Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 2.975
Filter
1.
Gut Microbes ; 16(1): 2350784, 2024.
Article in English | MEDLINE | ID: mdl-38727219

ABSTRACT

The gut microbiota constitutes a vast ecological system within the human body, forming a mutually interdependent entity with the host. In recent years, advancements in molecular biology technologies have provided a clearer understanding of the role of the gut microbiota. They not only influence the local immune status and metabolic functions of the host's intestinal tract but also impact the functional transformation of hematopoietic stem cells (HSCs) through the gut-blood axis. In this review, we will discuss the role of the gut microbiota in influencing hematopoiesis. We analyze the interactions between HSCs and other cellular components, with a particular emphasis on the direct functional regulation of HSCs by the gut microbiota and their indirect influence through cellular components in the bone marrow microenvironment. Additionally, we propose potential control targets for signaling pathways triggered by the gut microbiota to regulate hematopoietic function, filling crucial knowledge gaps in the development of this research field.


Subject(s)
Gastrointestinal Microbiome , Hematopoiesis , Hematopoietic Stem Cells , Hematopoiesis/physiology , Gastrointestinal Microbiome/physiology , Humans , Hematopoietic Stem Cells/microbiology , Animals , Signal Transduction , Bacteria/metabolism , Bacteria/classification , Bacteria/genetics , Gastrointestinal Tract/microbiology , Bone Marrow/microbiology , Bone Marrow/physiology
2.
Eur J Radiol ; 172: 111359, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38325186

ABSTRACT

PURPOSE: Excess fat accumulation contributes significantly to metabolic dysfunction and diseases. This study aims to systematically compare the accuracy of commercially available Dixon techniques for quantification of fat fraction in liver, skeletal musculature, and vertebral bone marrow (BM) of healthy individuals, investigating biases and sex-specific influences. METHOD: 100 healthy White individuals (50 women) underwent abdominal MRI using two-point and multi-echo Dixon sequences. Fat fraction (FF), proton density fat fraction (PDFF) and T2* values were calculated for liver, paravertebral muscles (PVM) and vertebral BM (Th8-L5). Agreement and systematic deviations were assessed using linear correlation and Bland-Altman plots. RESULTS: High correlations between FF and PDFF were observed in liver (r = 0.98 for women; r = 0.96 for men), PVM (r = 0.92 for women; r = 0.93 for men) and BM (r = 0.97 for women; r = 0.95 for men). Relative deviations between FF and PDFF in liver (18.92 % for women; 13.32 % for men) and PVM (1.96 % for women; 11.62 % for men) were not significant. Relative deviations in BM were significant (38.13 % for women; 27.62 % for men). Bias correction using linear models reduced discrepancies. T2* times were significantly shorter in BM (8.72 ms for women; 7.26 ms for men) compared to PVM (13.45 ms for women; 13.62 ms for men) and liver (29.47 ms for women; 26.35 ms for men). CONCLUSION: While no significant differences were observed for liver and PVM, systematic errors in BM FF estimation using two-point Dixon imaging were observed. These discrepancies - mainly resulting from organ-specific T2* times - have to be considered when applying two-point Dixon approaches for assessment of fat content. As suitable correction tools, linear models could provide added value in large-scale epidemiological cohort studies. Sex-specific differences in T2* should be considered.


Subject(s)
Bone Marrow , Magnetic Resonance Imaging , Male , Humans , Female , Bone Marrow/diagnostic imaging , Bone Marrow/physiology , Magnetic Resonance Imaging/methods , Muscle, Skeletal/diagnostic imaging , Adipose Tissue/diagnostic imaging , Liver/diagnostic imaging
3.
Obes Rev ; 25(3): e13674, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38092420

ABSTRACT

Obesity has taken the face of a pandemic with less direct concern among the general population and scientific community. However, obesity is considered a low-grade systemic inflammation that impacts multiple organs. Chronic inflammation is also associated with different solid and blood cancers. In addition, emerging evidence demonstrates that individuals with obesity are at higher risk of developing blood cancers and have poorer clinical outcomes than individuals in a normal weight range. The bone marrow is critical for hematopoiesis, lymphopoiesis, and myelopoiesis. Therefore, it is vital to understand the mechanisms by which obesity-associated changes in BM adiposity impact leukemia development. BM adipocytes are critical to maintain homeostasis via different means, including immune regulation. However, obesity increases BM adiposity and creates a pro-inflammatory environment to upregulate clonal hematopoiesis and a leukemia-supportive environment. Obesity further alters lymphopoiesis and myelopoiesis via different mechanisms, which dysregulate myeloid and lymphoid immune cell functions mentioned in the text under different sequentially discussed sections. The altered immune cell function during obesity alters hematological malignancies and leukemia susceptibility. Therefore, obesity-induced altered BM adiposity, immune cell generation, and function impact an individual's predisposition and severity of leukemia, which should be considered a critical factor in leukemia patients.


Subject(s)
Hematologic Neoplasms , Leukemia , Humans , Bone Marrow/pathology , Bone Marrow/physiology , Adiposity , Obesity/complications , Obesity/pathology , Inflammation/pathology , Leukemia/etiology , Leukemia/pathology , Hematologic Neoplasms/pathology
4.
Nat Rev Endocrinol ; 19(11): 626-638, 2023 11.
Article in English | MEDLINE | ID: mdl-37587198

ABSTRACT

Adipose tissue is a dynamic component of the bone marrow, regulating skeletal remodelling and secreting paracrine and endocrine factors that can affect haematopoiesis, as well as potentially nourishing the bone marrow during periods of stress. Bone marrow adipose tissue is regulated by multiple factors, but particularly nutrient status. In this Review, we examine how bone marrow adipocytes originate, their function in normal and pathological states and how bone marrow adipose tissue modulates whole-body homoeostasis through actions on bone cells, haematopoietic stem cells and extra-medullary adipocytes during nutritional challenges. We focus on both rodent models and human studies to help understand the unique marrow adipocyte, its response to the external nutrient environment and its effects on the skeleton. We finish by addressing some critical questions that to date remain unanswered.


Subject(s)
Adipose Tissue , Bone Marrow Cells , Bone Marrow , Humans , Adipocytes/physiology , Bone Marrow/pathology , Bone Marrow/physiology , Bone Marrow Cells/physiology , Obesity/pathology , Weight Loss
5.
Nat Cancer ; 4(8): 1193-1209, 2023 08.
Article in English | MEDLINE | ID: mdl-37550517

ABSTRACT

Aging facilitates the expansion of hematopoietic stem cells (HSCs) carrying clonal hematopoiesis-related somatic mutations and the development of myeloid malignancies, such as myeloproliferative neoplasms (MPNs). While cooperating mutations can cause transformation, it is unclear whether distinct bone marrow (BM) HSC-niches can influence the growth and therapy response of HSCs carrying the same oncogenic driver. Here we found different BM niches for HSCs in MPN subtypes. JAK-STAT signaling differentially regulates CDC42-dependent HSC polarity, niche interaction and mutant cell expansion. Asymmetric HSC distribution causes differential BM niche remodeling: sinusoidal dilation in polycythemia vera and endosteal niche expansion in essential thrombocythemia. MPN development accelerates in a prematurely aged BM microenvironment, suggesting that the specialized niche can modulate mutant cell expansion. Finally, dissimilar HSC-niche interactions underpin variable clinical response to JAK inhibitor. Therefore, HSC-niche interactions influence the expansion rate and therapy response of cells carrying the same clonal hematopoiesis oncogenic driver.


Subject(s)
Myeloproliferative Disorders , Neoplasms , Humans , Aged , Myeloproliferative Disorders/genetics , Myeloproliferative Disorders/therapy , Myeloproliferative Disorders/pathology , Bone Marrow/pathology , Bone Marrow/physiology , Hematopoietic Stem Cells/pathology , Bone and Bones/pathology , Tumor Microenvironment/genetics
6.
Cancer Commun (Lond) ; 43(6): 637-660, 2023 06.
Article in English | MEDLINE | ID: mdl-37120719

ABSTRACT

BACKGROUND: Tumors possess incessant growth features, and expansion of their masses demands sufficient oxygen supply by red blood cells (RBCs). In adult mammals, the bone marrow (BM) is the main organ regulating hematopoiesis with dedicated manners. Other than BM, extramedullary hematopoiesis is discovered in various pathophysiological settings. However, whether tumors can contribute to hematopoiesis is completely unknown. Accumulating evidence shows that, in the tumor microenvironment (TME), perivascular localized cells retain progenitor cell properties and can differentiate into other cells. Here, we sought to better understand whether and how perivascular localized pericytes in tumors manipulate hematopoiesis. METHODS: To test if vascular cells can differentiate into RBCs, genome-wide expression profiling was performed using mouse-derived pericytes. Genetic tracing of perivascular localized cells employing NG2-CreERT2:R26R-tdTomato mouse strain was used to validate the findings in vivo. Fluorescence-activated cell sorting (FACS), single-cell sequencing, and colony formation assays were applied for biological studies. The production of erythroid differentiation-specific cytokine, erythropoietin (EPO), in TME was checked using quantitative polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA, magnetic-activated cell sorting and immunohistochemistry. To investigate BM function in tumor erythropoiesis, BM transplantation mouse models were employed. RESULTS: Genome-wide expression profiling showed that in response to platelet-derived growth factor subunit B (PDGF-B), neural/glial antigen 2 (NG2)+ perivascular localized cells exhibited hematopoietic stem and progenitor-like features and underwent differentiation towards the erythroid lineage. PDGF-B simultaneously targeted cancer-associated fibroblasts to produce high levels of EPO, a crucial hormone that necessitates erythropoiesis. FACS analysis using genetic tracing of NG2+ cells in tumors defined the perivascular localized cell-derived subpopulation of hematopoietic cells. Single-cell sequencing and colony formation assays validated the fact that, upon PDGF-B stimulation, NG2+ cells isolated from tumors acted as erythroblast progenitor cells, which were distinctive from the canonical BM hematopoietic stem cells. CONCLUSIONS: Our data provide a new concept of hematopoiesis within tumor tissues and novel mechanistic insights into perivascular localized cell-derived erythroid cells within TME. Targeting tumor hematopoiesis is a novel therapeutic concept for treating various cancers that may have profound impacts on cancer therapy.


Subject(s)
Erythropoiesis , Neoplasms , Animals , Mice , Bone Marrow/physiology , Cell Differentiation , Mammals , Neoplasms/metabolism , Pericytes , Tumor Microenvironment
7.
Stem Cells ; 41(6): 541-551, 2023 06 15.
Article in English | MEDLINE | ID: mdl-37061819

ABSTRACT

In mammals, post-injury repair and regenerative events rely predominantly on stem cell function. Stem cell transplantation has achieved considerable success in animals but remains unfavorable for humans because of the unavoidable drawbacks. Nevertheless, substantial evidence suggests the regenerative potential of endogenous stem cells can be improved for functional and structural recovery of tissue damage or in disease conditions. Endogenous stem cells are mostly quiescent under steady-state conditions and reside in their niche. Once faced with tissue injury, physiological and molecular changes within the niche or from distant tissues activate the migration, proliferation, and differentiation of stem cells, contributing to tissue repair. Tissue regeneration is augmented by artificially amplifying the factors that promote stem cell mobilization or enhance the homing of endogenous stem cells. This cell-free strategy, known as "in situ tissue regeneration," represents a safer and more efficient means to conduct tissue regeneration. Bone marrow (BM) is considered the central niche and main reservoir of many types of stem cells. These stem cells hold great therapeutic potential for the regeneration of multiple injured tissues. Herein, we review recent strategies for promoting in situ tissue regeneration through BM-derived stem cell mobilization or homing in animal models as well as in human trials. With the advancement in biomaterial engineering, chemoattractant signals combined with functionalized bioscaffolds have accomplished sustained activation of endogenous BM-derived stem cells that can be used as an attractive strategy for efficient in situ tissue regeneration.


Subject(s)
Hematopoietic Stem Cell Mobilization , Hematopoietic Stem Cell Transplantation , Animals , Humans , Bone Marrow/physiology , Cell Movement/physiology , Mammals
8.
Elife ; 122023 03 06.
Article in English | MEDLINE | ID: mdl-36876630

ABSTRACT

Hematopoiesis is regulated by the bone marrow (BM) stroma. However, cellular identities and functions of the different BM stromal elements in humans remain poorly defined. Based on single-cell RNA sequencing (scRNAseq), we systematically characterized the human non-hematopoietic BM stromal compartment and we investigated stromal cell regulation principles based on the RNA velocity analysis using scVelo and studied the interactions between the human BM stromal cells and hematopoietic cells based on ligand-receptor (LR) expression using CellPhoneDB. scRNAseq led to the identification of six transcriptionally and functionally distinct stromal cell populations. Stromal cell differentiation hierarchy was recapitulated based on RNA velocity analysis and in vitro proliferation capacities and differentiation potentials. Potential key factors that might govern the transition from stem and progenitor cells to fate-committed cells were identified. In situ localization analysis demonstrated that different stromal cells were localized in different niches in the bone marrow. In silico cell-cell communication analysis further predicted that different stromal cell types might regulate hematopoiesis through distinct mechanisms. These findings provide the basis for a comprehensive understanding of the cellular complexity of the human BM microenvironment and the intricate stroma-hematopoiesis crosstalk mechanisms, thus refining our current view on human hematopoietic niche organization.


Subject(s)
Bone Marrow , Hematopoietic Stem Cells , Humans , Bone Marrow/physiology , Hematopoietic Stem Cells/metabolism , Stem Cell Niche/physiology , Bone Marrow Cells/metabolism , Hematopoiesis/genetics , Sequence Analysis, RNA , RNA/metabolism
9.
Haematologica ; 108(8): 2205-2217, 2023 08 01.
Article in English | MEDLINE | ID: mdl-36861412

ABSTRACT

CD169, a specific marker for macrophages, is a member of the sialic acid-binding immunoglobulin-like lectin (Siglec) family which acts as an adhesion molecule implicated in cell-cell interaction via sialylated glycoconjugates. Although CD169+ macrophages have been found to participate in erythroblastic island (EBI) formation and support erythropoiesis under homeostasis and stress, the exact role of CD169 and its counter receptor in EBI remains unknown. Herein, we generated CD169-CreERT knock-in mice and investigated the function of CD169 in EBI formation and erythropoiesis using CD169-null mice. EBI formation was impaired in vitro by both blockade of CD169 using anti-CD169 antibody and deletion of CD169 on macrophages. Furthermore, CD43 expressed by early erythroblasts (EB) was identified as the counter receptor for CD169 in mediating the EBI formation via surface plasmon resonance and imaging flow cytometry. Interestingly, CD43 was proven to be a novel indicator of erythroid differentiation due to the progressive decrease of CD43 expression as EB mature. Although CD169-null mice did not display defects in bone marrow (BM) EBI formation in vivo, CD169 deficiency impeded BM erythroid differentiation probably via CD43 under stress erythropoiesis, in concert with the role of CD169 recombinant protein in hemin-induced K562 erythroid differentiation. These findings have shed light on the role of CD169 in EBI under steady and stress erythropoiesis through binding with its counter receptor CD43, suggesting that CD169-CD43 interaction might be a promising therapeutic target for erythroid disorders.


Subject(s)
Bone Marrow , Erythroblasts , Animals , Mice , Erythroblasts/metabolism , Bone Marrow/physiology , Erythropoiesis , Macrophages/metabolism , Cell Differentiation , Mice, Knockout
10.
J Exp Med ; 220(4)2023 04 03.
Article in English | MEDLINE | ID: mdl-36719648

ABSTRACT

Emergency myelopoiesis (EM) is a hematopoietic response against systemic infections that quickly supplies innate immune cells. As lymphopoiesis is strongly suppressed during EM, the role of lymphocytes in that process has not received much attention. Here, we found that myeloid-like B cells (M-B cells), which express myeloid markers, emerge in the bone marrow (BM) after the induction of EM. M-B cells were mainly derived from pre-B cells and preferentially expressed IL-10, which directly stimulates hematopoietic progenitors to enhance their survival and myeloid-biased differentiation. Indeed, lacking IL-10 in B cells, blocking IL-10 in the BM with a neutralizing antibody, and deleting the IL-10 receptor in hematopoietic progenitors significantly suppressed EM, which failed to clear microbes in a cecal ligation and puncture model. Thus, a distinct B cell subset generated during infection plays a pivotal role in boosting EM, which suggests the on-demand reinforcement of EM by adaptive immune cells.


Subject(s)
B-Lymphocytes , Interleukin-10 , Myelopoiesis , Bone Marrow/physiology , Bone Marrow Cells , Hematopoiesis , Myeloid Cells
11.
Curr Opin Hematol ; 30(3): 80-85, 2023 05 01.
Article in English | MEDLINE | ID: mdl-36718814

ABSTRACT

PURPOSE OF REVIEW: Terminal erythroid differentiation occurs in specialized niches called erythroblastic islands. Since their discovery in 1958, these niches have been described as a central macrophage surrounded by differentiating erythroblasts. Here, we review the recent advances made in the characterization of these islands and the role they could play in anaemia of inflammation. RECENT FINDINGS: The utilization of multispectral imaging flow cytometry (flow cytometry with microscopy) has enabled for a more precise characterization of the niche that revealed the presence of maturing granulocytes in close contact with the central macrophage. These erythromyeloblastic islands (EMBIs) can adapt depending on the peripheral needs. Indeed, during inflammation wherein inflammatory cytokines limit erythropoiesis and promote granulopoiesis, EMBIs present altered structures with increased maturing granulocytes and decreased erythroid precursors. SUMMARY: Regulation of the structure and function of the EMBI in the bone marrow emerges as a potential player in the pathophysiology of acute and chronic inflammation and its associated anaemia.


Subject(s)
Anemia , Bone Marrow , Humans , Bone Marrow/physiology , Erythroblasts , Erythropoiesis/physiology , Anemia/etiology , Inflammation
12.
J Foot Ankle Surg ; 62(1): 75-79, 2023.
Article in English | MEDLINE | ID: mdl-35659478

ABSTRACT

Bone marrow stimulation (BMS) is indicated for patients who have symptomatic osteochondral lesions of the talus (OLT). Despite differences in ankle biomechanics and cartilage morphology between men and women, there is scant evidence examining whether these differences affect surgical outcomes. The purpose of this study was to compare the outcomes in men and women following BMS for OLTs. A retrospective analysis comparing female and male patients treated with BMS for OLT between 2007 and 2015 was performed. Clinical outcomes were evaluated using the Foot and Ankle Outcome Scores (FAOS) and Short-Form 12 (SF-12). Magnetic resonance imaging at final follow-up was evaluated with the modified magnetic resonance observation of cartilage repair tissue score. Thirty-one females and 38 males were included. In female patients, the mean FAOS pain score improved from 60 ± 16 preoperatively to 84 ± 8.9 at 1- to 2-year follow-up (p < .01), and then decreased to 80±13 at final follow-up at 3-4 years. In male patients, the mean FAOS pain score improved from 65±17 preoperatively to 83±9.2 at 1-2 year follow-up (p < .01), and then decreased to 76±14.6 at final follow-up at 3-4 years. Lateral lesions were more common in male patients. Medial lesions were more common in female patients. The outcomes following BMS in both female and male patients were good with no significant differences at short-term follow-up. FAOS scores in male patients were more likely to decrease after 1 to 2 years postsurgery, implying a possibly faster decline than in female patients.


Subject(s)
Cartilage, Articular , Intra-Articular Fractures , Talus , Humans , Male , Female , Retrospective Studies , Bone Marrow/diagnostic imaging , Bone Marrow/physiology , Talus/diagnostic imaging , Talus/surgery , Talus/injuries , Sex Factors , Magnetic Resonance Imaging , Pain , Treatment Outcome , Cartilage, Articular/diagnostic imaging , Cartilage, Articular/surgery , Cartilage, Articular/pathology
13.
Nat Commun ; 13(1): 7657, 2022 12 10.
Article in English | MEDLINE | ID: mdl-36496394

ABSTRACT

Innate and adaptive immune cells participate in the homeostatic regulation of hematopoietic stem cells (HSCs). Here, we interrogate the contribution of myeloid cells, the most abundant cell type in the mammalian bone marrow, in a clinically relevant mouse model of neutropenia. Long-term genetic depletion of neutrophils and eosinophils results in activation of multipotent progenitors but preservation of HSCs. Depletion of myeloid cells abrogates HSC expansion, loss of serial repopulation and lymphoid reconstitution capacity and remodeling of HSC niches, features previously associated with hematopoietic aging. This is associated with mitigation of interferon signaling in both HSCs and their niches via reduction of NK cell number and activation. These data implicate myeloid cells in the functional decline of hematopoiesis, associated with activation of interferon signaling via a putative neutrophil-NK cell axis. Innate immunity may thus come at the cost of system deterioration through enhanced chronic inflammatory signaling to stem cells and their niches.


Subject(s)
Hematopoiesis , Hematopoietic Stem Cells , Mice , Animals , Hematopoietic Stem Cells/metabolism , Myeloid Cells , Bone Marrow/physiology , Interferons/metabolism , Cell Differentiation , Mammals
14.
Elife ; 112022 Sep 30.
Article in English | MEDLINE | ID: mdl-36178184

ABSTRACT

Generation of bone marrow (BM) from embryonic stem cells (ESCs) promises to accelerate the development of future cell therapies for life-threatening disorders. However, such approach is limited by technical challenges to produce a mixture of functional BM progenitor cells able to replace all hematopoietic cell lineages. Herein, we used blastocyst complementation to simultaneously produce BM cell lineages from mouse ESCs in a rat. Based on fluorescence-activated cell sorting analysis and single-cell RNA sequencing, mouse ESCs differentiated into multiple hematopoietic and stromal cell types that were indistinguishable from normal mouse BM cells based on gene expression signatures and cell surface markers. Receptor-ligand interactions identified Cxcl12-Cxcr4, Lama2-Itga6, App-Itga6, Comp-Cd47, Col1a1-Cd44, and App-Il18rap as major signaling pathways between hematopoietic progenitors and stromal cells. Multiple hematopoietic progenitors, including hematopoietic stem cells (HSCs) in mouse-rat chimeras derived more efficiently from mouse ESCs, whereas chondrocytes predominantly derived from rat cells. In the dorsal aorta and fetal liver of mouse-rat chimeras, mouse HSCs emerged and expanded faster compared to endogenous rat cells. Sequential BM transplantation of ESC-derived cells from mouse-rat chimeras rescued lethally irradiated syngeneic mice and demonstrated long-term reconstitution potential of donor HSCs. Altogether, a fully functional BM was generated from mouse ESCs using rat embryos as 'bioreactors'.


Subject(s)
Bone Marrow , Hematopoietic Stem Cell Transplantation , Mice , Animals , Rats , Bone Marrow/physiology , CD47 Antigen , Chimera , Ligands , Embryonic Stem Cells , Bone Marrow Cells
15.
Nat Neurosci ; 25(5): 555-560, 2022 05.
Article in English | MEDLINE | ID: mdl-35301477

ABSTRACT

It remains unclear how immune cells from skull bone marrow niches are recruited to the meninges. Here we report that cerebrospinal fluid (CSF) accesses skull bone marrow via dura-skull channels, and CSF proteins signal onto diverse cell types within the niches. After spinal cord injury, CSF-borne cues promote myelopoiesis and egress of myeloid cells into meninges. This reveals a mechanism of CNS-to-bone-marrow communication via CSF that regulates CNS immune responses.


Subject(s)
Bone Marrow , Skull , Bone Marrow/physiology , Cerebrospinal Fluid , Head , Meninges , Myeloid Cells/metabolism
16.
Cell Stem Cell ; 29(2): 232-247.e7, 2022 02 03.
Article in English | MEDLINE | ID: mdl-35065706

ABSTRACT

Host microbiota crosstalk is essential for the production and functional modulation of blood-cell lineages. Whether, and if so how, the microbiota influences hematopoietic stem cells (HSCs) is unclear. Here, we show that the microbiota regulates HSC self-renewal and differentiation under stress conditions by modulating local iron availability in the bone marrow (BM). In microbiota-depleted mice, HSC self-renewal was enhanced during regeneration, while the commitment toward differentiation was dramatically compromised. Mechanistically, microbiota depletion selectively impaired the recycling of red blood cells (RBCs) by BM macrophages, resulting in reduced local iron levels without affecting systemic iron homeostasis. Limiting iron availability in food (in vivo) or in culture (ex vivo), or by CD169+ macrophage depletion, enhanced HSC self-renewal and expansion. These results reveal an intricate interplay between the microbiota, macrophages, and iron, and their essential roles in regulating critical HSC fate decisions under stress.


Subject(s)
Bone Marrow , Microbiota , Animals , Bone Marrow/physiology , Cell Differentiation , Hematopoietic Stem Cells , Iron , Mice
17.
Leukemia ; 36(2): 333-347, 2022 02.
Article in English | MEDLINE | ID: mdl-34518644

ABSTRACT

We show that pro-inflammatory oncostatin M (OSM) is an important regulator of hematopoietic stem cell (HSC) niches in the bone marrow (BM). Treatment of healthy humans and mice with granulocyte colony-stimulating factor (G-CSF) dramatically increases OSM release in blood and BM. Using mice null for the OSM receptor (OSMR) gene, we demonstrate that OSM provides a negative feed-back acting as a brake on HSPC mobilization in response to clinically relevant mobilizing molecules G-CSF and CXCR4 antagonist. Likewise, injection of a recombinant OSM molecular trap made of OSMR complex extracellular domains enhances HSC mobilization in poor mobilizing C57BL/6 and NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice. Mechanistically, OSM attenuates HSC chemotactic response to CXCL12 and increases HSC homing to the BM signaling indirectly via BM endothelial and mesenchymal cells which are the only cells expressing OSMR in the BM. OSM up-regulates E-selectin expression on BM endothelial cells indirectly increasing HSC proliferation. RNA sequencing of HSCs from Osmr-/- and wild-type mice suggest that HSCs have altered cytoskeleton reorganization, energy usage and cycling in the absence of OSM signaling in niches. Therefore OSM is an important regulator of HSC niche function restraining HSC mobilization and anti-OSM therapy combined with current mobilizing regimens may improve HSPC mobilization for transplantation.


Subject(s)
Bone Marrow/physiology , Granulocyte Colony-Stimulating Factor/administration & dosage , Hematopoietic Stem Cell Mobilization/methods , Hematopoietic Stem Cells/cytology , Oncostatin M/metabolism , Stem Cell Niche , Animals , Bone Marrow/drug effects , Female , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/metabolism , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Inbred NOD
18.
Adv Exp Med Biol ; 1376: 61-75, 2022.
Article in English | MEDLINE | ID: mdl-34480334

ABSTRACT

The bone marrow serves as a reservoir for a multifunctional assortment of stem, progenitor, and mature cells, located in functional anatomical micro-areas termed niches. Within the niche, hematopoietic and mesenchymal progenies establish a symbiotic relationship characterized by interdependency and interconnectedness. The fine-tuned physical and molecular interactions that occur in the niches guarantee physiological bone turnover, blood cell maturation and egression, and moderation of inflammatory and oxidative intramural stressful conditions. The disruption of bone marrow niche integrity causes severe local and systemic pathological settings, and thus bone marrow inhabitants have been the object of extensive study. In this context, research has revealed the importance of the autophagic apparatus for niche homeostatic maintenance. Archetypal autophagic players such as the p62 and the Atg family proteins have been found to exert a variety of actions, some autophagy-related and others not; they moderate the essential features of mesenchymal and hematopoietic stem cells and switch their operational schedules. This chapter focuses on our current understanding of bone marrow functionality and the role of the executive autophagic apparatus in the niche framework. Autophagic mediators such as p62 and Atg7 are currently considered the most important orchestrators of stem and mature cell dynamics in the bone marrow.


Subject(s)
Bone Marrow , Stem Cell Niche , Autophagy , Bone Marrow/physiology , Bone Marrow Cells , Hematopoietic Stem Cells/metabolism , Homeostasis
19.
Acta Radiol ; 63(2): 245-252, 2022 Feb.
Article in English | MEDLINE | ID: mdl-33497273

ABSTRACT

BACKGROUND: Polyphenols in extra virgin olive oil (EVOO) have been found to reduce the expression of PPARγ2, inhibit adipocyte differentiation, and enhance the formation of osteoblasts from bone marrow stem cells. However, the underlying mechanisms of their action remain unknown. PURPOSE: To determine the sequential effects of EVOO on marrow fat expansion induced by estrogen deprivation using 3.0-T proton magnetic resonance (MR) spectroscopy in an ovariectomy (OVX) rabbit model of postmenopausal bone loss over a six-month period. MATERIAL AND METHODS: A total of 45 female New Zealand rabbits were equally divided into sham-operation, OVX controls, and OVX treated with EVOO for six months. Marrow fat fraction was measured by MR spectroscopy at baseline conditions, and three and six months postoperatively, respectively. Serum bone biomarkers, lumbar and femoral bone mineral density, microtomographic parameters, biomechanical properties, and quantitative parameters of marrow adipocytes were studied. RESULTS: OVX was associated with marrow adiposity in a time-dependent manner, accompanied with increased bone turnover and impaired bone mass and trabecular microarchitecture. In OVX rabbits, EVOO markedly alleviated trabecular bone loss and reduced the accumulation of lipid droplets including adipocyte size, density, and areas of fat deposits in the bone marrow. EVOO prevented such changes in terms of both marrow adiposity and bone remodeling. CONCLUSION: Early EVOO treatment may exert beneficial effects on bone by modulating marrow adiposity, which would support their protective effect against bone pathologies.


Subject(s)
Adiposity/drug effects , Bone Marrow/drug effects , Olive Oil/pharmacology , Osteoporosis, Postmenopausal/physiopathology , PPAR gamma/antagonists & inhibitors , Polyphenols/pharmacology , Proton Magnetic Resonance Spectroscopy , Adiposity/physiology , Animals , Biomechanical Phenomena , Bone Density/drug effects , Bone Marrow/physiology , Bone Marrow Cells/cytology , Disease Models, Animal , Female , Humans , Osteogenesis , Ovariectomy , Rabbits
20.
J Vis Exp ; (190)2022 12 16.
Article in English | MEDLINE | ID: mdl-36591983

ABSTRACT

The medullary niche is a complex ecosystem that is essential to maintain homeostasis for resident cells. Indeed, the bone marrow, which includes a complex extracellular matrix and various cell types, such as mesenchymal stem cells, osteoblasts, and endothelial cells, is deeply involved in hematopoietic stem cell regulation through direct cell-cell interactions, as well as cytokine production. To closely mimic this in vivo structure and conduct experiments reflecting the responses of the human bone marrow, several 3D models have been created based on biomaterials, relying primarily on primary stromal cells. Here, a protocol is described to obtain a minimal and standardized system that is easy to set up and provides features of bone marrow-like structure, which combines different cell populations including endothelial cells, and reflects the heterogeneity of in vivo bone marrow tissue. This 3D bone marrow-like structure-assembled using calcium phosphate-based particles and human cell lines, representative of the bone marrow microenvironment-allows the monitoring of a wide variety of biological processes by combining or replacing different primary cell populations within the system. The final 3D structures can then either be harvested for image analysis after fixation, paraffin-embedding, and histological/immunohistochemical staining for cell localization within the system, or dissociated to collect each cellular component for molecular or functional characterization.


Subject(s)
Bone Marrow , Neoplasms , Humans , Bone Marrow/physiology , Endothelial Cells , Ecosystem , Hematopoietic Stem Cells , Stromal Cells , Bone Marrow Cells , Neoplasms/metabolism , Stem Cell Niche/physiology , Tumor Microenvironment
SELECTION OF CITATIONS
SEARCH DETAIL
...