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Circulation Dec 2023Reducing cardiovascular disease burden among women remains challenging. Epidemiologic studies have indicated that polycystic ovary syndrome (PCOS), the most common...
BACKGROUND
Reducing cardiovascular disease burden among women remains challenging. Epidemiologic studies have indicated that polycystic ovary syndrome (PCOS), the most common endocrine disease in women of reproductive age, is associated with an increased prevalence and extent of coronary artery disease. However, the mechanism through which PCOS affects cardiac health in women remains unclear.
METHODS
Prenatal anti-Müllerian hormone treatment or peripubertal letrozole infusion was used to establish mouse models of PCOS. RNA sequencing was performed to determine global transcriptomic changes in the hearts of PCOS mice. Flow cytometry and immunofluorescence staining were performed to detect myocardial macrophage accumulation in multiple PCOS models. Parabiosis models, cell-tracking experiments, and in vivo gene silencing approaches were used to explore the mechanisms underlying increased macrophage infiltration in PCOS mouse hearts. Permanent coronary ligation was performed to establish myocardial infarction (MI). Histologic analysis and small-animal imaging modalities (eg, magnetic resonance imaging and echocardiography) were performed to evaluate the effects of PCOS on injury after MI. Women with PCOS and control participants (n=200) were recruited to confirm findings observed in animal models.
RESULTS
Transcriptomic profiling and immunostaining revealed that hearts from PCOS mice were characterized by increased macrophage accumulation. Parabiosis studies revealed that monocyte-derived macrophages were significantly increased in the hearts of PCOS mice because of enhanced circulating Ly6C monocyte supply. Compared with control mice, PCOS mice showed a significant increase in splenic Ly6C monocyte output, associated with elevated hematopoietic progenitors in the spleen and sympathetic tone. Plasma norepinephrine (a sympathetic neurotransmitter) levels and spleen size were consistently increased in women with PCOS when compared with those in control participants, and norepinephrine levels were significantly correlated with circulating CD14CD16 monocyte counts. Compared with animals without PCOS, PCOS animals showed significantly exacerbated atherosclerotic plaque development and post-MI cardiac remodeling. Conditional silencing in PCOS mice significantly suppressed cardiac inflammation and improved cardiac injury after MI.
CONCLUSIONS
Our data documented previously unrecognized mechanisms through which PCOS could affect cardiovascular health in women. PCOS may promote myocardial macrophage accumulation and post-MI cardiac remodeling because of augmented splenic myelopoiesis.
Topics: Pregnancy; Female; Humans; Mice; Animals; Polycystic Ovary Syndrome; Ventricular Remodeling; Myocardial Infarction; Heart Injuries; Inflammation; Norepinephrine
PubMed: 37937441
DOI: 10.1161/CIRCULATIONAHA.123.065827 -
Cancer Cell Nov 2023Acute myeloid leukemia (AML) poses a singular challenge for chimeric antigen receptor (CAR) therapy owing to its phenotypic heterogeneity and similarity to normal...
Acute myeloid leukemia (AML) poses a singular challenge for chimeric antigen receptor (CAR) therapy owing to its phenotypic heterogeneity and similarity to normal hematopoietic stem/progenitor cells (HSPCs). Here we expound a CAR strategy intended to efficiently target AML while minimizing HSPC toxicity. Quantification of target expression in relapsed/refractory patient samples and normal HSPCs reveals a therapeutic window for gated co-targeting of ADGRE2 and CLEC12A: We combine an attenuated ADGRE2-CAR with a CLEC12A-chimeric costimulatory receptor (ADCLEC.syn1) to preferentially engage ADGRE2CLEC12A leukemic stem cells over ADGRE2CLEC12A normal HSPCs. ADCLEC.syn1 prevents antigen escape in AML xenograft models, outperforms the ADGRE2-CAR alone and eradicates AML despite proximate myelopoiesis in humanized mice. Off-target HSPC toxicity is similar to that of a CD19-CAR and can be mitigated by reducing CAR T cell-derived interferon-γ. Overall, we demonstrate the ability of target density-adapted cooperative CAR targeting to selectively eliminate AML and potentially obviate the need for hematopoietic rescue.
Topics: Humans; Animals; Mice; Cell Line, Tumor; T-Lymphocytes; Leukemia, Myeloid, Acute; Immunotherapy, Adoptive; Hematopoietic Stem Cells; Receptors, Mitogen; Lectins, C-Type
PubMed: 37802054
DOI: 10.1016/j.ccell.2023.09.010 -
Signal Transduction and Targeted Therapy Jul 2023Traumatic brain injury (TBI) accelerates fracture healing, but the underlying mechanism remains largely unknown. Accumulating evidence indicates that the central nervous...
Traumatic brain injury (TBI) accelerates fracture healing, but the underlying mechanism remains largely unknown. Accumulating evidence indicates that the central nervous system (CNS) plays a pivotal role in regulating immune system and skeletal homeostasis. However, the impact of CNS injury on hematopoiesis commitment was overlooked. Here, we found that the dramatically elevated sympathetic tone accompanied with TBI-accelerated fracture healing; chemical sympathectomy blocks TBI-induced fracture healing. TBI-induced hypersensitivity of adrenergic signaling promotes the proliferation of bone marrow hematopoietic stem cells (HSCs) and swiftly skews HSCs toward anti-inflammation myeloid cells within 14 days, which favor fracture healing. Knockout of β3- or β2-adrenergic receptor (AR) eliminate TBI-mediated anti-inflammation macrophage expansion and TBI-accelerated fracture healing. RNA sequencing of bone marrow cells revealed that Adrb2 and Adrb3 maintain proliferation and commitment of immune cells. Importantly, flow cytometry confirmed that deletion of β2-AR inhibits M2 polarization of macrophages at 7th day and 14th day; and TBI-induced HSCs proliferation was impaired in β3-AR knockout mice. Moreover, β3- and β2-AR agonists synergistically promote infiltration of M2 macrophages in callus and accelerate bone healing process. Thus, we conclude that TBI accelerates bone formation during early stage of fracture healing process by shaping the anti-inflammation environment in the bone marrow. These results implicate that the adrenergic signals could serve as potential targets for fracture management.
Topics: Mice; Animals; Fracture Healing; Bone Marrow; Myelopoiesis; Mice, Knockout; Brain Injuries, Traumatic; Adrenergic Agents
PubMed: 37402714
DOI: 10.1038/s41392-023-01457-w -
International Journal of Molecular... Jun 2023Hematopoietic stem cells (HSCs) are defined based on their capacity to replenish themselves (self-renewal) and give rise to all mature hematopoietic cell types... (Review)
Review
Hematopoietic stem cells (HSCs) are defined based on their capacity to replenish themselves (self-renewal) and give rise to all mature hematopoietic cell types (multi-lineage differentiation) over their lifetime. HSCs are mainly distributed in the bone marrow during adult life, harboring HSC populations and a hierarchy of different kinds of cells contributing to the "niche" that supports HSC regulation, myelopoiesis, and lymphopoiesis. In addition, HSC-like progenitors, innate immune cell precursors such as macrophages, mast cells, natural killer cells, innate lymphoid cells, and megakaryocytes and erythrocyte progenitor cells are connected by a series of complex ontogenic relationships. The first source of mast cells is the extraembryonic yolk sac, on embryonic day 7. Mast cell progenitors circulate and enter peripheral tissues where they complete their differentiation. Embryonic mast cell populations are gradually replaced by definitive stem cell-derived progenitor cells. Thereafter, mast cells originate from the bone marrow, developing from the hematopoietic stem cells via multipotent progenitors, common myeloid progenitors, and granulocyte/monocyte progenitors. In this review article, we summarize the knowledge on mast cell sources, particularly focusing on the complex and multifaceted mechanisms intervening between the hematopoietic process and the development of mast cells.
Topics: Mast Cells; Immunity, Innate; Lymphocytes; Cell Differentiation; Hematopoiesis; Hematopoietic Stem Cells; Cell Lineage
PubMed: 37445862
DOI: 10.3390/ijms241310679 -
Journal of Hematology & Oncology Jul 2023Tumor-associated myeloid cells (TAMCs) are among the most important immune cell populations in the tumor microenvironment, and play a significant role on the efficacy of... (Review)
Review
Tumor-associated myeloid cells (TAMCs) are among the most important immune cell populations in the tumor microenvironment, and play a significant role on the efficacy of immune checkpoint blockade. Understanding the origin of TAMCs was found to be the essential to determining their functional heterogeneity and, developing cancer immunotherapy strategies. While myeloid-biased differentiation in the bone marrow has been traditionally considered as the primary source of TAMCs, the abnormal differentiation of splenic hematopoietic stem and progenitor cells, erythroid progenitor cells, and B precursor cells in the spleen, as well as embryo-derived TAMCs, have been depicted as important origins of TAMCs. This review article provides an overview of the literature with a focus on the recent research progress evaluating the heterogeneity of TAMCs origins. Moreover, this review summarizes the major therapeutic strategies targeting TAMCs with heterogeneous sources, shedding light on their implications for cancer antitumor immunotherapies.
Topics: Humans; Neoplasms; Myeloid Cells; Immunotherapy; Bone Marrow; Hematopoietic Stem Cells; Tumor Microenvironment
PubMed: 37415162
DOI: 10.1186/s13045-023-01473-x -
Mitochondrial pyruvate metabolism and glutaminolysis toggle steady-state and emergency myelopoiesis.The Journal of Experimental Medicine Sep 2023To define the metabolic requirements of hematopoiesis, we examined blood lineages in mice conditionally deficient in genes required for long-chain fatty acid oxidation...
To define the metabolic requirements of hematopoiesis, we examined blood lineages in mice conditionally deficient in genes required for long-chain fatty acid oxidation (Cpt2), glutaminolysis (Gls), or mitochondrial pyruvate import (Mpc2). Genetic ablation of Cpt2 or Gls minimally impacted most blood lineages. In contrast, deletion of Mpc2 led to a sharp decline in mature myeloid cells and a slower reduction in T cells, whereas other hematopoietic lineages were unaffected. Yet MPC2-deficient monocytes and neutrophils rapidly recovered due to a transient and specific increase in myeloid progenitor proliferation. Competitive bone marrow chimera and stable isotope tracing experiments demonstrated that this proliferative burst was progenitor intrinsic and accompanied by a metabolic switch to glutaminolysis. Myeloid recovery after loss of MPC2 or cyclophosphamide treatment was delayed in the absence of GLS. Reciprocally, MPC2 was not required for myeloid recovery after cyclophosphamide treatment. Thus, mitochondrial pyruvate metabolism maintains myelopoiesis under steady-state conditions, while glutaminolysis in progenitors promotes emergency myelopoiesis.
Topics: Mice; Animals; Myelopoiesis; Hematopoiesis; Bone Marrow; Cyclophosphamide; Pyruvates
PubMed: 37249600
DOI: 10.1084/jem.20221373 -
BioRxiv : the Preprint Server For... Mar 2024The bone marrow is the organ responsible for blood production. Diverse non-hematopoietic cells contribute essentially to hematopoiesis. However, these cells and their...
The bone marrow is the organ responsible for blood production. Diverse non-hematopoietic cells contribute essentially to hematopoiesis. However, these cells and their spatial organization remain largely uncharacterized as they have been technically challenging to study in humans. Here, we used fresh femoral head samples and performed single-cell RNA sequencing (scRNA-Seq) to profile 29,325 enriched non-hematopoietic bone marrow cells and discover nine transcriptionally distinct subtypes. We next employed CO-detection by inDEXing (CODEX) multiplexed imaging of 18 individuals, including both healthy and acute myeloid leukemia (AML) samples, to spatially profile over one million single cells with a novel 53-antibody panel. We discovered a relatively hyperoxygenated arterio-endosteal niche for early myelopoiesis, and an adipocytic, but not endosteal or perivascular, niche for early hematopoietic stem and progenitor cells. We used our atlas to predict cell type labels in new bone marrow images and used these predictions to uncover mesenchymal stromal cell (MSC) expansion and leukemic blast/MSC-enriched spatial neighborhoods in AML patient samples. Our work represents the first comprehensive, spatially-resolved multiomic atlas of human bone marrow and will serve as a reference for future investigation of cellular interactions that drive hematopoiesis.
PubMed: 38559168
DOI: 10.1101/2024.03.14.585083 -
Cancers Jun 2023Myeloid leukemia of Down syndrome (ML-DS) is characterized by a distinct natural history and is classified by the World Health Organization (WHO) as an independent... (Review)
Review
Myeloid leukemia of Down syndrome (ML-DS) is characterized by a distinct natural history and is classified by the World Health Organization (WHO) as an independent entity, occurring with unique clinical and molecular features. The presence of a long preleukemic, myelodysplastic phase, called transient abnormal myelopoiesis (TAM), precedes the initiation of ML-DS and is defined by unusual chromosomal findings. Individuals with constitutional trisomy 21 have a profound dosage imbalance in the hematopoiesis-governing genes located on chromosome 21 and thus are subject to impaired fetal as well as to neonatal erythro-megakaryopoiesis. Almost all neonates with DS develop quantitative and morphological hematological abnormalities, yet still only 5-10% of them present with one of the preleukemic or leukemic conditions of DS. The acquired mutations in the key hematopoietic transcription factor gene , found solely in cells trisomic for chromosome 21, are considered to be the essential step for the selective growth advantage of leukemic cells. While the majority of cases of TAM remain clinically 'silent' or undergo spontaneous remission, the remaining 20% to 30% of them progress into ML-DS until the age of 4 years. The hypersensitivity of ML-DS blasts to chemotherapeutic agents, including but not limited to cytarabine, and drugs' increased infectious and cardiac toxicity have necessitated the development of risk-adapted treatment protocols for children with ML-DS. Recent advances in cytogenetics and specific molecular mechanisms involved in the evolution of TAM and ML-DS are reviewed here, as well as their integration in the improvement of risk stratification and targeted management of ML-DS.
PubMed: 37444375
DOI: 10.3390/cancers15133265 -
Cell May 2024Non-hematopoietic cells are essential contributors to hematopoiesis. However, heterogeneity and spatial organization of these cells in human bone marrow remain largely...
Non-hematopoietic cells are essential contributors to hematopoiesis. However, heterogeneity and spatial organization of these cells in human bone marrow remain largely uncharacterized. We used single-cell RNA sequencing (scRNA-seq) to profile 29,325 non-hematopoietic cells and discovered nine transcriptionally distinct subtypes. We simultaneously profiled 53,417 hematopoietic cells and predicted their interactions with non-hematopoietic subsets. We employed co-detection by indexing (CODEX) to spatially profile over 1.2 million cells. We integrated scRNA-seq and CODEX data to link predicted cellular signaling with spatial proximity. Our analysis revealed a hyperoxygenated arterio-endosteal neighborhood for early myelopoiesis, and an adipocytic localization for early hematopoietic stem and progenitor cells (HSPCs). We used our CODEX atlas to annotate new images and uncovered mesenchymal stromal cell (MSC) expansion and spatial neighborhoods co-enriched for leukemic blasts and MSCs in acute myeloid leukemia (AML) patient samples. This spatially resolved, multiomic atlas of human bone marrow provides a reference for investigation of cellular interactions that drive hematopoiesis.
PubMed: 38714197
DOI: 10.1016/j.cell.2024.04.013 -
Cardiovascular Research Feb 2024Cardiometabolic disorders are chief causes of morbidity and mortality, with chronic inflammation playing a crucial role in their pathogenesis. The release of... (Review)
Review
Cardiometabolic disorders are chief causes of morbidity and mortality, with chronic inflammation playing a crucial role in their pathogenesis. The release of differentiated myeloid cells with elevated pro-inflammatory potential, as a result of maladaptively trained myelopoiesis may be a crucial factor for the perpetuation of inflammation. Several cardiovascular risk factors, including sedentary lifestyle, unhealthy diet, hypercholesterolemia, and hyperglycemia, may modulate bone marrow hematopoietic progenitors, causing sustained functional changes that favour chronic metabolic and vascular inflammation. In the present review, we summarize recent studies that support the function of long-term inflammatory memory in progenitors of the bone marrow for the development and progression of cardiometabolic disease and related inflammatory comorbidities, including periodontitis and arthritis. We also discuss how maladaptive myelopoiesis associated with the presence of mutated hematopoietic clones, as present in clonal hematopoiesis, may accelerate atherosclerosis via increased inflammation.
Topics: Humans; Bone Marrow; Hematopoietic Stem Cells; Myelopoiesis; Atherosclerosis; Inflammation; Hematopoiesis
PubMed: 36655373
DOI: 10.1093/cvr/cvad003