scholarly journals Neurogenic Heterotopic Ossifications Recapitulate Hematopoietic Stem Cell Niche Development Within an Adult Osteogenic Muscle Environment

2021 ◽  
Vol 9 ◽  
Author(s):  
Dorothée Girard ◽  
Frédéric Torossian ◽  
Estelle Oberlin ◽  
Kylie A. Alexander ◽  
Jules Gueguen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Nervous System ◽  
Transforming Growth Factor ◽  
Bone Development ◽  
Developmental State ◽  
Oncostatin M ◽  
Hematopoietic Stem ◽  
Heterotopic Ossifications ◽  
Stromal Microenvironment ◽  
Hematopoietic Stem Cell Niche

Hematopoiesis and bone interact in various developmental and pathological processes. Neurogenic heterotopic ossifications (NHO) are the formation of ectopic hematopoietic bones in peri-articular muscles that develop following severe lesions of the central nervous system such as traumatic cerebral or spinal injuries or strokes. This review will focus on the hematopoietic facet of NHO. The characterization of NHO demonstrates the presence of hematopoietic marrow in which quiescent hematopoietic stem cells (HSC) are maintained by a functional stromal microenvironment, thus documenting that NHOs are neo-formed ectopic HSC niches. Similarly to adult bone marrow, the NHO permissive environment supports HSC maintenance, proliferation and differentiation through bidirectional signaling with mesenchymal stromal cells and endothelial cells, involving cell adhesion molecules, membrane-bound growth factors, hormones, and secreted matrix proteins. The participation of the nervous system, macrophages and inflammatory cytokines including oncostatin M and transforming growth factor (TGF)-β in this process, reveals how neural circuitry fine-tunes the inflammatory response to generate hematopoietic bones in injured muscles. The localization of NHOs in the peri-articular muscle environment also suggests a role of muscle mesenchymal cells and bone metabolism in development of hematopoiesis in adults. Little is known about the establishment of bone marrow niches and the regulation of HSC cycling during fetal development. Similarities between NHO and development of fetal bones make NHOs an interesting model to study the establishment of bone marrow hematopoiesis during development. Conversely, identification of stage-specific factors that specify HSC developmental state during fetal bone development will give more mechanistic insights into NHO.

scholarly journals Dual cholinergic signals regulate daily migration of hematopoietic stem cells and leukocytes

Blood ◽  
2019 ◽  
Vol 133 (3) ◽  
pp. 224-236 ◽  
Author(s):  
Andrés García-García ◽  
Claudia Korn ◽  
María García-Fernández ◽  
Olivia Domingues ◽  
Javier Villadiego ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Nervous System ◽  
Adrenergic Receptor ◽  
Leukocyte Trafficking ◽  
Vascular Cell Adhesion ◽  
Cholinergic Activity ◽  
Vascular Cell ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells

AbstractHematopoietic stem and progenitor cells (HSPCs) and leukocytes circulate between the bone marrow (BM) and peripheral blood following circadian oscillations. Autonomic sympathetic noradrenergic signals have been shown to regulate HSPC and leukocyte trafficking, but the role of the cholinergic branch has remained unexplored. We have investigated the role of the cholinergic nervous system in the regulation of day/night traffic of HSPCs and leukocytes in mice. We show here that the autonomic cholinergic nervous system (including parasympathetic and sympathetic) dually regulates daily migration of HSPCs and leukocytes. At night, central parasympathetic cholinergic signals dampen sympathetic noradrenergic tone and decrease BM egress of HSPCs and leukocytes. However, during the daytime, derepressed sympathetic noradrenergic activity causes predominant BM egress of HSPCs and leukocytes via β3–adrenergic receptor. This egress is locally supported by light-triggered sympathetic cholinergic activity, which inhibits BM vascular cell adhesion and homing. In summary, central (parasympathetic) and local (sympathetic) cholinergic signals regulate day/night oscillations of circulating HSPCs and leukocytes. This study shows how both branches of the autonomic nervous system cooperate to orchestrate daily traffic of HSPCs and leukocytes.

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 Changes in the Multipotent Stromal Mesenchymal Cells from the Bone Marrow of the Patients with Hematological Diseases in Debut and after the Treatment

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5014-5014
Author(s):  
Irina N. Shipounova ◽  
Nataliya A. Petinati ◽  
Nina J. Drize ◽  
Aminat A. Magomedova ◽  
Ekaterina A. Fastova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Stromal Cells ◽  
Myeloid Leukemia ◽  
Marker Gene ◽  
Malignant Cells ◽  
Hematopoietic Stem ◽  
Stromal Microenvironment ◽  
Expression Of Genes

Introduction. Stromal microenvironment of the bone marrow (BM) is essential for normal hematopoiesis; the very same cells are involved in the interaction with the leukemic stem cells. The aim of the study was to reveal the alterations in stromal microenvironment of patients in debut and after the therapy using multipotent mesenchymal stromal cells (MSC) as a model. Methods. MSC of patients with acute myeloid leukemia (AML, N=32), acute lymphoblastic leukemia (ALL, N=20), chronic myeloid leukemia (CML, N=19), and diffuse large B-cell lymphoma without BM involvement (DLBCL, N=17) were isolated by standard method from the patients' BM. Each BM sample was acquired during diagnostic aspiration after the informed signed consent was obtained from the patient. Groups of BM donors comparable by age and gender were used as controls for each nosology. Gene expression was analyzed with real-time RT-PCR. The significance of differences was evaluated with Mann-Whitney U-test. Results. The results of gene expression analysis are summarized in Table. The expression of genes regulating hematopoietic stem and precursor cells (JAG1, LIF, IL6) was significantly upregulated in MSC of the patients in debut, except for DLBCL. The latter was characterized with upregulation of osteogenic marker gene SPP1 and downregulation of FGFR1 gene. The upregulation of the expression of genes regulating proliferation of stromal cells (PDGFRA, FGFR1) and adipogenic marker gene (PPARG) was common for AML and CML. Both acute leukemias were characterized by the upregulation of genes associated with inflammation and regulation of hematopoietic precursors (CSF1, IL1B, IL1BR1) and by the downregulation of chondrogenic differentiation marker gene (SOX9). CML and DLBCL demonstrated the upregulation of FGFR2. BM of the DLBCL patients did not contain any malignant cells; nevertheless, stromal precursors from the BM were significantly affected. This indicates the distant effects of DLBCL malignant cells on the patients' BM. Myeloid malignancies seem to affect MSC more profoundly then lymphoid ones. Effect of leukemic cells on stromal microenvironment in case of myeloid leukemia was more pronounced. The treatment significantly affected gene expression in MSC of patients. In all studied nosologies the IL6 gene expression was upregulated, which may reflect the inflammation processes ongoing in the organism. The expression of LIF was upregulated and ICAM1, downregulated in MSCs of AML, ALL, and CML patients. In the MSC of patients with AML, who had received the highest doses of cytostatic drugs to achieve remission, a significant decrease in the expression of most studied genes was found. In patients with ALL with long-term continuing treatment in combination with lower doses of drugs, IL1B expression was increased, while the decrease in expression was detected for a number of genes regulating hematopoietic stem cells (SDF1, TGFB1), differentiation and proliferation (SOX9, FGFR1, FGFR2). Treatment of CML patients is based on tyrosine kinase inhibitors in doses designed for long-term use, and is less damaging for MSC. The upregulation of TGFB1, SOX9, PDGFRA genes and downregulation of IL1B gene was revealed. MCS of DLBCL patients, unlike the other samples, were analyzed after the end of treatment. Nevertheless, significant upregulation of IL8 and FGFR2 genes was found. Thus, both the malignant cells and chemotherapy affect stromal precursor cells. The changes are not transient; they are preserved for a few months at least. MSCs comprise only a minor subpopulation in the BM in vivo. When expanded in vitro, they demonstrate significant changes between groups of patients and healthy donors. Conclusions. Leukemia cells adapt the stromal microenvironment. With different leukemia, the same changes are observed in the expression of genes in MSC. MSC of patients with acute forms have a lot of changes which coincide among these two diseases. MSC of AML patients are most affected both in debut and after the therapy. Treatment depends on the nosology and in varying degrees changes the MSC. This work was supported by the Russian Foundation for Basic Research, project no. 17-00-00170. Disclosures Chelysheva: Novartis: Consultancy, Honoraria; Fusion Pharma: Consultancy. Shukhov:Novartis: Consultancy; Pfizer: Consultancy. Turkina:Bristol Myers Squibb: Consultancy; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; Novartis: Consultancy, Speakers Bureau; fusion pharma: Consultancy.

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 Signals from the Sympathetic Nervous System Regulate Hematopoietic Stem Cell Egress from Bone Marrow

Cell ◽  
2006 ◽  
Vol 124 (2) ◽  
pp. 407-421 ◽  
Author(s):  
Yoshio Katayama ◽  
Michela Battista ◽  
Wei-Ming Kao ◽  
Andrés Hidalgo ◽  
Anna J. Peired ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Nervous System ◽  
Stem Cell ◽  
Sympathetic Nervous System ◽  
Hematopoietic Stem Cell ◽  
Hematopoietic Stem ◽  
Sympathetic Nervous

Protection of CML Progenitors from Bcr-Abl Tyrosine Kinase Inhibitor Mediated Apoptosis by the Bone Marrow Stromal Microenvironment.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3378-3378
Author(s):  
Bin Zhang ◽  
Heiko Konig ◽  
Tinisha Mcdonald ◽  
Tessa L. Holyoake ◽  
Dario Campana ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Tyrosine Kinase ◽  
Progenitor Cells ◽  
Direct Contact ◽  
Hematopoietic Stem ◽  
Transwell Insert ◽  
Abl Tyrosine Kinase ◽  
Stromal Microenvironment ◽  
Cd34 Cells ◽  
Tki Treatment

Abstract The therapeutic success of imatinib mesylate (IM) in chronic myeloid leukemia (CML) is impaired by persistence of malignant hematopoietic stem and progenitor cells (HSPC). The bone marrow microenvironment regulates the self-renewal, proliferation and differentiation of HSPC. We investigated the role of microenvironmental interactions in resistance of CML HSPC to elimination by BCR-ABL tyrosine kinase inhibitors (TKI). CML CD34+CD38− primitive progenitor cells and CD34+CD38+ committed progenitor cells were cultured for 96 hours with IM (5μM), nilotinib (5μM) and dasatinib(150nM), in medium supplemented with low concentrations of growth factors, with and without irradiated primary human marrow stromal cells (immortalized by ectopic telomerase expression) followed by an assessment of apoptosis and proliferation. Culture with stroma did not result in significant alteration of apoptosis in the absence of TKI treatment (3.1±0.7% apoptosis for primitive progenitors with stroma and 2.7±0.9% without stroma, 3.7±0.2% for committed progenitors with stroma and 4.7±2.1% without stroma). Coculture with stroma completely protected CML primitive and committed progenitors from TKI-induced apoptosis. CML CD34+CD38− cells demonstrated 20±6% apoptosis following culture with IM in the absence of stroma, but only 3.8±1% apoptosis in the presence of stroma (p=0.04, n=4). Similarly, apoptosis with nilotinib decreased from 12.5±1.8% without stroma to 2.9±0.3% with stroma (p=0.033), and apoptosis with dasatinib decreased from 7.1±0.04% without stroma to 2.7±0.2% with stroma (p=0.001). Apoptosis of CML CD34+CD38+ cells also significantly decreased following TKI treatment with 12.9±4.0%, 10.6±3.2%, 8.4±2.3% apoptosis observed after IM, nilotinib and dasatinib treatment respectively without stroma and 7.1±1.2%, 4.8±1.0%, 3.7±0.4% with stroma, (p=0.04, p=0.03 and p=0.02 respectively, n=4). Culture with stroma resulted in mild reduction in CML progenitor proliferation in the absence of TKI treatment, but TKI treatment resulted in similar degrees of inhibition of proliferation regardless of the presence of stroma. Culture of CML CD34+ cells in a Transwell insert with 0.45μm pores, allowing free diffusion of stromal factors but preventing direct contact with stroma, was associated with reduction in the protective effect of stroma coculture (32.2% apoptosis without stroma, 14.7% with stroma, and 24.6% with Transwell insert). Addition of blocking antibodies to a4 integrin and N-cadherin did not affect survival of CML CD34+ cells in the absence of IM, but resulted in enhanced apoptosis of CML CD34+ cells cocultured with stroma after addition of IM (20.4% apoptosis without antibody, 28.9% with anti-N-cadherin, and 29.8% with anti-integrin antibody). We conclude that the bone marrow stromal microenvironment protects CML primitive and committed progenitors from pro-apoptotic effects of BCR-ABL TKI treatment. Direct contact-mediated interactions, likely through VLA-4 and N-Cadherin, play an important role in protecting CML CD34+ cells from TKI-mediated apoptosis. These observations indicate that measures aimed at interfering with the protective effects of stroma could be of benefit for the eradication of residual malignant progenitors in CML patients receiving BCR-ABL TKI treatment.

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