell Niche ◽  
Hsc Niche ◽  
Cell Niche

Abstract Although recent data suggests that osteoblasts play a key role within the hematopoietic stem cell (HSC) niche, the mechanisms underpinning this remain to be fully defined. The studies described herein examine the role in hematopoiesis of Osteopontin (Opn), a multidomain, phosphorylated glycoprotein, synthesized by osteoblasts, with well-described roles in cell adhesion, inflammatory responses, angiogenesis, and tumor metastasis. We demonstrate a previously unrecognized critical role for Opn in regulation of the physical location and proliferation of HSCs. Within marrow, Opn expression is restricted to the endosteal bone surface and contributes to HSC transmarrow migration toward the endosteal region, as demonstrated by the markedly aberrant distribution of HSCs in Opn–/– mice after transplantation. Primitive hematopoietic cells demonstrate specific adhesion to Opn in vitro via β1 integrin. Furthermore, exogenous Opn potently suppresses the proliferation of primitive HPCs in vitro, the physiologic relevance of which is demonstrated by the markedly enhanced cycling of HSC in Opn–/– mice. These data therefore provide strong evidence that Opn is an important component of the HSC niche which participates in HSC location and as a physiologic-negative regulator of HSC proliferation.

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 Rebuilding the hematopoietic stem cell niche: recent developments and future prospects

2021 ◽  
Author(s):  
Chandralekha Chatterjee ◽  
Peter Schertl ◽  
Miriam Frommer ◽  
Anita Ludwig-Husemann ◽  
Anna Mohra ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Stem Cell Niche ◽  
Future Prospects ◽  
Hematopoietic Stem ◽  
Hematopoietic Stem Cell Niche ◽  
Recent Developments ◽  
Cell Niche

scholarly journals Osteoclasts promote the formation of hematopoietic stem cell niches in the bone marrow

2012 ◽  
Vol 209 (3) ◽  
pp. 537-549 ◽  
Author(s):  
Anna Mansour ◽  
Grazia Abou-Ezzi ◽  
Ewa Sitnicka ◽  
Sten Eirik W. Jacobsen ◽  
Abdelilah Wakkach ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Endochondral Ossification ◽  
Osteoblastic Differentiation ◽  
Hematopoietic Stem ◽  
Mesenchymal Progenitors ◽  
Hsc Niche ◽  
Niche Formation

Formation of the hematopoietic stem cell (HSC) niche in bone marrow (BM) is tightly associated with endochondral ossification, but little is known about the mechanisms involved. We used the oc/oc mouse, a mouse model with impaired endochondral ossification caused by a loss of osteoclast (OCL) activity, to investigate the role of osteoblasts (OBLs) and OCLs in the HSC niche formation. The absence of OCL activity resulted in a defective HSC niche associated with an increased proportion of mesenchymal progenitors but reduced osteoblastic differentiation, leading to impaired HSC homing to the BM. Restoration of OCL activity reversed the defect in HSC niche formation. Our data demonstrate that OBLs are required for establishing HSC niches and that osteoblastic development is induced by OCLs. These findings broaden our knowledge of the HSC niche formation, which is critical for understanding normal and pathological hematopoiesis.

scholarly journals In memory of Paul Sylvain Frenette, a pioneering explorer of the hematopoietic stem cell niche who left far too early

2021 ◽  
Author(s):  
Jean-Pierre Lévesque ◽  
Louise E Purton ◽  
Andrés Hidalgo ◽  
Leonard Zon ◽  
Yoshio Katayama ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Stem Cell Niche ◽  
Hematopoietic Stem ◽  
Hematopoietic Stem Cell Niche ◽  
Cell Niche

HLF Expression Defines the Human Hematopoietic Stem Cell State.

Blood ◽  
2021 ◽  
Author(s):  
Bernhard Lehnertz ◽  
Jalila Chagraoui ◽  
Tara MacRae ◽  
Elisa Tomellini ◽  
Sophie Corneau ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Fetal Liver ◽  
Cell Activity ◽  
Mouse Strains ◽  
Marker Genes ◽  
Hematopoietic Stem ◽  
Cell State ◽  
Human Hscs ◽  
Stem Cell State

Hematopoietic stem cells (HSCs) sustain blood cell homeostasis throughout life and can regenerate all blood lineages following transplantation. Despite this clear functional definition, highly enriched isolation of human HSCs can currently only be achieved through combinatorial assessment of multiple surface antigens. While several transgenic HSC reporter mouse strains have been described, no analogous approach to prospectively isolate human HSCs has been reported. To identify genes with the most selective expression in human HSCs, we profiled population- and single-cell transcriptomes of un-expanded and ex vivo cultured cord blood-derived HSPCs as well as peripheral blood, adult bone marrow, and fetal liver. Based on these analyses, we propose the master transcription factor HLF (Hepatic Leukemia Factor) as one of the most specific HSC marker genes. To directly track its expression in human hematopoietic cells, we developed a genomic HLF reporter strategy, capable of selectively labeling the most immature blood cells based on a single engineered parameter. Most importantly, HLF-expressing cells comprise all of the stem cell activity in culture and in vivo during serial transplantation. Taken together, these results experimentally establish HLF as a defining gene of the human hematopoietic stem cell state and outline a new approach to continuously mark these cells with high fidelity.

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