Sepsis is a severe illness characterized by systemic and multiorgan reactive responses and damage. However, the impact of sepsis on the bone marrow, particularly on bone marrow mesenchymal stem cells (BMSCs), is less reported. BMSCs are critical stromal cells in the bone marrow microenvironment that maintain bone stability and hematopoietic homeostasis; however, the impairment caused by sepsis remains unknown.

To investigate the effects of sepsis on BMSCs and the underlying mechanisms.

BMSCs were obtained from healthy donors and patients with sepsis. We compared the self-renewal capacity, differentiation potential, and hematopoietic supportive ability in vitro. Senescence of septic BMSCs was assessed using β-galactosidase staining, senescence-associated secretory phenotype, intracellular reactive oxygen species levels, and the expression of P16 and P21. Finally, the changes in septic BMSCs after nicotinamide adenine dinucleotide (NAD) treatment were evaluated.

Septic BMSCs showed decreased proliferation and self-renewal, bias towards adipogenic differentiation, and weakened osteogenic differentiation. Additionally, hematopoietic supportive capacity declines in sepsis. The levels of aging markers were significantly higher in the septic BMSCs. After NAD treatment, the proliferation capacity of septic BMSCs showed a recovery trend, with increased osteogenic and hematopoietic supportive capacities. Sepsis resulted in decreased expression of sirtuin 3 (SIRT3) in BMSCs, whereas NAD treatment restored SIRT3 expression, enhanced superoxide dismutase enzyme activity, reduced intracellular reactive oxygen species levels, maintained mitochondrial stability and function, and ultimately rejuvenated septic BMSCs.

Sepsis accelerates the aging of BMSCs, as evidenced by a decline in self-renewal and osteogenic capabilities, as well as weakened hematopoietic support functions. These deficiencies can be effectively reversed via the NAD/SIRT3/superoxide dismutase pathway.

• Sepsis
• Bone mesenchymal stem cells
• Hematopoietic stem cells
• Senescence
• Nicotinamide adenine dinucleotide

• Burkholderia cepacia complex
• Mycobacterium abscessus
• Pseudomonas aeruginosa
• adaptation
• chronic infection
• hypoxia
• lung disease

• Cystic Fibrosis/microbiology
• Cystic Fibrosis/complications
• Humans
• Adaptation, Physiological
• Pseudomonas aeruginosa/physiology
• Persistent Infection/microbiology
• Burkholderia cepacia complex/physiology
• Mycobacterium abscessus/physiology
• Hypoxia
• Oxygen/metabolism

• 20/FFP-P/8717 Taighde Éireann

• Humans
• Male
• Middle Aged
• Female
• Aged
• Adult
• Mutation
• Neoplasms/genetics
• Neoplasms/drug therapy
• Retrospective Studies
• Aged, 80 and over
• Young Adult
• Clonal Hematopoiesis/genetics

• acute lymphoblastic leukemia
• diffuse large B-cell lymphoma
• gene expression
• multipotent mesenchymal stromal cells
• protein secretion

• Humans
• Mesenchymal Stem Cells/metabolism
• Mesenchymal Stem Cells/immunology
• Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunology
• Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology
• Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism
• Lymphoma, Large B-Cell, Diffuse/immunology
• Lymphoma, Large B-Cell, Diffuse/pathology
• Lymphoma, Large B-Cell, Diffuse/metabolism
• Male
• Adult
• Female
• Middle Aged
• Bone Marrow Cells/immunology
• Cell Proliferation
• Young Adult

• Humans
• Mice
• Animals
• Hepcidins/metabolism
• HEK293 Cells
• Mesenchymal Stem Cells
• Anti-Infective Agents/pharmacology
• Inflammation/metabolism
• Bone Marrow Cells
• Mammals

• ZIA CL002120 Intramural NIH HHS
• ZIA DE000714 Intramural NIH HHS
• ZIB DE000730 Intramural NIH HHS

• MSCs
• hematological cancers
• inflammation
• senescence
• tumor transformation

• Humans
• Bone Marrow
• Hematopoietic Stem Cells
• Hematologic Neoplasms
• Neoplasms/pathology
• Tumor Microenvironment
• Bone Marrow Cells/pathology
• Mesenchymal Stem Cells/physiology

• HIV
• bone marrow niche
• dysregulation
• haematopoiesis
• haematopoietic stem/progenitor cell

• bone marrow microenvironment
• dormancy
• hematopoietic niche
• micrometastases
• osteoblast niche
• reawakening

• W81XWH-09-1-0119 Department of Defence
• 1 R21 CA142537-01A1 National Institute of Health

• Cord blood
• Ex vivo expansion
• Hematopoietic stem cell
• Homing

• Humans
• Fetal Blood
• Neoplasm Recurrence, Local
• Hematopoietic Stem Cells
• Graft vs Host Disease/prevention & control
• Hematopoietic Stem Cell Transplantation

• Angelica sinensis polysaccharide
• Bone marrow stroma
• Hematopoietic stem/progenitor cell
• Oxidative stress
• Stress-induced premature senescence

In many leukemia patients, a poor prognosis is attributed either to the development of chemotherapy resistance by leukemic stem cells (LSCs) or to the inefficient engraftment of transplanted hematopoietic stem/progenitor cells (HSPCs) into the bone marrow (BM). Here, we build a 3D in vitro model system of bone marrow organoids (BMOs) that recapitulate several structural and cellular components of native BM. These organoids are formed in a high-throughput manner from the aggregation of endothelial and mesenchymal cells within hydrogel microwells. Accordingly, the mesenchymal compartment shows partial maintenance of its self-renewal and multilineage potential, while endothelial cells self-organize into an interconnected vessel-like network. Intriguingly, such an endothelial compartment enhances the recruitment of HSPCs in a chemokine ligand/receptor-dependent manner, reminiscent of HSPC homing behavior in vivo. Additionally, we also model LSC migration and nesting in BMOs, thus highlighting the potential of this system as a well accessible and scalable preclinical model for candidate drug screening and patient-specific assays.

• B cell biology
• development
• function
• hypoxia
• hypoxia-inducible factor signaling
• metabolism

• Adaptive Immunity
• Animals
• B-Lymphocytes/metabolism
• Hypoxia/metabolism
• Mammals/metabolism
• Oxygen/metabolism
• T-Lymphocytes

• National Natural Science Foundation of China
• Natural Science Foundation of Chongqing

• acute myeloid leukemia (AML)
• cell‐derived exosomes
• mesenchymal stromal cells (MSCs)

• Animals
• Cell Differentiation/physiology
• Cell Proliferation
• Humans
• Leukemia, Myeloid, Acute/genetics
• Leukemia, Myeloid, Acute/metabolism
• Mesenchymal Stem Cells/physiology
• Mice
• Proteomics
• Tumor Microenvironment

• National Key Research and Development Program of China
• Natural Science Foundation of Zhejiang Province
• Fundamental Research Funds for the Central Universities

Acute myeloid leukemias (AML) comprise a wide array of different entities, which have in common a rapid expansion of myeloid blast cells leading to displacement of normal hematopoietic cells and also disruption of the microenvironment in the bone marrow niches. Based on an insight into the complex cellular interactions in the bone marrow niches in non-neoplastic conditions in general, this review delineates the complex relationship between leukemic cells and reactive cells of the tumor microenvironment (TME) in AML. A special focus is directed on niche cells and various T-cell subsets as these also provide a potential therapeutic rationale considering e.g. immunomodulation. The TME of AML on the one hand plays a vital role for sustaining and promoting leukemogenesis but - on the other hand - it also has adverse effects on abnormal blasts developing into overt leukemia hindering their proliferation and potentially removing such cells. Thus, leukemic cells need to and develop strategies in order to manipulate the TME. Interference with those strategies might be of particular therapeutic potential since mechanisms of resistance related to tumor cell plasticity do not apply to it.

• AML
• T-cells
• TME
• bone marrow niches
• bone marrow stromal cells

• bone marrow
• emperipolesis
• hematopoietic stem and progenitor cell (HSPC)
• heterogeneity
• immune
• megakaryocyte (MK)
• niche

• 26670 Cancer Research UK
• MC_PC_17230 Medical Research Council
• MR/V005421/1 Medical Research Council
• Wellcome Trust

Genetic and epigenetic lesions within hematopoietic cell populations drive diverse hematological malignancies. Myelodysplastic syndromes (MDS) are a group of myeloid neoplasms affecting the hematopoietic stem cells characterized by recurrent genetic abnormalities, myelodysplasia (a pathological definition of abnormal bone marrow structure), ineffective hematopoiesis resulting in blood cytopenia, and a propensity to evolve into acute myelogenous leukemia. Although there is evidence that the accumulation of a set of genetic mutations is an essential event in MDS, there is an increased appreciation of the contribution of specific microenvironments, niches, in the pathogenesis of MDS and response to treatment. In physiologic hematopoiesis, niches are critical functional units that maintain hematopoietic stem and progenitor cells and regulate their maturation into mature blood cells. In MDS and other hematological malignancies, altered bone marrow niches can promote the survival and expansion of mutant hematopoietic clones and provide a shield from therapy. In this review, we focus on our understanding of the composition and function of hematopoietic niches and their role in the evolution of myeloid malignancies, with an emphasis on MDS.

• Hematological malignancies
• angiogenesis
• bone marrow niches
• endothelial cells
• hypoxia
• inflammation
• microenvironment
• stromal cells

Platinum-based chemotherapy is an effective treatment used in multiple tumor treatments, but produces severe side effects including neurotoxicity, anemia, and immunosuppression, which limits its anti-tumor efficacy and increases the risk of infections. Electroacupuncture (EA) is often used to ameliorate these side effects, but its mechanism is unknown. Here, we report that EA on ST36 and SP6 prevents cisplatin-induced neurotoxicity and immunosuppression. EA induces neuroprotection, prevents pain-related neurotoxicity, preserves bone marrow (BM) hematopoiesis, and peripheral levels of leukocytes. EA activates sympathetic BM terminals to release pituitary adenylate cyclase activating polypeptide (PACAP). PACAP-receptor PAC1-antagonists abrogate the effects of EA, whereas PAC1-agonists mimic EA, prevent neurotoxicity, immunosuppression, and preserve BM hematopoiesis during cisplatin chemotherapy. Our results indicate that PAC1-agonists may provide therapeutic advantages during chemotherapy to treat patients with advanced neurotoxicity or neuropathies limiting EA efficacy.

• chemotherapy
• electroacupuncture
• hematopoiesis
• immunosuppression
• neuromodulation
• neurotoxic

Oxygen availability varies throughout the human body in health and disease. Under physiological conditions, oxygen availability drops from the lungs over the blood stream towards the different tissues into the cells and the mitochondrial cavities leading to physiological low oxygen conditions or physiological hypoxia in all organs including primary lymphoid organs. Moreover, immune cells travel throughout the body searching for damaged cells and foreign antigens facing a variety of oxygen levels. Consequently, physiological hypoxia impacts immune cell function finally controlling innate and adaptive immune response mainly by transcriptional regulation via hypoxia-inducible factors (HIFs). Under pathophysiological conditions such as found in inflammation, injury, infection, ischemia and cancer, severe hypoxia can alter immune cells leading to dysfunctional immune response finally leading to tissue damage, cancer progression and autoimmunity. Here we summarize the effects of physiological and pathophysiological hypoxia on innate and adaptive immune activity, we provide an overview on the control of immune response by cellular hypoxia-induced pathways with focus on the role of HIFs and discuss the opportunity to target hypoxia-sensitive pathways for the treatment of cancer and autoimmunity.

• B cells
• HIF
• ILC
• T cells
• hypoxia
• macrophages
• monocytes
• neutrophils
• oxygen

• Antigen retrieval
• FFPE
• Fixative
• Immunofluorescence
• Microwave heating

• Antigens/analysis
• Biomarkers/analysis
• Biopsy
• Bone Marrow/immunology
• Cellular Microenvironment
• Color
• Fluorescent Antibody Technique
• Humans
• Microscopy, Fluorescence
• Microwaves
• Paraffin Embedding
• Tissue Fixation

• 26670 Cancer Research UK
• MR/V005421/1 Medical Research Council
• C61367/A26670 Cancer Research UK
• 203151/Z/16/Z Wellcome Trust

• adaptive compensation
• drug resistance
• hematopoietic stem cells
• leukemia
• mTOR

• CD146
• NESTIN
• bone marrow
• capillaries
• endosteum
• hematopoietic stem cells
• micro-vessels
• niche

• Bone marrow
• Hematology
• Hematopoietic stem cells
• Immunology
• T cells

• ECM molecules
• HSC niche
• adhesion mechanisms
• extra-cellular vesicles
• fate decision
• hematopoietic stem cells
• physiological cues
• stromal cells

The global emergence of clinical diseases caused by enterohemorrhagic Escherichia coli (EHEC) is an issue of great concern. EHEC release Shiga toxins (Stxs) as their key virulence factors, and investigations on the cell-damaging mechanisms toward target cells are inevitable for the development of novel mitigation strategies. Stx-mediated hemolytic uremic syndrome (HUS), characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal injury, is the most severe outcome of an EHEC infection. Hemolytic anemia during HUS is defined as the loss of erythrocytes by mechanical disruption when passing through narrowed microvessels. The formation of thrombi in the microvasculature is considered an indirect effect of Stx-mediated injury mainly of the renal microvascular endothelial cells, resulting in obstructions of vessels. In this review, we summarize and discuss recent data providing evidence that HUS-associated hemolytic anemia may arise not only from intravascular rupture of erythrocytes, but also from the extravascular impairment of erythropoiesis, the development of red blood cells in the bone marrow, via direct Stx-mediated damage of maturing erythrocytes, leading to “non-hemolytic” anemia.

• AB5 toxin
• EHEC
• Gb3Cer
• Gb4Cer
• developing erythrocytes
• erythropoiesis
• glycosphingolipids
• hemolytic anemia
• red blood cells

• Animals
• Bone Marrow Cells/cytology
• Bone Marrow Cells/metabolism
• Hematologic Neoplasms/genetics
• Hematologic Neoplasms/metabolism
• Hematologic Neoplasms/physiopathology
• Hematopoietic Stem Cells/cytology
• Hematopoietic Stem Cells/metabolism
• Humans
• Neoplastic Stem Cells/cytology
• Neoplastic Stem Cells/metabolism

• MC_PC_17230 Medical Research Council
• 15692 Cancer Research UK
• Wellcome Trust
• MR/V005421/1 Medical Research Council
• 26670 Cancer Research UK
• P30 CA016672 NCI NIH HHS
• MC_PC_12009 Medical Research Council

The unfolded protein response (UPR) is an evolutionarily conserved adaptive response triggered by the stress of the endoplasmic reticulum (ER) due, among other causes, to altered cell protein homeostasis (proteostasis). UPR is mediated by three main sensors, protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 6α (ATF6α), and inositol-requiring enzyme-1α (IRE1α). Given that proteostasis is frequently disregulated in cancer, UPR is emerging as a critical signaling network in controlling the survival, selection, and adaptation of a variety of neoplasias, including breast cancer, prostate cancer, colorectal cancer, and glioblastoma. Indeed, cancer cells can escape from the apoptotic pathways elicited by ER stress by switching UPR into a prosurvival mechanism instead of cell death. Although most of the studies on UPR focused on solid tumors, this intricate network plays a critical role in hematological malignancies, and especially in multiple myeloma (MM), where treatment with proteasome inhibitors induce the accumulation of unfolded proteins that severely perturb proteostasis, thereby leading to ER stress, and, eventually, to apoptosis. However, UPR is emerging as a key player also in acute leukemias, where recent evidence points to the likelihood that targeting UPR-driven prosurvival pathways could represent a novel therapeutic strategy. In this review, we focus on the oncogene-specific regulation of individual UPR signaling arms, and we provide an updated outline of the genetic, biochemical, and preclinical therapeutic findings that support UPR as a relevant, novel target in acute leukemias.

• apoptosis
• genetic anomalies
• prognosis
• survival
• targeted therapy

Mesenchymal stromal cells (MSC) are a promising tool for cellular therapy and regenerative medicine. One major difficulty in establishing a MSC expansion protocol is the large volume of bone marrow (BM) required. We studied whether cells trapped within a collection bag and filter system could be considered as a source of MSC.

From the 20 BM collection bag and filter systems, we recovered an average of 1.68 × 10⁸ mononuclear cells, which is the equivalent to 60 ml of filtered BM. Mononuclear cells were expanded ex vivo to 17 × 10⁶ MSC, with purity shown by a CD44⁺, CD105⁺, CD90⁺ and CD73⁺ immunophenotype, a reduction of 20% proliferating cells in a mixed lymphocyte reaction and also the ability of adipocyte differentiation.

Long-term MSC cultures were established from the usually discarded BM collection bag and filter, maintaining an appropriate phenotype and function, being suitable for both investigation and clinical settings.

Mesenchymal stromal cells (MSC) are a promising tool for cellular therapy and regenerative medicine. One major difficulty in obtaining MSC is the large volume of bone marrow (BM) required from a healthy donor. From usually discarded collection bags of BM collected for transplant, we recovered a number of cells equivalent to 60 ml of BM and expanded functional MSC with high purity. We believe that those recovered cells are an alternative to BM for obtaining MSC. The routinely recovery of such cells in reference centers, in a way similar to a public cord-blood bank, could benefit the scientific community, once further research is conducted to confirm results.

• MSC
• adipogenic differentiation
• bone marrow
• collection bag
• filter system
• mesenchymal stromal cells
• mixed lymphocyte reaction
• mononuclear cells

Intra-bone marrow transplantation (IBMT) has been adapted for mouse models to improve the seeding efficiency of transplanted hematopoietic stem and progenitor cells. Commonly used injection volumes for IBMT into the tibia differ between 10 and 40 μL even though considerable amounts of injected cells leak into the blood circulation immediately after injection. Injection of 3 μL trypan blue into the tibia of dead BALB/c mice showed staining in large vessels of hind limbs, even without supporting circulation. We therefore tested the effective capacity of the medullary cavity of dissected tibiae and femora of different mouse strains by bioluminescence imaging after injection of luciferase expressing cells. Cell leakage was already observed at 3 μL of injection volume and the measured emission rate increased significantly when 5 and 10 μL of volume with the same cell concentration were injected. Surprisingly, increasing injection volumes containing constant cell amounts resulted in comparable emission rates, suggesting a similar amount of leaked and absorbed cells independent of the injection volume. However, the absorption of a specific amount of injected cells could not be confirmed, as the ratio of leaked to absorbed cells was similar between IBMT that were performed with a constant injection volume containing either low or high cell amounts. In summary, for optimal cell transplantation via IBMT in mice we suggest to inject a high concentrated cell suspension with a maximum injection volume of 3 μL.

• Animals
• Bone Marrow Transplantation/methods
• Cell Movement/physiology
• Femur/physiopathology
• Femur/transplantation
• Hematopoietic Stem Cell Transplantation/methods
• Hematopoietic Stem Cells/cytology
• Hematopoietic Stem Cells/metabolism
• Humans
• Mice
• Tibia/physiopathology
• Tibia/transplantation
• Transplantation, Heterologous/methods

• bone marrow niche
• hematopoietic stem and progenitor cells
• homing
• microfluidics
• tissue chip

• Antigens, CD34/metabolism
• Biomarkers/metabolism
• Bone Marrow/metabolism
• Cell Communication
• Cell Line, Tumor
• Fluorescent Dyes/metabolism
• Hematopoietic Stem Cells/pathology
• Humans
• Lab-On-A-Chip Devices
• Microtechnology
• Stem Cell Niche

• R21 HL117704 NHLBI NIH HHS
• T32 EB014836 NIBIB NIH HHS
• R01 HL130856 NHLBI NIH HHS
• R21HL117704 NIH HHS
• R01HL135853 NHLBI NIH HHS
• R01 HL135853 NHLBI NIH HHS
• UL1 TR001420 NCATS NIH HHS
• R01HL130856 NHLBI NIH HHS

• Ageing-related disease
• Epigenetics
• Foetal programming
• Haematopoietic system
• Pro-health intervention

• Differentiation
• Hematopoietic stem and progenitor cell
• JAK/STAT
• Liver
• Notch signaling
• γδT cells

• HSC
• LSC
• hematopoiesis
• redox-active compound
• stem cell function

Mesenchymal stromal cells (MSCs) are key elements in the bone marrow (BM) niche where they interact with hematopoietic stem progenitor cells (HSPCs) by offering physical support and secreting soluble factors, which control HSPC maintenance and fate. Although necessary for their maintenance, MSCs are a rare population in the BM, they are plastic adherent and can be ex vivo expanded to reach numbers adequate for clinical use. In light of HSPC supportive properties, MSCs have been employed in phase I/II clinical trials of hematopoietic stem cell transplantation (HSCT) to facilitate engraftment of hematopoietic stem cells (HSCs). Moreover, they have been utilized to expand ex vivo HSCs before clinical use. The available clinical evidence from these trials indicate that MSC administration is safe, as no acute and long-term adverse events have been registered in treated patients, and may be efficacious in promoting hematopoietic engraftment after HSCT. In this review, we critically discuss the role of MSCs as component of the BM niche, as recent advances in defining different mesenchymal populations in the BM have considerably increased our understanding of this complex environment. Moreover, we will revise published literature on the use of MSCs to support HSC engraftment and expansion, as well as consider potential new MSC application in the clinical context of ex vivo gene therapy with autologous HSC.

Diminishing potential to replace damaged tissues is a hallmark for ageing of somatic stem cells, but the mechanisms remain elusive. Here, we present proteome-wide atlases of age-associated alterations in human haematopoietic stem and progenitor cells (HPCs) and five other cell populations that constitute the bone marrow niche. For each, the abundance of a large fraction of the ~12,000 proteins identified is assessed in 59 human subjects from different ages. As the HPCs become older, pathways in central carbon metabolism exhibit features reminiscent of the Warburg effect, where glycolytic intermediates are rerouted towards anabolism. Simultaneously, altered abundance of early regulators of HPC differentiation reveals a reduced functionality and a bias towards myeloid differentiation. Ageing causes alterations in the bone marrow niche too, and diminishes the functionality of the pathways involved in HPC homing. The data represent a valuable resource for further analyses, and for validation of knowledge gained from animal models.

Ageing causes an inability to replace damaged tissue. Here, the authors perform proteomics analyses of human haematopoietic stem cells and other cells in the bone marrow niche at different ages and show changes in central carbon metabolism, reduced bone marrow niche function, and enhanced myeloid differentiation.

Hematopoietic stem cells (HSCs) balance self-renewal and differentiation to maintain homeostasis. With aging, the frequency of polar HSCs decreases. Cell polarity in HSCs is controlled by the activity of the small RhoGTPase cell division control protein 42 (Cdc42). Here we demonstrate—using a comprehensive set of paired daughter cell analyses that include single-cell 3D confocal imaging, single-cell transplants, single-cell RNA-seq, and single-cell transposase-accessible chromatin sequencing (ATAC-seq)—that the outcome of HSC divisions is strongly linked to the polarity status before mitosis, which is in turn determined by the level of the activity Cdc42 in stem cells. Aged apolar HSCs undergo preferentially self-renewing symmetric divisions, resulting in daughter stem cells with reduced regenerative capacity and lymphoid potential, while young polar HSCs undergo preferentially asymmetric divisions. Mathematical modeling in combination with experimental data implies a mechanistic role of the asymmetric sorting of Cdc42 in determining the potential of daughter cells via epigenetic mechanisms. Therefore, molecules that control HSC polarity might serve as modulators of the mode of stem cell division regulating the potential of daughter cells.

Stem cells are unique cells that can differentiate to produce more stem cells or other types of cells and can divide both symmetrically (to produce daughter cells with the same fate) and asymmetrically (to produce one daughter cell that retains stem cell potential and one that differentiates). The mechanisms that control the outcome of stem cell divisions have been the focus of many studies; however, they remain mainly unknown. Here, we have analyzed these mechanisms in murine hematopoietic stem cells (HSCs) by directly comparing the epigenetic signature, the transcriptome, and the function of the two daughter cells stemming from the first division of either a young or an aged HSC. We observe that, while young HSCs divide mainly asymmetrically, aged HSCs divide primarily symmetrically. We find that the mode of division is tightly linked to stem cell polarity and is regulated by the activity level of the small RhoGTPase cell division control protein 42 (Cdc42). In addition, we show that the potential of daughter cells is further linked to the amount of the epigenetic mark H4K16ac and also to the amount of open chromatin allocated to a daughter cell, but it is not linked to its transcriptome. In summary, our study suggests that HSC polarity linked to Cdc42 activity drives the mode of division, while epigenetic mechanisms determine the functional outcome of the stem cell division.

• Aging/metabolism
• Animals
• Asymmetric Cell Division/genetics
• Bone Marrow Cells/cytology
• Bone Marrow Cells/metabolism
• Cell Aggregation
• Cell Division/genetics
• Cell Lineage/drug effects
• Cell Polarity/drug effects
• Cellular Senescence/genetics
• Chromatin
• Epigenesis, Genetic
• Hematopoietic Stem Cells/cytology
• Hematopoietic Stem Cells/metabolism
• Mice, Inbred C57BL
• Transcriptome/genetics
• Wnt-5a Protein/pharmacology
• cdc42 GTP-Binding Protein/metabolism

• R01 DK104814 NIDDK NIH HHS
• R01 HL134617 NHLBI NIH HHS

• Ankle
• Arthroscopy
• Bone marrow
• Cartilage repair
• Stem cells

• Adipocytes/metabolism
• Adipocytes/pathology
• Animals
• Bone Marrow Cells/metabolism
• Bone Marrow Cells/pathology
• Bone and Bones/injuries
• Bone and Bones/metabolism
• Bone and Bones/pathology
• Cartilage/injuries
• Cartilage/metabolism
• Cartilage/pathology
• Cell Differentiation
• Cells, Immobilized/metabolism
• Cells, Immobilized/pathology
• Cells, Immobilized/transplantation
• Chondrocytes/metabolism
• Chondrocytes/pathology
• Humans
• Mesenchymal Stem Cell Transplantation/methods
• Mesenchymal Stem Cells/metabolism
• Mesenchymal Stem Cells/pathology
• Osteoblasts/metabolism
• Osteoblasts/pathology
• Tissue Engineering/methods

• Cord blood
• Ex vivo
• Expansion
• Hematopoietic stem cell
• Nanofiber

• Cell Proliferation
• Cord Blood Stem Cell Transplantation
• Fetal Blood/cytology
• Humans
• Nanofibers/administration & dosage
• Nanofibers/chemistry

• Bile acid
• ER stress
• Hematopoietic stem cell
• Proteostasis
• Unfolded protein response

• biological bystander effects
• human hematopoiesis
• space radiation

Hematopoiesis is one of the best studied adult stem-cell systems, with a differentiation hierarchy progressing from immature hematopoietic stem cells to over 10 distinct mature cell types. Recent technological breakthroughs now make it possible to define transcriptional profiles in thousands of individual cells. Facilitated by the wealth of prior data on cell purification and analysis strategies, hematopoiesis has been one of the earliest experimental systems to which many of these new single-cell sequencing technologies have been applied. In this review, the authors focus on recent studies, which have shed light on heterogeneity within individual populations as well as the relationships between populations, and also attempt to characterize the differences between normal and disease/perturbed states.

• Animals
• Cellular Microenvironment/genetics
• Cellular Microenvironment/immunology
• Gene Expression Regulation
• Humans
• Hypoxia/genetics
• Hypoxia/immunology
• Hypoxia/metabolism
• Hypoxia-Inducible Factor 1/metabolism
• Immune System/cytology
• Immune System/immunology
• Immune System/metabolism
• Immunity
• Immunity, Innate
• Immunomodulation
• Inflammation/genetics
• Inflammation/immunology
• Inflammation/metabolism
• Inflammation/pathology
• Signal Transduction
• Transcription, Genetic

• P30 DK048520 NIDDK NIH HHS
• I01 BX002182 BLRD VA
• R37 DK050189 NIDDK NIH HHS
• R01 DK095491 NIDDK NIH HHS
• R01 DK104713 NIDDK NIH HHS
• R01 DK103712 NIDDK NIH HHS

Multiple myeloma (MM) is one of the most common forms of hematologic malignancy resulting from cancerous proliferation of mature malignant plasma cells (MPCs). But despite the real improvement in therapeutics in the past years, it remains largely incurable. MM is the most frequent cancer to involve bone due to the stimulation of osteoclast (OCL) differentiation and activity. OCLs have a unique capacity to resorb bone. However, recent studies reveal that they are not restrained to this sole function. They participate in the control of angiogenesis, medullary niches, and immune responses, including in MM. Therefore, therapeutic approaches targeting OCLs probably affect not only bone resorption but also many other functions, and OCLs should not be considered anymore only as targets to improve the bone phenotype but also to modulate bone microenvironment. In this review, we explore these novel contributions of OCLs to MM which reveal their strong implication in the MM physiopathology. We also underline the therapeutic interest of targeting OCLs not only to overcome bone lesions, but also to improve bone microenvironment and anti-tumoral immune responses.

• hematopoietic niche
• immunomodulation
• multiple myeloma
• myeloma bone disease
• osteoclast
• osteoimmunology