scholarly journals Hematopoietic Stem Cell Function in β-Thalassemia Is Impaired and Is Rescued By Targeting the Bone Marrow Niche

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 967-967
Author(s):  
Annamaria Aprile ◽  
Alessandro Gulino ◽  
Isabella Villa ◽  
Stefano Beretta ◽  
Ivan Merelli ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Metabolism ◽  
Molecular Mechanisms ◽  
Common Finding ◽  
Bone Marrow Niche ◽  
Hematopoietic Stem ◽  
Bm Niche ◽  
Stromal Component ◽  
Hsc Niche ◽  
Bone Deposition

Hematopoietic stem cells (HSC) are regulated by signals from the bone marrow (BM) niche and little is known about their fate in altered hematological conditions associated to non-malignant diseases. In β-thalassemia ineffective erythropoiesis and secondary alterations, as abnormal regulation of bone metabolism, iron overload and hormonal factors, induce changes in the BM homeostasis with a potential impact on HSC-niche interaction. We addressed these unexplored issues in the murine disease model and in patients' cells. We investigated hematopoiesis in thalassemic Hbbth3/+ (th3) mutant mice and we found lower frequency, reduced quiescence and reconstituting potential of HSC. th3 HSC have impaired self-renewal, which is rescued upon transplantation in a normal BM, proving an active role of the niche microenvironment. Both stromal and hematopoietic components of the BM niche are altered in th3 mice. Consistently with the common finding of osteoporosis in patients, we found reduced bone deposition with decreased levels of parathyroid hormone (PTH), which is a key regulator of bone metabolism but also of HSC activity. Low PTH negatively affects bone deposition and expression of the Notch-ligand Jag1 by th3 mesenchymal and osteolineage cells, thus reducing the activation of Notch1 in HSC and consequently impairing their function. In vivo activation of PTH signaling through the reestablished Jag1-Notch1 pathway restores the functional pool of th3 HSC by correcting HSC-niche crosstalk. In addition to the stromal component of the BM, hematopoietic cells with a key role in regulating the fate of HSC, such as megakaryocytes (Mk), were found defective in maturation, possibly due to reduced circulating levels of thrombopoietin (TPO). We are currently investigating the molecular causes of dysmegakaryopoiesis and the Mk-HSC interaction in thalassemic mice. Strikingly, reduced HSC quiescence was confirmed in samples from patients affected by β-thalassemia, along with impaired stromal niche and megakaryopoiesis, thus highlighting the clinical relevance of our findings. Further investigation will unravel the multiple molecular mechanisms that affect in trans HSC functions in the complexity of the stressed thalassemic BM microenvironment. Our results uncover a defect of HSC in β-thalassemia, induced by an altered BM niche and provide new relevant insight for improving transplantation and gene therapy approaches. Disclosures No relevant conflicts of interest to declare.

scholarly journals Hematopoietic stem cell function in β-thalassemia is impaired and is rescued by targeting the bone marrow niche

Blood ◽  
2020 ◽  
Vol 136 (5) ◽  
pp. 610-622 ◽  
Author(s):  
Annamaria Aprile ◽  
Alessandro Gulino ◽  
Mariangela Storto ◽  
Isabella Villa ◽  
Stefano Beretta ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cross Talk ◽  
Cell Function ◽  
Active Role ◽  
Common Finding ◽  
Bone Marrow Niche ◽  
Hematopoietic Stem ◽  
Bm Niche ◽  
Hsc Niche

Abstract Hematopoietic stem cells (HSCs) are regulated by signals from the bone marrow (BM) niche that tune hematopoiesis at steady state and in hematologic disorders. To understand HSC-niche interactions in altered nonmalignant homeostasis, we selected β-thalassemia, a hemoglobin disorder, as a paradigm. In this severe congenital anemia, alterations secondary to the primary hemoglobin defect have a potential impact on HSC-niche cross talk. We report that HSCs in thalassemic mice (th3) have an impaired function, caused by the interaction with an altered BM niche. The HSC self-renewal defect is rescued after cell transplantation into a normal microenvironment, thus proving the active role of the BM stroma. Consistent with the common finding of osteoporosis in patients, we found reduced bone deposition with decreased levels of parathyroid hormone (PTH), which is a key regulator of bone metabolism but also of HSC activity. In vivo activation of PTH signaling through the reestablished Jagged1 and osteopontin levels correlated with the rescue of the functional pool of th3 HSCs by correcting HSC-niche cross talk. Reduced HSC quiescence was confirmed in thalassemic patients, along with altered features of the BM stromal niche. Our findings reveal a defect in HSCs in β-thalassemia induced by an altered BM microenvironment and provide novel and relevant insight for improving transplantation and gene therapy approaches.

scholarly journals Bone marrow stromal cells from MDS and AML patients show increased adipogenic potential with reduced Delta-like-1 expression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Marie-Theresa Weickert ◽  
Judith S. Hecker ◽  
Michèle C. Buck ◽  
Christina Schreck ◽  
Jennifer Rivière ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Fate ◽  
Stromal Cells ◽  
Adipogenic Differentiation ◽  
Cell Types ◽  
Bone Marrow Niche ◽  
Differentiation Potential ◽  
Hematopoietic Stem ◽  
Bm Niche

AbstractMyelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are clonal hematopoietic stem cell disorders with a poor prognosis, especially for elderly patients. Increasing evidence suggests that alterations in the non-hematopoietic microenvironment (bone marrow niche) can contribute to or initiate malignant transformation and promote disease progression. One of the key components of the bone marrow (BM) niche are BM stromal cells (BMSC) that give rise to osteoblasts and adipocytes. It has been shown that the balance between these two cell types plays an important role in the regulation of hematopoiesis. However, data on the number of BMSC and the regulation of their differentiation balance in the context of hematopoietic malignancies is scarce. We established a stringent flow cytometric protocol for the prospective isolation of a CD73+ CD105+ CD271+ BMSC subpopulation from uncultivated cryopreserved BM of MDS and AML patients as well as age-matched healthy donors. BMSC from MDS and AML patients showed a strongly reduced frequency of CFU-F (colony forming unit-fibroblast). Moreover, we found an altered phenotype and reduced replating efficiency upon passaging of BMSC from MDS and AML samples. Expression analysis of genes involved in adipo- and osteogenic differentiation as well as Wnt- and Notch-signalling pathways showed significantly reduced levels of DLK1, an early adipogenic cell fate inhibitor in MDS and AML BMSC. Matching this observation, functional analysis showed significantly increased in vitro adipogenic differentiation potential in BMSC from MDS and AML patients. Overall, our data show BMSC with a reduced CFU-F capacity, and an altered molecular and functional profile from MDS and AML patients in culture, indicating an increased adipogenic lineage potential that is likely to provide a disease-promoting microenvironment.

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.

Functional and Molecular Alterations of Bone Marrow Mesenchymal Stem and Progenitor Cells in Patients with Myelodysplastic Syndrome with Ring Sideroblast

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1489-1489
Author(s):  
Monika Dolinska ◽  
Pingnan Xiao ◽  
Anne-Sofie Johansson ◽  
Lakshmi Sandhow ◽  
Makoto Kondo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Endothelial Cells ◽  
Myelodysplastic Syndrome ◽  
Stromal Cell ◽  
Molecular Mechanisms ◽  
Bone Marrow Niche ◽  
Differentiation Potential ◽  
Hematopoietic Stem ◽  
Molecular Alterations

Abstract Myelodysplastic Syndrome with Ring Sideroblast (MDS-RS), a clonal hematopoietic cell neoplasm, is low risk MDS, characterized by anemia, hyperplastic ineffective erythropoiesis and marrow ring sideroblasts. Mouse studies have shown that bone marrow niche, including endothelial cells, osteoblasts, adipocytes and mesenchymal stem cells (MSCs), contribute to progression of various hematological disorders. However, in vivo contribution of the different bone marrow stromal cells to the progression of MDS-RS in patients remains largely unknown. To investigate this, we have phenotypically, molecularly and functionally characterized the BM native stromal cell subsets including MSCs freshly isolated by multi-color fluorescence activated cell sorting (FACS) from bone marrow of MDS-RS patients and age-matched healthy donors. We found: 1) the MDS-RS MSCs, estimated by colony forming unit-fibroblast (CFU-F), shared similar immunophenotype with normal MSCs (CD45-CD235a-CD31-CD44-, most of which were CD271+CD146+CD106+); 2) the frequency of CFU-Fs was significantly increased in the phenotypically defined MSCs of MDS-RS bone marrow compared to that of age-matched healthy controls (p=0.005); 3) multi-lineage differentiation assay revealed impaired osteogenic differentiation potential, but enhanced adipogenic differentiation potential of MDS-RS MSCs; 4) FACS analysis showed increased frequency of the adhesion receptor integrin α4 (ITGA4) in the CD44- MSCs from MDS-RS bone marrow (p=0.013); 5) Correspondingly, RNA-sequencing of the freshly isolated bone marrow MSCs and endothelial cells revealed altered gene expression profile of these cells in MDS-RS patients. Among those, ITGA4, ITGA11, ITGAE and ITGB1 are upregulated in the MDS-RS MSCs, indicating potential abnormal adhesive interaction of the MSCs with hematopoietic stem cells in the patients. In addition, the cell cycling gene KI67 is upregulated whereas cell cycle negative regulators, like CDKN1A and CDKN1C are downregulated in the MDS-RS MSCs, which is consistent with their increased CFU-F activity. Interestingly, we detected abnormal expression of hematopoietic growth factors such as downregulation of ANGPTL4 in the MDS-RS MSCs and upregulation of ANGPT1 in the MDS-RS endothelial cells. The functional relationship between the stromal cell alterations and the abnormal hematopoiesis as well as the underlying molecular mechanisms are currently under investigation. Taken together, our data provide new evidence for phenotypic, functional and molecular alterations of bone marrow mesenchymal cells in MDS-RS patients. The molecular pathways mediating bone marrow niche alteration could be potential therapeutic targets for new treatment of MDS-RS. Disclosures No relevant conflicts of interest to declare.

scholarly journals Treatment-induced arteriolar revascularization and miR-126 enhancement in bone marrow niche protect leukemic stem cells in AML

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Bin Zhang ◽  
Le Xuan Truong Nguyen ◽  
Dandan Zhao ◽  
David E. Frankhouser ◽  
Huafeng Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Molecular Mechanisms ◽  
Severe Disease ◽  
Confocal Imaging ◽  
Bone Marrow Niche ◽  
Leukemic Stem Cells ◽  
Vascular Changes ◽  
Bm Niche ◽  
The Impact

Abstract Background During acute myeloid leukemia (AML) growth, the bone marrow (BM) niche acquires significant vascular changes that can be offset by therapeutic blast cytoreduction. The molecular mechanisms of this vascular plasticity remain to be fully elucidated. Herein, we report on the changes that occur in the vascular compartment of the FLT3-ITD+ AML BM niche pre and post treatment and their impact on leukemic stem cells (LSCs). Methods BM vasculature was evaluated in FLT3-ITD+ AML models (MllPTD/WT/Flt3ITD/ITD mouse and patient-derived xenograft) by 3D confocal imaging of long bones, calvarium vascular permeability assays, and flow cytometry analysis. Cytokine levels were measured by Luminex assay and miR-126 levels evaluated by Q-RT-PCR and miRNA staining. Wild-type (wt) and MllPTD/WT/Flt3ITD/ITD mice with endothelial cell (EC) miR-126 knockout or overexpression served as controls. The impact of treatment-induced BM vascular changes on LSC activity was evaluated by secondary transplantation of BM cells after administration of tyrosine kinase inhibitors (TKIs) to MllPTD/WT/Flt3ITD/ITD mice with/without either EC miR-126 KO or co-treatment with tumor necrosis factor alpha (TNFα) or anti-miR-126 miRisten. Results In the normal BM niche, CD31+Sca-1high ECs lining arterioles have miR-126 levels higher than CD31+Sca-1low ECs lining sinusoids. We noted that during FLT3-ITD+ AML growth, the BM niche lost arterioles and gained sinusoids. These changes were mediated by TNFα, a cytokine produced by AML blasts, which induced EC miR-126 downregulation and caused depletion of CD31+Sca-1high ECs and gain in CD31+Sca-1low ECs. Loss of miR-126high ECs led to a decreased EC miR-126 supply to LSCs, which then entered the cell cycle and promoted leukemia growth. Accordingly, antileukemic treatment with TKI decreased the BM blast-produced TNFα and increased miR-126high ECs and the EC miR-126 supply to LSCs. High miR-126 levels safeguarded LSCs, as shown by more severe disease in secondary transplanted mice. Conversely, EC miR-126 deprivation via genetic or pharmacological EC miR-126 knock-down prevented treatment-induced BM miR-126high EC expansion and in turn LSC protection. Conclusions Treatment-induced CD31+Sca-1high EC re-vascularization of the leukemic BM niche may represent a LSC extrinsic mechanism of treatment resistance that can be overcome with therapeutic EC miR-126 deprivation. Graphic abstract

scholarly journals Neuronal regulation of bone marrow stem cell niches

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 614 ◽  
Author(s):  
Claire Fielding ◽  
Simón Méndez-Ferrer
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Steady State ◽  
Sympathetic Innervation ◽  
Hematopoietic Stem ◽  
Regulatory Processes ◽  
Lineage Differentiation ◽  
Bm Niche ◽  
Neuronal Regulation ◽  
Hsc Niche

The bone marrow (BM) is the primary site of postnatal hematopoiesis and hematopoietic stem cell (HSC) maintenance. The BM HSC niche is an essential microenvironment which evolves and responds to the physiological demands of HSCs. It is responsible for orchestrating the fate of HSCs and tightly regulates the processes that occur in the BM, including self-renewal, quiescence, engraftment, and lineage differentiation. However, the BM HSC niche is disturbed following hematological stress such as hematological malignancies, ionizing radiation, and chemotherapy, causing the cellular composition to alter and remodeling to occur. Consequently, hematopoietic recovery has been the focus of many recent studies and elucidating these mechanisms has great biological and clinical relevance, namely to exploit these mechanisms as a therapeutic treatment for hematopoietic malignancies and improve regeneration following BM injury. The sympathetic nervous system innervates the BM niche and regulates the migration of HSCs in and out of the BM under steady state. However, recent studies have investigated how sympathetic innervation and signaling are dysregulated under stress and the subsequent effect they have on hematopoiesis. Here, we provide an overview of distinct BM niches and how they contribute to HSC regulatory processes with a particular focus on neuronal regulation of HSCs under steady state and stress hematopoiesis.

scholarly journals The Hematopoietic Bone Marrow Niche Ecosystem

2021 ◽  
Vol 9 ◽  
Author(s):  
Julia Fröbel ◽  
Theresa Landspersky ◽  
Gülce Percin ◽  
Christina Schreck ◽  
Susann Rahmig ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Stress ◽  
Stress Responses ◽  
Current Knowledge ◽  
Cell Formation ◽  
Bone Marrow Niche ◽  
Transient Effects ◽  
Hematopoietic Stem ◽  
Bm Niche

The bone marrow (BM) microenvironment, also called the BM niche, is essential for the maintenance of fully functional blood cell formation (hematopoiesis) throughout life. Under physiologic conditions the niche protects hematopoietic stem cells (HSCs) from sustained or overstimulation. Acute or chronic stress deregulates hematopoiesis and some of these alterations occur indirectly via the niche. Effects on niche cells include skewing of its cellular composition, specific localization and molecular signals that differentially regulate the function of HSCs and their progeny. Importantly, while acute insults display only transient effects, repeated or chronic insults lead to sustained alterations of the niche, resulting in HSC deregulation. We here describe how changes in BM niche composition (ecosystem) and structure (remodeling) modulate activation of HSCs in situ. Current knowledge has revealed that upon chronic stimulation, BM remodeling is more extensive and otherwise quiescent HSCs may be lost due to diminished cellular maintenance processes, such as autophagy, ER stress response, and DNA repair. Features of aging in the BM ecology may be the consequence of intermittent stress responses, ultimately resulting in the degeneration of the supportive stem cell microenvironment. Both chronic stress and aging impair the functionality of HSCs and increase the overall susceptibility to development of diseases, including malignant transformation. To understand functional degeneration, an important prerequisite is to define distinguishing features of unperturbed niche homeostasis in different settings. A unique setting in this respect is xenotransplantation, in which human cells depend on niche factors produced by other species, some of which we will review. These insights should help to assess deviations from the steady state to actively protect and improve recovery of the niche ecosystem in situ to optimally sustain healthy hematopoiesis in experimental and clinical settings.

scholarly journals Modeling the human bone marrow niche in mice: From host bone marrow engraftment to bioengineering approaches

2018 ◽  
Vol 215 (3) ◽  
pp. 729-743 ◽  
Author(s):  
Ander Abarrategi ◽  
Syed A. Mian ◽  
Diana Passaro ◽  
Kevin Rouault-Pierre ◽  
William Grey ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mouse Models ◽  
Hematopoietic Cells ◽  
Human Growth ◽  
Human Bone ◽  
Human Bone Marrow ◽  
Bone Marrow Niche ◽  
Hematopoietic Stem ◽  
Bm Niche ◽  
Stem And Progenitor Cells

Xenotransplantation of patient-derived samples in mouse models has been instrumental in depicting the role of hematopoietic stem and progenitor cells in the establishment as well as progression of hematological malignancies. The foundations for this field of research have been based on the development of immunodeficient mouse models, which provide normal and malignant human hematopoietic cells with a supportive microenvironment. Immunosuppressed and genetically modified mice expressing human growth factors were key milestones in patient-derived xenograft (PDX) models, highlighting the importance of developing humanized microenvironments. The latest major improvement has been the use of human bone marrow (BM) niche–forming cells to generate human–mouse chimeric BM tissues in PDXs, which can shed light on the interactions between human stroma and hematopoietic cells. Here, we summarize the methods used for human hematopoietic cell xenotransplantation and their milestones and review the latest approaches in generating humanized BM tissues in mice to study human normal and malignant hematopoiesis.

scholarly journals Inducible Sbds Deletion Impairs Bone Marrow Niche Capacity to Engraft Donor Bone Marrow After Transplantation

2021 ◽  
Author(s):  
Ji Zha ◽  
Lori K Kunselman ◽  
Hongbo M Xie ◽  
Brian Ennis ◽  
Yash B. Shah ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Failure ◽  
Bone Marrow Niche ◽  
Growth Factor Signaling ◽  
Hematopoietic Stem ◽  
Bone Marrow Failure Syndromes ◽  
Bm Niche ◽  
Pathway Activation ◽  
Donor Bone Marrow ◽  
Novel Therapeutic Strategies

Bone marrow (BM) niche-derived signals are critical for facilitating engraftment after hematopoietic stem cell (HSC) transplantation (HSCT). HSCT is required for restoration of hematopoiesis in patients with inherited bone marrow failure syndromes (iBMFS). Shwachman-Diamond syndrome (SDS) is a rare iBMFS associated with mutations in SBDS. Previous studies have demonstrated that SBDS deficiency in osteolineage niche cells causes bone marrow dysfunction that promotes leukemia development. However, it is unknown whether BM niche defects caused by SBDS deficiency also impair efficient engraftment of healthy donor HSC following HSCT, a hypothesis that could explain morbidity seen after clinical HSCT for patients with SDS. Here, we report a mouse model with inducible Sbds deletion in hematopoietic and osteolineage cells. Primary and secondary BM transplantation (BMT) studies demonstrated that SBDS deficiency within BM niches caused poor donor hematopoietic recovery and specifically poor HSC engraftment after myeloablative BMT. We have additionally identified multiple molecular and cellular defects within niche populations that are driven by SBDS deficiency and that are accentuated or develop specifically following myeloablative conditioning. These abnormalities include altered frequencies of multiple niche cell subsets including mesenchymal lineage cells, macrophages and endothelial cells; disruption of growth factor signaling, chemokine pathway activation, and adhesion molecule expression; and p53 pathway activation, and signals involved in cell cycle arrest. Taken together, this study demonstrates that SBDS deficiency profoundly impacts recipient hematopoietic niche function in the setting of HSCT, suggesting that novel therapeutic strategies targeting host niches could improve clinical HSCT outcomes for patients with SDS.

Role of Cell Adhesion in the Maintenance of Hematopoietic Stem Cells in the Bone Marrow Niche.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 669-669
Author(s):  
Fumio Arai ◽  
Atsushi Hirao ◽  
Kentaroh Hosokawa ◽  
Toshio Suda
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Cell Adhesion ◽  
Side Population ◽  
Bone Marrow Niche ◽  
Bone Surface ◽  
Hematopoietic Stem ◽  
Bm Niche

Abstract Interaction of HSCs with their particular microenvironments, known as the stem cell niches, is critical for adult hematopoiesis in the bone marrow (BM). HSCs are keeping the balance of the quiescence and the self-renewal in the stem cell niche, and are maintaining long-term hematopoiesis. We have demonstrated that HSCs expressing the receptor tyrosine kinase Tie2 are quiescent and anti-apoptotic, transplantable and comprise a side-population (SP) of HSCs, which contact closely to angiopoietin-1, a ligand for Tie2, expressing osteoblasts (OBs) in the BM niche. Tie2 and Ang-1 are part of a key signaling interaction between HSCs and niche cells. This signaling pathway regulates the feature of HSCs in the BM niche. The interaction of Tie2 with Ang-1 in vitro is sufficient to maintain the long-term blood-repopulating (LTR) activity of HSCs in vivo by preventing cell division. In addition, Ang-1 enhanced the ability of HSCs to become quiescent and also induced their adhesion to bone surface, resulting protection of HSC compartment from stresses which suppress hematopoiesis (Arai et al., Cell, 2004). In this study, we focused on the role of cell adhesion molecule on the maintenance of HSCs in BM niche. A previous paper reported that both quiescent HSCs and some of osteoblasts express N-cadherin. We found that Tie2+ HSC expressed N- and VE-cadherin, and OBs expressed N-, P-, and OB-cadherin. This suggests that an adherens junction between HSCs and OBs created via N-cadherin may contribute to HSC maintenance. Furthermore, N-cadherin overexpressing OP9 stromal cells (OP9/N-cadherin) maintained LTC-IC more than control OP9 cells did. Overexpression of N-cadherin in HSCs also maintained colony formation. In addition, in the presence of Ang-1 in coculture of OP9/N-cadherin and HSCs facilitated the maintenance of CFU-C and HPP-CFC formation after long-term culture. Furthermore, Ang-1 treatment upregulated the expression of N-cadherin in Tie2+ HSCs as well as β1-integrin. It suggests that Tie2/Ang-1 signaling enhanced cell-cell adhesion between HSCs and OBs. Altogether, these observations led us to the novel model that the localization of HSCs on bone surface is regulated by stem cell specific adhesion molecules such as N-cadherin. Once the HSCs adjacently localize to OBs, Ang-1 produced by OBs may activate Tie2 on the HSCs and promote tight adhesion of HSCs in the niche, resulting in quiescence and enhanced survival of HSCs.

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