Erythrocytes support tissue oxygen-dependent energy metabolism by enabling oxygen transport and are essential for maintaining metabolic homeostasis. Their differentiation and development are orchestrated by multilayered regulatory networks that play a decisive role in sustaining hematopoietic homeostasis. Although key regulators and signaling pathways governing erythropoiesis have been extensively characterized, how these mechanisms are integrated across developmental transitions, stress responses, and disease states remains incompletely understood. Here, we provide a comprehensive overview of the structural basis, developmental programs, and regulatory logic of erythropoiesis. We first summarize the structural features of erythrocytes, with a focus on the membrane skeleton and its spatiotemporal assembly and relevant regulatory mechanisms. We then outline the developmental trajectories and stage-specific characteristics of erythropoiesis under both steady-state and stress conditions. Building on this framework, we integrate current knowledge on the multilayered regulatory networks governing erythropoiesis, including transcriptional control, epigenetic regulation, metabolic reprogramming, and signals from the hematopoietic microenvironment. Furthermore, using representative erythrocyte-related disorders as a lens, we discuss how dysregulation of these pathways contributes to disease pathogenesis. Finally, we highlight recent advances and key challenges in the translational applications of erythrocytes, including in vitro generation, drug delivery, immunomodulation, and regenerative medicine. This review aims to establish an integrated conceptual framework for erythroid development and to provide insights for future mechanistic studies and clinical translation.
Conventionally, it is believed that the biological functions of RNA are confined to the interior of cells, and the existence of functional RNAs on cell surface as well as their potential mechanisms of action have long remained unclear. In recent years, the discovery and functional research of cell surface RNA have completely revolutionized this traditional perception, confirming its important biological significance as a class of novel surface functional molecules. This review systematically summarizes the latest research advances in the field of cell surface RNA, focusing on four aspects: its classification and characteristics, detection and identification technologies, biogenesis and transport mechanisms, as well as biological functions. It also summarizes the current technical bottlenecks and key scientific challenges in this field, providing a reference for interdisciplinary studies in RNA biology, glycobiology, and immunology.
Lineage tracing is a fundamental technique for dissecting cell fate decisions and development process. With recent advances in high-throughput sequencing and single-cell sequencing technologies, cellular barcoding-based lineage tracing strategies have transitioned from low-throughput labeling methods to high-resolution, multidimensional lineage reconstruction. In this review, we systematically summarize four major barcoding paradigms: viral integration-based random integration barcodes, transposon-based random integration barcodes, recombinase-mediated DNA rearrangement (e.g., Cre-loxP), and CRISPR-Cas9-based mutation recording systems. We describe their principles, representative studies, technical advantages, and limitations. Furthermore, we discuss the core bottlenecks in terms of editing precision, integration of spatiotemporal information, and non-invasive lineage tracing, with a focus on cutting-edge advancements such as prime editing, sequential recording systems, strategies for integrating spatial transcriptomics, and epigenetic tracing. Overall, single-cell lineage tracing is evolving from clonal labeling toward the multi-dimensional integration of lineage, state, and space. In the future, the deep integration of precise gene-editing tools with high-resolution spatial omics technologies is expected to enable dynamic and systematic analysis of cellular fate trajectories, thereby providing critical technical support for research in developmental biology and regenerative medicine.
The Chinese Association for Physiological Sciences (CAPS), founded in 1926, is one of the earliest and most influential national academic organizations in the field of biological sciences in China. Over the past century, the development of CAPS has been closely linked with the modernization of medical education, the growth of experimental life sciences, national scientific reconstruction, and the increasing demand for public health. Based on historical materials prepared for the centennial of CAPS, this article reviews the major stages of its development, including its foundation and institutional establishment, post-1949 reorganization and disciplinary expansion, revival after the reform and opening-up, internationalization in the new century, and modernization of governance in the new era. From 1926 to 1949, CAPS established an academic community through annual meetings, membership development, and the founding of the Chinese Journal of Physiology, providing an important platform for Chinese physiological research to communicate with the international scientific community. From 1949 to 1977, the society restored its organizational network and expanded into the Chinese Association for Physiological Sciences, reflecting the broader formation of physiology-related disciplines in the new national scientific and educational system. Since 1978, CAPS has resumed national academic conferences and journal publication, strengthened talent cultivation, teaching reform, disciplinary planning, and international cooperation, and gradually transformed from a meeting-oriented society into a comprehensive academic organization. In the new era, the establishment of Party committee, a board of supervisors, improved professional committee management, digital office systems, and international conferences has further promoted standardized, modernized, and internationalized governance. The century-long history of CAPS shows that academic excellence, service to national needs, talent development, the inheritance of scientific spirit, and open collaboration constitute the key experience for the sustainable development of a scientific society and have together shaped an organizational culture characterized by rigor, innovation, collaboration, and dedication.
Metabolic reprogramming lies at the core of the malignant features of acute myeloid leukemia stem cells (LSCs), and represents a critical window for selective targeting. Unlike quiescent hematopoietic stem cells (HSCs) that mainly rely on glycolysis to maintain low levels of reactive oxygen species, LSCs acquire remarkable metabolic plasticity during malignant transformation, enabling them to simultaneously utilize glycolysis and oxidative phosphorylation (OXPHOS) to meet biosynthetic demands and establish therapeutic resistance. These divergences between LSCs and HSCs are rooted in profound regulatory differences in terms of energy metabolism pathways, mitochondrial functional regulation and metabolic-epigenetic crosstalk networks. This review comprehensively summarizes the molecular basis of metabolic regulation in HSCs and LSCs, discusses the regulatory mechanisms of metabolic reprogramming in LSCs, and explores precise therapeutic strategies targeting the specific metabolic programs of LSCs, thereby providing new insights for overcoming therapeutic resistance in leukemia.
Multiple myeloma ranks as the second most prevalent hematological malignancy. It remains incurable and is characterized by frequent drug resistance and disease relapse. Mitochondria, as a key hub for cellular energy metabolism and homeostasis regulation, have been found to have functional abnormalities in various cancers. The occurrence, progression and drug resistance of multiple myeloma are also closely linked to mitochondrial dysfunction. Existing research has shown that multiple myeloma cells acquire survival advantages and escape therapeutic elimination by enhancing oxidative phosphorylation, reprogramming glycolysis, maintaining redox homeostasis, regulating calcium homeostasis and mitochondrial quality control, as well as inhibiting mitochondria-dependent apoptosis. Multiple types of drugs and combination therapy strategies targeting the above processes have shown potential in preclinical studies. This review summarizes the main role of mitochondrial dysfunction in the development and drug resistance of multiple myeloma, as well as the research progress of targeted therapy, providing new ideas for targeted therapy of multiple myeloma.
The bone marrow vascular microenvironment is primarily composed of endothelial cells (ECs) and mesenchymal stem/stromal cells (MSCs), which maintain hematopoietic homeostasis by regulating the quiescence, activation, proliferation, and differentiation of hematopoietic stem cells (HSCs). During leukemogenesis and disease progression, malignant cells remodel the vascular microenvironment, leading to aberrant vascular architecture, disruption of endothelial barrier integrity, phenotypic conversion of MSCs toward a pro-inflammatory/pro-survival state, and the dismantling of normal signaling networks among ECs, MSCs, and HSCs, alongside the establishment of aberrant communication axes. These alterations, on one hand, disrupt the supportive HSC niche, resulting in bone marrow failure-associated pancytopenia. On the other hand, the remodeled vascular microenvironment transforms into a sanctuary that promotes leukemia cell proliferation, migration, and drug resistance, ultimately driving disease relapse and poor prognosis. This review systematically elucidates the mechanisms underlying leukemia-induced remodeling of the bone marrow vascular microenvironment and, based on these findings, summarizes emerging therapeutic strategies targeting the vascular microenvironment, aiming to provide a theoretical foundation and translational directions for overcoming therapy resistance in leukemia.
Myelodysplastic neoplasms (MDS) are a clonal malignant bone marrow disease with high heterogeneity and a high risk of transformation into acute myeloid leukemia (AML). However, the progression of MDS varies significantly, and the available therapeutic drugs are limited. Brefeldin A (BFA), a natural antibiotic, has not been systematically elucidated for its anti-MDS activity and underlying molecular mechanisms. In this study, SKM-1 and MDS-L cell lines and patient primary bone marrow samples were adopted. Multiple experimental approaches, including CCK-8 assay, colony formation assay, flow cytometry, transmission electron microscopy, RT-qPCR, immunofluorescence staining, transcriptome sequencing, and Western blot, were comprehensively utilized to systematically investigate the effects of BFA on MDS cell proliferation, cell cycle, endoplasmic reticulum stress (ERS), and autophagy. The in vivo anti-tumor validation was conducted using mouse xenograft models. The results showed that BFA significantly inhibited the proliferation of MDS cell lines and patient-derived bone marrow mononuclear cells (BMMCs). Mechanistically, BFA activated the inositol-requiring enzyme 1alpha (IRE1α) pathway to trigger ERS, and then ERS initiated autophagy and caused cell cycle arrest at G2/M phase, ultimately exerting its anti-MDS effect. In vivo experiments preliminarily confirmed that BFA could effectively inhibit MDS progression. These results suggest the fundamental mechanisms by which BFA suppresses MDS, providing a theoretical basis for its development as a new therapeutic drug for MDS.
Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia and is accompanied by a range of complications affecting the cardiovascular system, kidneys, retina, and nervous system. In the context of diabetes, the bone marrow (BM) and hematopoietic stem and progenitor cells (HSPCs) are not only targets of metabolic dysregulation, but also play an active role in driving chronic inflammation and tissue damage. Prolonged hyperglycemia markedly disrupts HSPC bone marrow niche homeostasis, leading to decreased HSPC numbers, impaired mobilization, and biased differentiation. As a result, the hematopoietic system shifts from supporting tissue repair and immune homeostasis to driving pro-inflammatory hematopoiesis. Diabetes induces metabolic reprogramming and epigenetic remodeling in HSPCs, as well as in supportive cells within the BM niche. Aberrant metabolic states interact with epigenetic regulation to reshape transcriptional programs in HSPCs, thereby establishing a stable inflammatory hematopoietic phenotype. In addition, diabetes-associated trained immunity enables HSPCs to acquire pro-inflammatory memory and transmit this bias to their myeloid progeny, providing a mechanistic link between metabolic memory and chronic inflammation. This review systematically summarizes abnormalities in the number and function of hematopoietic cells under diabetic conditions, as well as the roles of metabolic reprogramming and epigenetic regulation in hematopoietic imbalance. It focuses on recent progress in diabetes-associated hematopoietic remodeling and metabolic memory, aiming to provide a hematopoietic perspective for understanding the pathophysiological processes underlying diabetes-induced multi-organ alterations and to offer a reference for exploring potential hematopoietic intervention targets for diabetic complications.
Stem cells, as a class of cells possessing self-renewal and multipotent differentiation potential, exhibit functional diversity influenced by both intrinsic regulatory networks and external microenvironments. Traditional population-level research methods struggle to precisely resolve cellular heterogeneity, thereby limiting in-depth understanding of stem cell biology. Recent breakthroughs in single-cell analysis technologies have opened new avenues for detailed observation at the cellular level. This review focuses on hematopoietic stem cells as a primary example, summarizing the principles and advancements of single-cell transcriptomics, epigenomics, proteomics, metabolomics, spatialomics, and multi-omics integration analysis. It explores their applications in revealing stem cell heterogeneity, differentiation pathways, and state regulation mechanisms, while also outlining future directions for single-cell technologies in stem cell research.
Sphingolipids are a class of bioactive lipids that serve as both structural components of cellular membranes and key regulators of signal transduction. Their metabolic derivatives, including ceramide (Cer), sphingosine (Sph), and sphingosine-1-phosphate (S1P), play important regulatory roles in diverse biological processes, such as cell proliferation, apoptosis, autophagy, and stress responses. In selected acute myeloid leukemia (AML) models, sphingolipid metabolic remodeling characterized by disrupted Cer homeostasis has been observed and is closely associated with AML cell survival, therapeutic resistance, and disease relapse. In this review, we focus on the key processes involved in sphingolipid metabolic remodeling in AML, discuss their roles in sustaining AML cell survival and mediating drug resistance, and summarize potential therapeutic strategies targeting critical nodes of sphingolipid metabolism.
Myeloproliferative neoplasms are a group of clonal proliferative diseases originating from hematopoietic stem cells, with a risk of transformation to acute myeloid leukemia. Primary myelofibrosis (PMF) is a subtype of myeloproliferative neoplasms. Mutations in Janus kinase 2 (JAK2), calreticulin (CALR), and thrombopoietin receptor (MPL) genes are the main pathogenic factors in PMF patients. Current therapeutic strategies, including JAK2 inhibitors, are only effective in a subset of PMF patients, highlighting an urgent need for the development of novel interventions. Experimental models of PMF, including cellular models, animal models, and in vitro organoid models, play crucial roles in exploring pathogenesis and screening potential therapeutic agents. This review comprehensively summarizes these experimental model systems, compares the advantages and disadvantages of different models, and discusses the limitations of current research and prospects for future directions, in order to provide assistance for the development of therapeutic strategies for PMF.
Red blood cell-derived extracellular vesicles (RBC-EVs) are one of the most abundant types of extracellular vesicles (EVs) in the blood, playing a crucial role in intercellular communication, disease progression, and medical applications. The structure of RBC-EVs differs from that of red blood cells (RBCs), characterized by phosphatidylserine externalization, reduced membrane proteins, and encapsulation of bioactive molecules such as hemoglobin and miRNAs. RBC-EVs primarily exist as microvesicles and exosomes, which are generated through membrane budding and the multivesicular bodies pathway, respectively. Their clearance in vivo mainly relies on phagocytosis by hepatic Kupffer cells. Physiologically, RBC-EVs maintain the normal physiological functions of RBCs by removing damaged and senescent signals from the RBC membrane, regulate organismal homeostasis through participation in nitric oxide balance and anticoagulant processes, and also engage in immune regulation and exert certain antiviral effects. Additionally, they serve as intercellular information carriers to function in various diseases. Endowed with advantages such as high biocompatibility and low immunogenicity, RBC-EVs have demonstrated enormous clinical application potential as carriers for small-molecule drugs (e.g., nucleic acids) in fields including hematological diseases, liver diseases, and cancer. This review systematically summarizes the composition and structure, biogenesis and clearance mechanisms, main physiological functions, clinical applications, and future prospects of RBC-EVs.
Nicotinamide adenine dinucleotide [NAD(H), consisting of its oxidized form NAD+ and reduced form NADH] and nicotinamide adenine dinucleotide phosphate [NADP(H), consisting of its oxidized form NADP⁺ and reduced form NADPH] are core molecular pair governing metabolic regulation, which exert central functions in modulating cellular energy metabolism, redox homeostasis and biosynthesis. The imbalance of intracellular ratio of NAD(H) to NADP(H) can lead to serious pathophysiological consequences and trigger a wide spectrum of diseases. NAD kinases (NADKs), the sole enzymes that phosphorylate NAD(H) to NADP(H), therefore sit at the hub of NAD(H)/NADP(H) balance control. Because NADP+ cannot cross subcellular membranes, eukaryotic NADKs are classified into two isoforms: cytosolic NADK1 and mitochondrial NADK2. The catalytic activity of NADKs is regulated at the transcriptional and post-translational modification levels, and aberrant expression or dysfunction of NADKs is closely linked to the initiation and progression of numerous diseases. Targeted intervention strategies against NADKs thus represent a promising therapeutic avenue for the clinical treatments of tumors, metabolic disorders, and other related diseases.
Murine blood sampling is essential for pharmacokinetic research and chronic disease modeling. However, conventional techniques such as tail vein or retro-orbital blood collection have low sample volumes and limited frequency, rendering these approaches inadequate for long-term, volume-intensive studies. This study aimed to establish subclavian cardiac puncture (SCP) as a technique for repeated, high-volume blood collection in mice, and to define its maximum safe volume and frequency without compromising systemic physiology. Thirty-six healthy adult C57BL/6 mice (20-30 g, with equal male and female numbers) were randomized into six groups: control, sham, and four experimental cohorts receiving weekly blood removal at 7.5%, 15%, 22.5%, or 30% of total blood volume (TBV) for four weeks (n = 6 per group). Under isoflurane anesthesia, blood collection was performed on mice via SCP. Mice were secured in supine position before puncture, with needle inserted 1-1.5 cm horizontally at the midpoint of left clavicle; slow blood aspiration upon pulsatile blood backflow effectively prevented pneumothorax and cardiac trauma. All syringes and collection tubes were pre-rinsed with EDTA-2K anticoagulant, and TBV was calculated by the standard 72 mL/kg body weight formula to guarantee accurate blood withdrawal proportion. Monitoring indicators included weight, systolic blood pressure, water intake, fur condition, and hematological indices, such as red blood cell count (RBC), hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC). Morphological observations of blood smears were also conducted. The results showed that the 30% TBV group tolerated blood collection for two weeks; the 22.5% TBV group for three weeks; and the 7.5% and 15% TBV groups for all four weeks without distress. The 30% TBV group showed the smallest increase in body weight and developed mild anisocytosis at the later stage of the experiment; in this stage, blood pressure decreased compared to the baseline level on day 0 of blood collection, and RBC, HGB, HCT, and MCHC values were below the normal reference ranges on day 21 of blood collection. The 22.5% TBV group also showed a later-stage decrease in blood pressure, with RBC, HGB, and HCT values below the normal reference ranges on day 21 of blood collection. These results suggest that the refined SCP enables safe, repeated, high-volume sampling in mice (with a safe blood collection volume of 15% TBV), supports pharmacokinetic and longitudinal biomarker studies, enhances data reliability, and reduces the number of animals used and stress.
Emerging evidence indicates that sperm-associated antigen 6 (SPAG6), a protein initially characterized for its role in ciliogenesis and spermatogenesis, plays critical roles not only in the genital system but also in the nervous, immune, and hematopoietic systems. More recently, SPAG6 has been increasingly implicated in cancer progression and treatment. In this review, we systematically summarize the molecular characterization of SPAG6 and delineate its functional roles and pathophysiological mechanisms across multiple organ systems. We also review its therapeutic relevance in cancer management, especially in hematopoietic malignancy. Notably, SPAG6 was found to be aberrantly overexpressed in clinical myelodysplastic syndrome (MDS) patients and promote the proliferation of MDS-L cells. While functional discrepancies of SPAG6 across experimental models warrant further in-depth exploration, elucidating its mechanisms in disease pathogenesis could offer valuable insights for developing targeted therapies for human diseases.
The present study aimed to investigate the expression pattern of Esco2 in acute myeloid leukemia (AML) and its role in regulating the biological behavior of AML cells. The expression level of ESCO2 and its association with prognosis in patients with AML were analyzed using the TCGA-LAML and GTEx datasets. An sgRNA-mediated Esco2 depletion model was established in MLL-AF9-driven AML cells, and its function was validated through both in vitro and in vivo experiments. A murine bone marrow transplantation model was used to evaluate the effects of Esco2 depletion on leukemia progression. Colony formation assay, cell proliferation assay, and Annexin V-based flow cytometry were performed to assess AML cell growth and apoptosis. Differential gene expression analysis and gene set enrichment analysis (GSEA) were conducted to explore Esco2-related pathways. The results showed that, compared with normal tissues, ESCO2 was significantly up-regulated in AML (P < 2.2 × 10-16), and high expression was significantly associated with poor prognosis (P = 0.04). Esco2 depletion markedly prolonged the survival of recipient mice (P = 0.0227) and reduced leukemic burden. In vitro experiments showed that Esco2 depletion suppressed proliferation and colony-forming capacity of AML cells and promoted apoptosis. Transcriptomic and Western blot analyses revealed that Esco2 depletion up-regulated the expression of E2F transcription factor 1 (E2F1) and cyclin-dependent kinase inhibitor 1A (Cdkn1a, p21) in AML cells, suggesting that Esco2 might be involved in cell cycle homeostasis and associated with cell cycle arrest and apoptosis. These results suggest that Esco2 is highly expressed in AML, whereas Esco2 depletion significantly suppresses leukemic cell proliferation and survival and delays AML progression, indicating its important biological significance in the occurrence and development of AML.
This study aimed to investigate the regulatory role and underlying molecular mechanisms of chromatin assembly factor 1 subunit CHAF1A in the function of hematopoietic stem cells (HSCs) in adult mice. A hematopoietic-specific Chaf1a knockout mouse model was established, and multiple approaches including flow cytometry, RNA-seq, ATAC-seq, and HINT-ATAC were integrated for multidimensional systematic analysis. CHAF1A depletion led to a pronounced reduction in peripheral blood platelet count. In the bone marrow, the number of LSK (lineage- Sca-1+ c-Kit+) cells and HSCs was markedly decreased, while no significant difference was observed in the number of hematopoietic progenitor cells (common myeloid progenitors, megakaryocyte-erythroid progenitors and granulocyte-monocyte progenitors) in the CHAF1A-deficient group. Additionally, no significant differences were observed in HSC cell cycle distribution or apoptosis. RNA-seq identified 904 upregulated and 781 downregulated genes in CHAF1A-deficient HSCs. Gene set enrichment analysis (GSEA) showed that stemness-related genes were significantly enriched in wild-type HSCs, while differentiation-related genes were significantly enriched in CHAF1A-deficient HSCs. ATAC-seq revealed reduced chromatin accessibility at the transcription start site (TSS) regions of HSCs in the CHAF1A-deficient group. HINT-ATAC analysis further showed that the activity of NF-Y family transcription factors was significantly higher in wild-type HSCs than in CHAF1A-deficient HSCs, while the activities of CEBPA and CEBPD were significantly higher in CHAF1A-deficient HSCs. Collectively, these results suggest that CHAF1A is essential for the maintenance of adult mouse HSCs. Specifically, CHAF1A enhances the activity of NF-Y family transcription factors to sustain HSC stemness and inhibits the function of CEBP family transcription factors to block HSC differentiation. Its regulatory mechanism involves the coordinated regulation of chromatin accessibility and transcription factor activity.
The aim of this study was to explore the role of long-chain acyl-CoA synthetase 1 (ACSL1) in cisplatin-induced skeletal muscle atrophy and the underlying mechanism. Wild-type mice were divided into cisplatin group and control group. The results of fluorescence quantitative PCR and sequencing of reference transcriptome showed that ACSL1 gene was significantly up-regulated in the skeletal muscle of cisplatin group compared with the control group, suggesting that ACSL1 may play a key role in cisplatin-induced skeletal muscle atrophy. To further investigate ACSL1's function and potential mechanism, the present study constructed an adeno-associated virus to achieve muscle-specific ACSL1 knockdown and established a cisplatin-induced skeletal muscle atrophy model. The results of immunofluorescence staining showed that compared with mice only receiving cisplatin intervention, mice receiving ACSL1 gene knockdown and cisplatin intervention had significantly increased muscle fiber cross-sectional area, maximum diameter, minimum diameter, and average diameter in their skeletal muscles. The results of RT-qPCR and immunohistochemical staining showed that knockdown of the ACSL1 gene in skeletal muscle down-regulated the mRNA expression levels of atrophy related gene 1 (Atrogin-1) and autophagy-related factors such as autophagy related protein 16 like protein 1 (Atg16L1), Atg12, and Atg7 in cisplatin-induced skeletal muscle atrophy, up-regulated the protein expression level of myogenin, and down-regulated Toll-like receptor 4 (TLR4) protein expression level, but had no significant effect on the mRNA expression levels of ferroptosis-related factors (except for cyclooxygenase-2) and inflammation-related factors such as stimulator of interferon genes (STING), Toll-like receptor 4 (TLR4) and TLR9 in cisplatin-induced skeletal muscle atrophy. These results suggest that specific knockdown of ACSL1 gene in skeletal muscle may alleviate cisplatin-induced skeletal muscle atrophy by down-regulating the expression of Atrogin-1, TLR4 and autophagy-related factors.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a widely prevalent chronic liver disease that presents significant challenges to public health and medical care worldwide, yet its underlying mechanisms remain incompletely understood. The gut microbiome plays a crucial role in MASLD. Liver inflammation is a key factor in the onset and progression of this disease, and the gut microbiota significantly influences the liver's immune system and inflammatory responses. This article aims to review how both pro-inflammatory and anti-inflammatory gut microbes regulate liver inflammation by activating liver immunity and enhancing liver immune protection, respectively, through the microbiota-gut-liver axis. This review seeks to provide valuable insights for the improvement and treatment of MASLD.
