Differentiation Of Hematopoietic Stem Cells Research Articles

MSCs with upregulated lipid metabolism block hematopoietic stem cell differentiation via exosomal CTP-1A in MDS

BackgroundMyelodysplastic syndrome (MDS) is a clonal disorder of hematopoietic stem cells (HSCs), characterized by ineffective hematopoiesis and a high risk of progression to acute myeloid leukemia. Elucidating the mechanism underlying the dysfunction of MDS-HSCs is crucial for exploring the pathogenesis of the syndrome. While previous studies have implicated mesenchymal stem cells (MSCs), a principal component of the bone marrow (BM) microenvironment, in the inhibition of normal hematopoiesis, the precise molecular mechanisms have not been fully elucidated. In this study, we investigated the effects of MSCs from MDS patients on hematopoietic functions of HSCs from a metabolic perspective.MethodsMSCs were isolated from BM of MDS patients. The proliferation, apoptosis, differentiation and support for hematopoiesis of these cells were analyzed using CCK-8 assay, FC and induction medium and CFU (colony forming units) assay, respectively. Expression levels of metabolic molecules were used as indicators to screen MSCs with different metabolic pathways and were detected by RT-PCR and Western blotting. Exosome derived from MSCs were isolated from the culture supernatant and confirmed by Transmission Electron Microscope, Dynamic Light Scattering and Western blotting. The effects of these exosomes on HSCs were analyzed using the same methods as those used to assess MSCs function.ResultsOur findings demonstrated that MDS-MSCs exhibited significant functional impairments, including reduced proliferation, impaired differentiation, diminished support for hematopoiesis, and increased apoptosis. Notably, we observed an upregulation of lipid metabolism in these MSCs, which appears to contribute to their dysfunction. Intriguingly, the aberrant lipid metabolic profile can be effectively reversed by the administration of etomoxir (ETO), an inhibitor of carnitine palmitoyltransferase 1A (CPT-1A). Furthermore, MSCs with enhanced lipid metabolism could transmit this dysfunction to HSCs through the secretion of exosomes that are enriched in CPT-1A.ConclusionsWe suggest that the MDS BM microenvironment disrupts MSCs metabolism by increasing the expression of CPT-1A, which impairs the ability to support normal HSCs. Interestingly, the suppressive effect is mediated by exosomes rich in CPT-1A, which derived from MSCs. These findings provide novel insights into MDS MSCs-metabolism-Exosome axis in ineffective hematopoiesis and offer new strategies for the treatment of MDS.

Bone Marrow Niche in Cardiometabolic Disease: Mechanisms and Therapeutic Potential.

Cardiovascular and cardiometabolic diseases are leading causes of morbidity and mortality worldwide, driven in part by chronic inflammation. Emerging research suggests that the bone marrow microenvironment, or marrow niche, plays a critical role in both immune system regulation and disease progression. The bone marrow niche is essential for maintaining hematopoietic stem cells (HSCs) and orchestrating hematopoiesis. Under normal conditions, this niche ensures a return to immune homeostasis after acute stress. However, in the setting of inflammatory conditions such as those seen in cardiometabolic diseases, it becomes dysregulated, leading to enhanced myelopoiesis and immune activation. This review explores the reciprocal relationship between the bone marrow niche and cardiometabolic diseases, highlighting how alterations in the niche contribute to disease development and progression. The niche regulates HSCs through complex interactions with stromal cells, endothelial cells, and signaling molecules. However, in the setting of chronic diseases such as hypertension, atherosclerosis, and diabetes, inflammatory signals disrupt the balance between HSC self-renewal and differentiation, promoting the excessive production of proinflammatory myeloid cells that exacerbate the disease. Key mechanisms discussed include the effects of hyperlipidemia, hyperglycemia, and sympathetic nervous system activation on HSC proliferation and differentiation. Furthermore, the review emphasizes the role of epigenetic modifications and metabolic reprogramming in creating trained immunity, a phenomenon whereby HSCs acquire long-term proinflammatory characteristics that sustain disease states. Finally, we explore therapeutic strategies aimed at targeting the bone marrow niche to mitigate chronic inflammation and its sequelae. Novel interventions that modulate hematopoiesis and restore niche homeostasis hold promise for the treatment of cardiometabolic diseases. By interrupting the vicious cycle of inflammation and marrow dysregulation, such therapies may offer new avenues for reducing cardiovascular risk and improving patient outcomes.

Exploring Epigenetic Complexity in Regulation of Hematopoietic Stem Cells Niche: A Mechanistic Journey from Normal to Malignant Hematopoiesis.

Epigenetic regulation in hematopoietic stem cells (HSCs) research has emerged as a transformative molecular approach that enhances understanding of hematopoiesis and hematological disorders. This chapter investigates the intricate epigenetic mechanisms that control HSCs function, including deoxyribonucleic acid (DNA) methylation, histone modifications, and chromatin remodeling. It also explores the role of non-coding ribonucleic acid (RNAs) as epigenetic regulators, highlighting how changes in gene expression can occur without alterations to the DNA sequence. Epigenetic mechanisms play a pivotal in regulating HSC self-renewal and differentiation, processes essential for maintaining a balanced hematopoietic system in which lineage-specific hematopoietic stem and progenitor cells (HSPCs) pool is sustained. Recent advancements in epigenetic mapping and sequencing technologies have illuminated the dynamic epigenetic landscapes that characterize HSCs and their progeny. Numerous studies have revealed that dysregulation of epigenetic pathways is a hallmark of various hematological malignancies, including leukemias, lymphomas, and myelodysplastic syndromes. This review highlights key findings that demonstrate the impact of epigenetic abnormalities on the disruption of HSPC niches and the progression of oncogenesis in hematological malignancies. Furthermore, this chapter explores the therapeutic potential of targeting epigenetic modifications that are critical in formation and progression of hematologic malignancies. It also discusses the latest developments in epigenetic therapies, including the use of DNA methyltransferase inhibitors, histone deacetylase inhibitors, and emerging drugs targeting other epigenetic regulators. These therapies represent a promising strategy for resetting aberrant epigenetic states, potentially restoring normal hematopoiesis. Conclusively, this chapter offers a thorough overview of the current landscape and future directions of epigenetic research related to the maintenance of the HSPC niches. The insights presented here aim to contribute significantly to the field, offering a reference point for molecular approaches that enhance our understanding of hematopoiesis and its associated hematological malignancies.

Are rs1042059 and rs11591377 polymorphisms of BMI1 gene related to leukemia?

Hematologic malignancies, originating from uncontrolled growth of hematopoietic and lymphoid tissues, constitute 6.5% of all cancers worldwide. Various risk factors including genetic disorders and single nucleotide polymorphisms play a role in the pathogenesis of hematologic malignancies. BMI1 is one of the genes involved in regulating the self-renewal and differentiation of hematopoietic stem cells. 69 leukemia patients (45 AML, 18 ALL, and 6 CML) along with 80 control samples were selected. The frequency of rs1042059 and rs11591377 polymorphisms of BMI1 gene was evaluated using the Tetra-ARMS PCR technique. A significant difference in the prevalence of rs1042059 and rs11591377 polymorphisms was observed between the patient and control groups (P = < 0.001). The frequency of GA genotypes for both polymorphisms was higher in patients compared to the control group. Additionally, a significant difference was found in the prevalence of rs11591377 genotypes among the AML, ALL, and CML groups (P = 0.002) however, no significant difference was observed in the prevalence of rs1042059 genotypes among them (P = 0.578). Considering the significant decrease in the prevalence of allelic variants in the control group compared to the leukemia group, the association of BMI1 with leukemias should be considered as a diagnostic and prognostic factor.

3' UTR-truncated HMGA2 promotes erythroblasts production from human embryonic stem cells.

Cultured red blood cells represent an alternative resource for blood transfusions. However, important issues such as low yields and high costs remain. Recently, gene editing of hematopoietic stem cells has been conducted to induce erythroid differentiation in vitro for producing sufficient RBCs to meet the imbalance in blood supply and demand. The differentiation and expansion of hematopoietic stem and progenitor cells are regulated by transcription factors, such as high mobility group AT-hook 2 (HMGA2). In this study, we utilized CRISPR/Cas9 to establish a doxycycline-inducible HMGA2-expressing human embryonic stem cell (hESC) line. In a defined erythroid differentiation system, HMGA2 prolonged erythroid differentiation in vitro, enabling extensive expansion of human erythroblasts. The erythroblasts derived from the HMGA2-expressing hESC line are rich in polychromatic and orthochromatic erythroblasts expressing mostly α- and γ-globin and have the capacity to differentiate into RBCs. Our findings highlight the potential of combining hematopoietic transcription factors with genome editing techniques to enhance RBC production.

Early and delayed STAT1-dependent responses drive local trained immunity of macrophages in the spleen.

Trained immunity (TI) is the process wherein innate immune cells gain functional memory upon exposure to specific ligands or pathogens, leading to augmented inflammatory responses and pathogen clearance upon secondary exposure. While the differentiation of hematopoietic stem cells (HSCs) and reprogramming of bone marrow (BM) progenitors are well-established mechanisms underpinning durable TI protection, remodeling of the cellular architecture within the tissue during TI remains underexplored. Here, we study the effects of peritoneal Bacillus Calmette-Guérin (BCG) administration to find TI-mediated protection in the spleen against a subsequent heterologous infection by the Gram-negative pathogen Salmonella Typhimurium (S.Tm). Utilizing single cell RNA-sequencing and flow cytometry, we discerned STAT1-regulated genes in TI-associated resident and recruited splenic myeloid populations. The temporal dynamics of TI were further elucidated, revealing both early and delayed myeloid subsets with time-dependent, cell-type-specific STAT1 signatures. Using lineage tracing, we find that tissue-resident red pulp macrophages (RPM), initially depleted by BCG exposure, are restored from both tissue-trained, self-renewing macrophages and from bone marrow-derived progenitors, fostering long lasting local defense. Early inhibition of STAT1 activation, using specific JAK-STAT inhibitors, reduces both RPM loss and recruitment of trained monocytes. Our study suggests a temporal window soon after BCG vaccination, in which STAT1-dependent activation of long-lived resident cells in the tissue mediates localized protection.

Donkey-Hide Gelatin-Derived Carbon Dots Activate Erythropoiesis and Eliminate Oxidative Stress for Aplastic Anemia Treatment.

Aplastic anemia (AA) is a life-threatening hematologic disease with limited therapeutic options. Stalled erythropoiesis and oxidative stress-induced hemocyte apoptosis are the main pathological features of AA, yet therapeutic agents that address these issues remain elusive. In this study, we report distinctive donkey-hide gelatin-derived carbon dots (G-CDs) that enable erythropoiesis activation and oxidative stress elimination to tackle refractory AA. We demonstrate that G-CDs can promote the proliferation and erythroid differentiation of hematopoietic stem cells as well as erythrocyte maturation, activating the whole process of erythropoiesis. Moreover, G-CDs display multienzyme-like activities and dramatically alleviate the oxidative stress of bone marrow and peripheral blood via catalytic scavenging of multiple reactive oxygen species, reconstructing the hematopoietic microenvironment. Intravenously or orally administered to AA mice induced by chemotherapy drugs, G-CDs significantly boost the level of red blood cells and hemoglobin and lead to the complete recovery of hematopoietic function, showing better therapeutic performance than clinically approved erythropoietin (EPO) without adverse effects. By collaboratively addressing the issues of stalled erythropoiesis and oxidative stress, the G-CDs-based intervention strategy may offer a powerful paradigm for clinical AA management.

PLK1 inhibition impairs erythroid differentiation

Polo-like kinase 1 (PLK1), a key regulator of the G2/M phase in mitosis, is frequently overexpressed in numerous tumors. Although PLK1 inhibitors have emerged as promising therapeutic agents for cancer, their use has been linked to significant anemia in a subset of patients, yet the underlying mechanisms remain poorly understood. In this study, we utilized an in vitro human umbilical cord blood-derived CD34+ cell-based erythroid differentiation system, alongside a murine model, to investigate the impact of PLK1 inhibitors on erythropoiesis. Our results indicate that PLK1 inhibitors, specifically GSK461364 and BI6727, significantly suppress the proliferation of erythroid cells, resulting in G2/M phase cell cycle arrest, increased apoptosis in erythroid cells, and the formation of abnormally nucleated late-stage erythroblasts. In vivo, administration of PLK1 inhibitors in mice induced severe anemia, as evidenced by a marked reduction in red blood cells and hemoglobin levels. More specifically, PLK1 inhibition impaired the differentiation and erythroid commitment of hematopoietic stem cells in the bone marrow, resulting in abnormal accumulation of BFU-E cells and reduced proliferation and differentiation of CFU-E, and a decrease in the number of terminal erythrocytes. Mechanistically, PLK1 inhibitors primarily induce apoptosis in erythroid cells by reducing Mitochondrial membrane potential and arresting the cell cycle at the G2/M phase. Overall, our findings underscore the critical role of PLK1 in erythropoiesis and shed light on the mechanisms underlying PLK1 inhibitor-induced anemia, providing essential guidance for developing strategies to prevent and manage anemia in clinical applications of PLK1-targeted therapies.

A generalizable Hi-C foundation model for chromatin architecture, single-cell and multi-omics analysis across species.

Nuclear DNA is organized into a compact three-dimensional (3D) structure that impacts critical cellular processes. High-throughput chromosome conformation capture (Hi-C) is the most widely used method for measuring 3D genome architecture, while linear epigenomic assays, such as ATAC-seq, DNase-seq, and ChIP-seq, are extensively employed to characterize epigenomic regulation. However, the integrative analysis of chromatin interactions and associated epigenomic regulation remains challenging due to the pairwise nature of Hi-C data, mismatched resolution between Hi-C and epigenomic assays, and inconsistencies among analysis tools. Here we propose HiCFoundation, a Hi-C-based foundation model for integrative analysis linking chromatin structure to downstream regulatory function. HiCFoundation is trained from hundreds of Hi-C assays encompassing 118 million contact matrix submatrices. The model achieves state-of-the-art performance on multiple types of 3D genome analysis, including reproducibility analysis, resolution enhancement, and loop detection. We further demonstrate the model's generalizability through genome architecture analysis of 316 species. Notably, by enhancing low-coverage experimental Hi-C data, HiCFoundation reveals genome-wide loop loss during differentiation of hematopoietic stem and progenitor cells (HSPCs) to neutrophils. Additionally, HiCFoundation is able to predict multiple types of epigenomic activity from Hi-C input and further interprets the link between Hi-C input and epigenomic output to reveal the relationship between chromatin conformation and genome function. Finally, HiCFoundation can analyze single-cell Hi-C data, shedding light on genome structure at single-cell resolution. HiCFoundation thus provides a unified, efficient, generalizable, and interpretable foundation for genome architecture, single-cell and multi-omics analysis across species, paving the path for systematically studying genome 3D architecture and its regulatory mechanisms.

Reframing thalassaemia syndrome as a benign haematopoietic stem cell disorder.

Thalassaemia, caused by over 250 mutations in the beta globin gene, changes the haematopoietic stem cell (HSC) differentiation, leading to ineffective erythropoiesis. This Wider Perspective article overlooks its underlying nature as a benign HSC disorder with a significant impact on the erythroid cell lineage. The simplicity of managing symptoms through transfusions and iron chelation therapy has shifted the focus away from the development of cell-based treatments. The identification of the beta039 mutation by Chang and Kan in 1979 marked a turning point, suggesting as main approach the molecular level by correcting the beta globin chain imbalances through gene insertion and editing. However, challenges of technology have delayed the implementation of these strategies for over four decades. In contrast, the past two decades have witnessed significant advances in the treatment of HSC disorders of the myeloid clone which are driven by a 'target cell strategy'. Many current and innovative treatments for thalassaemia are now adopting this approach, highlighting the importance of identifying suitable candidates through risk stratification. This manuscript explores the evolving understanding of thalassaemia syndromes as congenital HSC disorders of the erythroid clone and examines the implications of this perspective for the development of future treatments.

The dynamics of hematopoiesis over the human lifespan.

Over a lifetime, hematopoietic stem cells (HSCs) adjust their lineage output to support age-aligned physiology. In model organisms, stereotypic waves of hematopoiesis have been observed corresponding to defined age-biased HSC hallmarks. However, how the properties of hematopoietic stem and progenitor cells change over the human lifespan remains unclear. To address this gap, we profiled individual transcriptome states of human hematopoietic stem and progenitor cells spanning gestation, maturation and aging. Here we define the gene expression networks dictating age-specific differentiation of HSCs and the dynamics of fate decisions and lineage priming throughout life. We additionally identifiy and functionally validate a fetal-specific HSC state with robust engraftment and multilineage capacity. Furthermore, we observe that classification of acute myeloid leukemia against defined transcriptional age states demonstrates that utilization of early life transcriptional programs associates with poor prognosis. Overall, we provide a disease-relevant framework for heterochronic orientation of stem cell ontogeny along the real time axis of the human lifespan.

A system-level model reveals that transcriptional stochasticity is required for hematopoietic stem cell differentiation

HSCs differentiation has been difficult to study experimentally due to the high number of components and interactions involved, as well as the impact of diverse physiological conditions. From a 200-node network, that was grounded on experimental data, we derived a 21-node regulatory network by collapsing linear pathways and retaining the functional feedback loops. This regulatory network core integrates key nodes and interactions underlying HSCs differentiation, including transcription factors, metabolic, and redox signaling pathways. We used Boolean, continuous, and stochastic dynamic models to simulate the hypoxic conditions of the HSCs niche, as well as the patterns and temporal sequences of HSCs transitions and differentiation. Our findings indicate that HSCs differentiation is a plastic process in which cell fates can transdifferentiate among themselves. Additionally, we found that cell heterogeneity is fundamental for HSCs differentiation. Lastly, we found that oxygen activates ROS production, inhibiting quiescence and promoting growth and differentiation pathways of HSCs.

Impact of tumor on the cell cycle and differentiation of hematopoietic stem cells

Today, there is a theory that proliferative potential of hematopoietic stem cells is depleted, and the balance of committed precursor cells shifts towards suppressors during the development of cancer. However, differentiation of hematopoietic stem cells can vary depending on the tumor type, localization, and microenvironment specifics. The study aimed to assess the impact of tumors of various origins on the CD34+ hematopoietic stem cells (n = 10). Assessment of the cell cycle and cell differentiation via both direct contact with the tumor and exchanging humoral factors only in transwells was conducted by flow cytometry. In the co-culture with К562, the number of hematopoietic stem cells being in their synthesis phase was 2.1%, while in the control it was 11.2% (p = 0.01); in the co-culture with SK-mel37, the number of hematopoietic stem cells being in the G2‒M cell cycle phase was reduced to 0.3% (p &lt; 0.05). 1301 and К562 directed the hematopoietic stem cell differentiation towards granulocyte-macrophage precursor cells (p &lt; 0.05), while 1301 and SK-mel37 directed it towards common multipotent progenitor cells. It is interesting that the number of pluripotent hematopoietic stem cells significantly increased (2-fold) compared to control after incubation with К562 in transwells (24.17% and 10.19%, respectively). Thus, properties of hematopoietic stem cells can vary depending on both tumor type and the way of interacting with these cells.

Role of MicroRNAs in Chronic Myeloid Leukemia (CML) Treatment, Biomarkers, and Resistance to Tyrosine Kinase Inhibitor: A Bioinformatics-Based Analysis

Chronic myeloid leukemia (CML) is a myeloproliferative disorder caused by the reciprocal translocation of the BCR-ABL1 oncogene, which activates tyrosine kinase resulting in uncontrolled cell proliferation and apoptosis suppression. Although Imatinib (IM) is an effective treatment, IM resistance remains a significant concern. Therefore, microRNAs (miRNAs) have emerged as potential alternative therapies. These short, non-coding RNAs (20-22 nucleotides) regulate gene expression by binding to the 3' untranslated region (3'UTR) of target genes. The study aims to identify miRNAs linked to CML, determine miRNA’s target genes, construct a protein-protein interaction (PPI) network, and analyze pathways and gene ontology. A literature search using the keywords “microRNA”, and “chronic myeloid leukemia” yielded relevant papers, which were screened and categorized into three groups: 1) miRNA associated with TKI resistance, 2) miRNA as biomarkers or leukemogenesis, and 3) miRNA as therapy. Target genes for the identified miRNAs were determined using DIANA tools and miRTarBase. Gene ontology and pathway analysis were conducted using DAVID, while PPI and network visualization were performed using STRING, Cytoscape, and ClueGO. Thirteen miRNAs were selected, targeting 782 genes and forming 16 clusters. ClueGO identified clusters associated with key biological processes, including G1/S cell cycle transition, miRNA-mediated gene silencing, hematopoietic stem cell differentiation, and apoptosis regulation. Target genes are also significant in the CML pathway and other cancer pathways, such as p53, ErbB, FoxO, autophagy, apoptosis, VEGF, TNF, and microRNA. Notably, hsa-miR-16 emerged as the most promising therapeutic and biomarker candidate for CML, highlighting its role in critical pathways.

Low-calorie and high-protein diet has diverse impacts on the muscle, bone, and bone marrow adipose tissues.

The present study was designed to evaluate the influence of a high-protein diet under conditions of calorie restriction (CR) in the muscle, adipose tissue, bone, and marrow adipose tissue (MAT). It included three groups of 20 female Wistar Hannover rats, fed with the following diets for 8wk: control group (C) fed with an AIN93M diet, CR group (R) fed with an AIN-93M diet modified to 30% CR, and CR + high-protein group (H) fed with an AIN-93M diet modified to 30% CR with 40% protein. Body composition was determined by DXA. The femur was used for histomorphometry and the estimation of adipocytes. Microcomputed tomography (μCT) was employed to analyze the bone structure. Hematopoietic stem cells from the bone marrow were harvested for osteoclastogenesis. Body composition revealed that the gain in lean mass surpassed the increase in fat mass only in the H group. Bone histomorphometry and μCT showed that a high-protein diet did not mitigate CR-induced bone deterioration. In addition, the number of bone marrow adipocytes and the differentiation of hematopoietic stem cells into osteoclasts were higher in H than in the other groups. These results indicated that under CR, a high-protein diet was beneficial for muscle mass. However, as the μCT scanning detected significant bone deterioration, this combined diet might accentuate the detrimental effect on the skeleton caused by CR. Remarkably, the H group rats exhibited greater MAT expansion and elevated hematopoietic stem cell differentiation into osteoclasts than the CR and control counterparts. These data suggest that a high protein may not be an appropriate strategy to preserve bone health under CR conditions.

NR4A1 and NR4A2 orphan nuclear receptors regulate endothelial-to-hematopoietic transition in mouse hematopoietic stem cell specification.

Hematopoietic stem cells (HSCs) sustain life-long hematopoiesis and emerge during mid-gestation from hemogenic endothelial progenitors via an endothelial-to-hematopoietic transition (EHT). The full scope of molecular mechanisms governing this process remains unclear. The NR4A subfamily of orphan nuclear receptors act as tumor suppressors in myeloid leukemogenesis and have never been implicated in HSC specification. Here, we report that Nr4a1 and Nr4a2 expression is upregulated in hemogenic endothelium during EHT. Progressive genetic ablation of Nr4a gene dosage results in a gradual decrease in numbers of nascent c-Kit+ hematopoietic progenitors in developing embryos, c-Kit+ cell cluster size in the dorsal aorta, and a block in HSC maturation, revealed by an accumulation of pro-HSCs and pre-HSC-type I cells and decreased numbers of pre-HSC-type II cells. Consistent with these observations, cells isolated from embryonic day 11.5 Nr4a1-/-; Nr4a2-/- aorta-gonads-mesonephros are devoid of in vivo long-term hematopoietic repopulating potential. Molecularly, employing spatial transcriptomic analysis we determined that the genetic ablation of Nr4a1 and Nr4a2 prevents Notch signaling from being downregulated in intra-aortic clusters and thus for pro-HSCs to mature into HSCs. Interestingly, this defect is partially rescued by ex vivo culture of dissected aorta-gonads-mesonephros with SCF, IL3 and FLT3L, which may bypass Notch-dependent regulation. Overall, our data reveal a role for the NR4A family of orphan nuclear receptors in EHT.

Abstract 4137935: Adipogenesis in Bone Marrow Niche under Cardiac Stress Worsens Cardiac Function

Background: We have recently reported that repetitive cardiac decompensation with multimorbidity often experienced by patients with heart failure (HF) is attributed to epigenetic modifications of hematopoietic stem cells (HSCs) in the bone marrow (BM). HF reprogrammed HSCs differentiation and altered tissue macrophage homeostasis. These findings demonstrate that the BM can carry an innate immune memory of cardiac stress that may exacerbate HF and predispose other organs to pathology. Aims: Because the stemness of HSCs is mainly regulated by mesenchymal stromal cells (MSCs) in the BM niche, we investigated phenotypic alterations of MSCs under cardiac stress. Methods&amp;Results: Transcriptome analysis of MSCs showed preferential differentiation toward adipocytes in murine pressure overload models. In vitro assays and histological BM sections also support this finding. Furthermore, single-cell RNA sequencing of MSCs demonstrated that the percentage of adipocyte-primed MSCs increased in proportion to the severity of cardiac dysfunction, and also correlated with the frequency of myeloid-lineage progenitor cells. To investigate the influence of adipo-lineage MSCs on HSCs, we conducted BM transplantation supplemented with MSCs from control or HF mice. Recipient mice transplanted with HF-MSCs showed significant increases in myeloid-biased multipotent progenitors in BM and myeloid cells in peripheral blood. Additionally, the number of proinflammatory cardiac macrophages was significantly increased in the HF-MSCs group, promoting cardiac fibrosis and dysfunction. Conclusions: Our results demonstrated that the BM niche could perceive cardiac stress in the form of adipocytic skewing of MSCs in the setting of HF, which changed the differentiation behavior in HSCs and ultimately led to further deterioration of cardiac function through the impaired differentiation of circulating monocytes into cardiac macrophages. Therefore, suppressing the adipocytic differentiation of MSCs could have a novel therapeutic potential to avoid repeated HF events.

Hematopoietic Stem Cell Function and Differentiation Is Regulated By DCAF7 through Polycomb Repressive Complex 1 (PRC1) Modulation

Hematopoietic Stem Cell Function and Differentiation Is Regulated By DCAF7 through Polycomb Repressive Complex 1 (PRC1) Modulation

Age-associated imbalance in immune cell regeneration varies across individuals and arises from a distinct subset of stem cells

The age-associated decline in immunity manifests as imbalanced adaptive and innate immune cells, which originate from the aging of the stem cells that sustain their regeneration. Aging variation across individuals is well recognized, but its mechanism remains unclear. Here, we used high-throughput single-cell technologies to compare mice of the same chronological age that exhibited early or delayed immune aging phenotypes. We found that some hematopoietic stem cells (HSCs) in early aging mice upregulated genes related to aging, myeloid differentiation, and stem cell proliferation. Delayed aging was instead associated with genes involved in stem cell regulation and the response to external signals. These molecular changes align with shifts in HSC function. We found that the lineage biases of 30% to 40% of the HSC clones shifted with age. Moreover, their lineage biases shifted in opposite directions in mice exhibiting an early or delayed aging phenotype. In early aging mice, the HSC lineage bias shifted toward the myeloid lineage, driving the aging phenotype. In delayed aging mice, HSC lineage bias shifted toward the lymphoid lineage, effectively counteracting aging progression. Furthermore, the anti-aging HSC clones did not increase lymphoid production but instead decreased myeloid production. Additionally, we systematically quantified the frequency of various changes in HSC differentiation and their roles in driving the immune aging phenotype. Taken together, our findings suggest that temporal variation in the aging of immune cell regeneration among individuals primarily arises from differences in the myelopoiesis of a distinct subset of HSCs. Therefore, interventions to delay aging may be possible by targeting a subset of stem cells.

Vasopressin drives aberrant myeloid differentiation of hematopoietic stem cells, contributing to depression in mice

Psychological stress is often linked to depression and can also impact the immune system, illustrating the interconnectedness of mental health and immune function. Hematopoietic stem cells (HSCs) can directly sense neuroendocrine signals in bone marrow and play a fundamental role in the maintenance of immune homeostasis. However, it is unclear how psychological stress impacts HSCs in depression. Here, we report that neuroendocrine factor arginine vasopressin (AVP) promotes myeloid-biased HSC differentiation by activating neutrophils. AVP administration increases neutrophil and Ly6Chi monocyte production by triggering HSCs that rely on intrinsic S100A9 in mice. When stimulated with AVP, neutrophils return to the bone marrow and release interleukin 36G (IL-36G), which interacts with interleukin 1 receptor-like 2 (IL-1RL2) on HSCs to produce neutrophils with high Elane expression that infiltrate the brain and induce neuroinflammation. Together, these findings define HSCs as a relay between psychological stress and myelopoiesis and identify the IL-36G-IL-1RL2 axis as a potential target for depression therapy.