scholarly journals The bone marrow niche components are adversely affected in sepsis

2020 ◽  
Vol 1 (1) ◽  
Author(s):  
Fan Yin ◽  
Han Qian ◽  
Caiwen Duan ◽  
Botao Ning
Keyword(s):  
Bone Marrow ◽  
Vascular Endothelial Cells ◽  
Cecal Ligation ◽  
Treg Cells ◽  
Multiple Organ ◽  
Bone Marrow Niche ◽  
Vascular Endothelial ◽  
Bm Niche ◽  
Cell Components ◽  
The Impact

Abstract Multiple organ dysfunction is an important cause of death in patients with sepsis. Currently, few studies have focused on the impact of sepsis on bone marrow (BM), especially on the cell components of BM niche. In this study, we performed mouse sepsis models by intraperitoneal injection of LPS and cecal ligation and puncture (CLP). The changes of niche major components in the mouse BM among vascular structures, mesenchymal stem cells and Treg cells were observed and analyzed. The results showed that pathological changes in BM was earlier and more prominent than in other organs, and various cell components of the BM niche changed significantly, of which vascular endothelial cells increased transiently with vascular remodeling and the regulatory T cells decreased over a long period of time. These results indicated that the components of the BM niche underwent series of adaptive changes in sepsis.

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 Bioengineering the Bone Marrow Vascular Niche

2021 ◽  
Vol 9 ◽  
Author(s):  
Thomas Bessy ◽  
Tomer Itkin ◽  
Diana Passaro
Keyword(s):  
Bone Marrow ◽  
Vascular System ◽  
Vascular Endothelial Cells ◽  
Vascular Endothelial ◽  
Experimental Systems ◽  
Bm Niche ◽  
Bone Marrow Vascular Niche ◽  
Structural Levels

The bone marrow (BM) tissue is the main physiological site for adult hematopoiesis. In recent years, the cellular and matrix components composing the BM have been defined with unprecedent resolution, both at the molecular and structural levels. With the expansion of this knowledge, the possibility of reproducing a BM-like structure, to ectopically support and study hematopoiesis, becomes a reality. A number of experimental systems have been implemented and have displayed the feasibility of bioengineering BM tissues, supported by cells of mesenchymal origin. Despite being known as an abundant component of the BM, the vasculature has been largely disregarded for its role in regulating tissue formation, organization and determination. Recent reports have highlighted the crucial role for vascular endothelial cells in shaping tissue development and supporting steady state, emergency and malignant hematopoiesis, both pre- and postnatally. Herein, we review the field of BM-tissue bioengineering with a particular focus on vascular system implementation and integration, starting from describing a variety of applicable in vitro models, ending up with in vivo preclinical models. Additionally, we highlight the challenges of the field and discuss the clinical perspectives in terms of adoptive transfer of vascularized BM-niche grafts in patients to support recovering hematopoiesis.

Hematopoietic insults damage bone marrow niche by activating p53 in vascular endothelial cells

2018 ◽  
Vol 63 ◽  
pp. 41-51.e1 ◽  
Author(s):  
Sha Si ◽  
Yaeko Nakajima-Takagi ◽  
Takahito Iga ◽  
Mayoko Tsuji ◽  
Libo Hou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Vascular Endothelial Cells ◽  
Bone Marrow Niche ◽  
Vascular Endothelial

scholarly journals IFNy Stimulation Induces Hematopoietic Stem Cell Homing and Niche Relocalization

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3726-3726
Author(s):  
Marcus A Florez ◽  
Katie A Matatall ◽  
Laura Ortinau ◽  
Roman Jaksik ◽  
Marek Kimmel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Terminal Differentiation ◽  
Bone Marrow Niche ◽  
Hematopoietic Stem ◽  
Bm Niche ◽  
The Impact

Interferon gamma (IFNy) is a pro-inflammatory cytokine that is upregulated during chronic infections and chronic diseases, such as aplastic anemia, and has been associated with pancytopenia and diminished hematopoiesis. Studies have shown that IFNy negatively regulates hematopoietic stem cell (HSC) homeostasis by decreasing self-renewal and promoting terminal differentiation. The tight regulation of HSC homeostasis is dependent upon the bone marrow (BM) microenvironment, or BM niche. The BM niche is composed of a network of cell types that provide elaborate cell-cell interactions, cellular metabolites, transcriptional regulators, and local and distant humoral and neural signals that allow for hematopoietic homeostasis. In particular, CXCL12-abundant reticular (CAR) cells are vital to HSC maintenance, as depletion of CXCL12, or its receptor, leads to HSC depletion. However, the mechanism which IFNy activates HSCs and influences its interaction with the BM niche is unknown. We hypothesize that IFNy promotes HSC terminal differentiation and loss of quiescence by altering HSC interactions with the BM niche. To assess changes in HSC interactions with the BM niche upon IFNy stimulation, we performed intravital imaging using CXCL12 GFP reporter mice before and after administration of recombinant IFNy. We found that HSCs stimulated with IFNy were significantly distanced from CAR cells compared to pre-treated controls. There was no change in distance with IFNy-receptor deficient HSCs, suggesting that movement away from the CAR cells was due to a cell autonomous IFNy-dependent mechanism. We performed gene expression analysis and transwell migration assays on HSCs from IFNy treated mice, and determined that there was no change in CXCL12 receptor (CXCR4) expression upon IFNy treatment, and IFNy did not alter migration towards CXCL12. These results suggest that HSC re-localization upon IFNy is independent of CXCL12 signaling. To explore the mechanism by which IFNy induces re-localization of HSCs, we first performed microarray analysis on HSCs from IFNy stimulated mice to assess what surface proteins were changed upon IFNy treatment. While there was no change in common HSC receptors thought to influence HSC homeostasis (cKit, Cdh2, Mpl, Itgb1, Itbg2, Itga4, and Itga1), we observed an increase in expression of bone marrow stromal antigen 2 (BST2). To explore the impact of BST2 on HSC homeostasis, quantification and proliferation analysis was performed on HSCs from Bst2-/- mice. Interestingly, Bst2-/- HSCs were significantly less proliferative and more abundant compared to controls. These studies suggest that BST2 may play a role in maintaining HSC homeostasis. The functional role of BST2 in cellular movement and adhesion has been studied in cancer. Increased BST2 expression has been associated with promoting the migration, adhesion and metastasis of various cancer cells. Since migration and adhesion is important for HSC homing, we assessed the effects of IFNy on HSC homing. Hematopoietic progenitors from IFNy-treated mice homed to the bone marrow with greater efficiency than PBS-treated controls, whereas progenitors from IFNy-receptor-deficientmice showed a decrease in homing. Additionally, WBM from IFNyR-/- had reduced engraftment than wildtype, consistent with a role for IFNy signaling in promoting HSC homing. The impact of BST2 on homing is currently being explored. In summary, we show that IFNy induces re-localization of HSCs away from quiescence-promoting CAR cells within the bone marrow niche via a mechanism that is independent of CXCL12 signaling. We further show that IFNy promotes HSC homing. The increased expression of BST2 on IFNy-stimulated HSCs appears to impact HSC proliferation and abundance in the bone marrow. Thus, BST2 may play a role in HSC activation and exit from quiescence. Expanding our understanding of the mechanism that drives HSC activation and terminal differentiation has important implications for patients who develop pancytopenia or bone marrow failure due to chronic inflammation. Disclosures No relevant conflicts of interest to declare.

Angiogenesis and Osteoclastogenesis Are Mutually Stimulated in Myeloma: A Role for VEGF and Osteopontin.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2500-2500
Author(s):  
Yoichi Tanaka ◽  
Masahiro Abe ◽  
Masahiro Hiasa ◽  
Toshihiro Hashimoto ◽  
Shinsuke Kido ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Culture Media ◽  
Vascular Endothelial Cells ◽  
Control Culture ◽  
Vascular Density ◽  
Vascular Endothelial ◽  
Cellular Interactions ◽  
The Impact

Abstract Angiogenesis and osteoclastogenesis occur in the bone marrow as myeloma (MM) progresses. Suppression of osteoclastogenesis by bisphosphonates reduced tumor burden as well as vascular density in the BM in myeloma animal models(Croucher et al. 2003). These evidences suggest a link between angiogenesis, osteoclastogenesis and MM tumor expansion which orchestrates a network of co-operative cellular interactions. We have previously demonstrated that a cell-cell interaction between osteoclasts (OCs) and MM cells potently enhanced MM cell growth and survival as well as angiogenesis. Such angiogenic effects were almost completely abrogated by antibodies against VEGF and osteopontin (OPN) in combination, suggesting VEGF and OPN as predominant angiogenic factors produced in MM bone marrow microenvironment. Angiogenesis is a multi-step process including migration, proliferation and sprouting in response to angiogenic stimuli. The impact of these factors on these angiogenic processes as well as on osteoclastogenesis by vascular cells is largely unknown. We therefore investigated roles for OPN and VEGF in combination in different steps in angiogenesis and in induction of osteoclastogenic activity by vascular endothelial cells. Conditioned media (CM) from co-cultures of peripheral blood mononuclear cell-derived OCs and RPMI8226 cells at 10 % enhanced survival of HUVEC under factor-deprived conditions 3-fold compared to control culture media, and transmigration of HUVEC 1.5-fold. Antibodies against VEGF and OPN each alone partially and both in combination mostly abrogated these effects of the CM. Consistently, VEGF and OPN co-operatively promoted survival and transmigration of HUVEC as well as angiogenesis in vitro. In order to further clarify a role for VEGF and OPN in a link between angiogenesis and osteoclastogenesis, we next examined osteoclastogenic activity produced by HUVEC upon VEGF and OPN stimulation using rabbit bone cell cultures on dentine slices. CM were collected from HUVEC cultured on either OPN- or type 1 collagen-coated wells in the presence or absence of VEGF. CM from OPN-coated wells with VEGF enhanced OC formation most potently(2.8-fold) compared to control culture media, while CM from OPN-coated wells without VEGF, type 1 collagen-coated wells with VEGF and type 1 collagen-coated wells without VEGF enhanced 2-, 1.8- and 1.2-fold, respectively, indicating co-operative actions of VEGF and OPN. Furthermore, such VEGF and OPN treatment was found to induce osteoclastogenic IL-8 by HUVEC most apparently among 125 different cytokines determined by cytokine antibody arrays. These results suggest that VEGF and OPN derived from MM cells and OCs cause angiogenesis as well as osteoclastogenesis at least in part through the enhancement of migration and survival and the induction of osteoclastogenic activity of vascular endothelial cells, thereby mutually stimulating angiogenesis and osteoclastogenesis. Therefore, VEGF and OPN may be a therapeutic target against MM bone marrow environment to ameliorate bone destruction along with MM expansion.

scholarly journals Endothelial-to-mesenchymal transition in lipopolysaccharide-induced acute lung injury drives a progenitor cell-like phenotype

2016 ◽  
Vol 310 (11) ◽  
pp. L1185-L1198 ◽  
Author(s):  
Toshio Suzuki ◽  
Yuji Tada ◽  
Rintaro Nishimura ◽  
Takeshi Kawasaki ◽  
Ayumi Sekine ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Vascular Endothelial Cells ◽  
Repair Process ◽  
Vascular Endothelial ◽  
Mesenchymal Transition ◽  
Oxidase Inhibition ◽  
Endothelial To Mesenchymal Transition

Pulmonary vascular endothelial function may be impaired by oxidative stress in endotoxemia-derived acute lung injury. Growing evidence suggests that endothelial-to-mesenchymal transition (EndMT) could play a pivotal role in various respiratory diseases; however, it remains unclear whether EndMT participates in the injury/repair process of septic acute lung injury. Here, we analyzed lipopolysaccharide (LPS)-treated mice whose total number of pulmonary vascular endothelial cells (PVECs) transiently decreased after production of reactive oxygen species (ROS), while the population of EndMT-PVECs significantly increased. NAD(P)H oxidase inhibition suppressed EndMT of PVECs. Most EndMT-PVECs derived from tissue-resident cells, not from bone marrow, as assessed by mice with chimeric bone marrow. Bromodeoxyuridine-incorporation assays revealed higher proliferation of capillary EndMT-PVECs. In addition, EndMT-PVECs strongly expressed c- kit and CD133. LPS loading to human lung microvascular endothelial cells (HMVEC-Ls) induced reversible EndMT, as evidenced by phenotypic recovery observed after removal of LPS. LPS-induced EndMT-HMVEC-Ls had increased vasculogenic ability, aldehyde dehydrogenase activity, and expression of drug resistance genes, which are also fundamental properties of progenitor cells. Taken together, our results demonstrate that LPS induces EndMT of tissue-resident PVECs during the early phase of acute lung injury, partly mediated by ROS, contributing to increased proliferation of PVECs.

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 PTPN21 Overexpression Promotes Osteogenic and Adipogenic Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells but Inhibits the Immunosuppressive Function

2019 ◽  
Vol 2019 ◽  
pp. 1-19 ◽  
Author(s):  
Huafang Wang ◽  
Xiaohang Ye ◽  
Haowen Xiao ◽  
Ni Zhu ◽  
Cong Wei ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Bone Marrow ◽  
Endothelial Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Cells ◽  
Vascular Endothelial Cells ◽  
Adipogenic Differentiation ◽  
Target Cells ◽  
Vascular Endothelial

Protein tyrosine phosphatases (PTPs) act as key regulators in various cellular processes such as proliferation, differentiation, and migration. Our previous research demonstrated that non-receptor-typed PTP21 (PTPN21), a member of the PTP family, played a critical role in the proliferation, cell cycle, and chemosensitivity of acute lymphoblastic leukemia cells. However, the role of PTPN21 in the bone marrow microenvironment has not yet been elucidated. In the study, we explored the effects of PTPN21 on human bone marrow-derived mesenchymal stem cells (BM-MSCs) via lentiviral-mediated overexpression and knock-down of PTPN21 in vitro. Overexpressing PTPN21 in BM-MSCs inhibited the proliferation through arresting cell cycle at the G0 phase but rendered them a higher osteogenic and adipogenic differentiation potential. In addition, overexpressing PTPN21 in BM-MSCs increased their senescence levels through upregulation of P21 and P53 and dramatically changed the levels of crosstalk with their typical target cells including immunocytes, tumor cells, and vascular endothelial cells. BM-MSCs overexpressing PTPN21 had an impaired immunosuppressive function and an increased capacity of recruiting tumor cells and vascular endothelial cells in a chemotaxis transwell coculture system. Collectively, our data suggested that PTPN21 acted as a pleiotropic factor in modulating the function of human BM-MSCs.

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.

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