Acute Myeloid Leukemia (AML) remains a therapeutic challenge due to immune evasion and relapse. T-cell immunoglobulin and mucin domain-containing-3 (TIM-3) is an immune checkpoint receptor aberrantly expressed on immune cells and leukemic stem cells (LSCs) in AML. Biologically, TIM-3 predominantly mediates deleterious effects, promoting T-cell/NK dysfunction and supporting LSC self-renewal, but this pathogenic expression also makes TIM-3 a therapeutically actionable target. This narrative review synthesizes current preclinical and clinical evidence on the role of TIM-3 in AML. We examined its structure, signaling pathways, and dual functions in promoting immune suppression and LSC self-renewal. A comprehensive analysis of ongoing therapeutic strategies, including monoclonal antibodies and cellular therapies, was conducted. Relevant literature was identified through searches of PubMed, Scopus, and Web of Science databases, with a focus on recently published studies. TIM-3 contributes to immune dysregulation by inducing T-cell exhaustion, impairing NK cell cytotoxicity, and enhancing immunosuppressive myeloid cells. Concurrently, its expression on LSCs drives leukemogenesis through autocrine signaling loops involving Galectin-9 and the β-catenin pathway. Preclinical studies show that TIM-3 blockade reduces leukemic stem-cell frequency and impairs LSC reconstitution in xenograft models, and can reinvigorate anti-leukemic immunity in experimental systems; however, these findings are preclinical and have not yet translated into consistent, randomized clinical benefit in human trials, underscoring the need for biomarker-guided and combination approaches in clinical development (Kikushige et al. Cell Stem Cell 17(3):341–352, 2015; Kikushige et al. Cell Stem Cell7(6):708–717, 2010; Zeidan et al. Lancet Haematol11(1):e38–e50, 2024). Clinically, the anti-TIM-3 antibody sabatolimab showed a tolerable safety profile and preliminary signals of activity when combined with hypomethylating agents; however, randomized phase II data did not demonstrate statistically significant improvements in the primary endpoints (complete response rate and progression-free survival), and the development program has since been re-evaluated in light of these results. TIM-3 also shows promise as a diagnostic and prognostic biomarker. TIM-3 plays an important and multifaceted role in AML pathogenesis, with evidence supporting both immune-regulatory functions and roles in leukemic stem cell biology; however, definitive proof that TIM-3 is essential for LSC maintenance across all AML subtypes requires additional genetic and functional validation. Targeting TIM-3 remains a biologically compelling strategy to address immune suppression and LSC biology in AML, but definitive clinical benefit has not been established in randomized studies to date; further investigation, especially in biomarker-enriched, low-tumor-burden settings and rational combinations, is required to define its clinical role.

Using the well-studied two-stage model of skin carcinogenesis, the first transgenic mouse with targeted expression of a polyamine metabolic enzyme was generated 30 years ago. Ornithine decarboxylase (ODC), a key regulating enzyme of polyamine biosynthesis, was constitutively expressed in the outer root sheath cells of hair follicles near the bulge stem cell niche using a keratin 6 promoter in K6/ODC mice. Early studies using K6/ODC mice demonstrated that polyamines play an essential role in the early promotional phase of skin tumorigenesis. Treatment with inhibitors of ODC activity blocked the formation of skin tumors and caused the rapid regression of existing tumors. We review how use of the K6/ODC mouse has shown that elevated polyamines in epithelial cells stimulate proliferation and invasiveness, recruit stem cells, alter chromatin remodeling and cell signaling leading to metabolic reprogramming, increase vascularization, activate underlying fibroblasts, and have powerful effects on immune cell function, all contributing to the development and progression of tumors.

Post-transcriptional regulation is pivotal for cellular differentiation, yet how translationally silent mRNAs are selectively reactivated remains elusive. Here, we identify the MEX3D-HIP1 (MX-H) pathway and its associated organelle, the MEX3D-associated lysosomal vesicle (MXLV), as a shared system governing mRNA activation during spermiogenesis. Our data support a model in which MEX3D acts as an RNA-associated E3 ligase that selectively promotes ubiquitination of RBPs within RBP-mRNA complexes. This ubiquitination signal recruits HIP1, triggering the formation of MXLV, an autophagic vesicle that degrades translationally silent mRNP complexes. Genetic ablation of MX-H components in male germ cells disrupts spermiogenesis, leading to the accumulation of mRNP aggregates and male infertility. Intriguingly, we discovered that this germline-restricted pathway is aberrantly activated in gastric cancer cells, where MXLV biogenesis promotes tumor progression. The strict restriction of MXLV to male germ cells under physiological conditions may provide a unique therapeutic window, suggesting that targeting this pathway could suppress tumor progression while minimizing adverse effects on normal physiological functions. Our work establishes MXLV as a specialized vesicular structure essential for cellular remodeling during development and reveals how a germline-specific membrane trafficking system is co-opted in pathological proteome remodeling in gastric cancer.

How tumors manipulate neural circuits to evade immunity is unclear. In a recent study, Wei et al. reveal, in lung adenocarcinoma, a vagal sensory-brain stem sympathetic circuit that suppresses macrophages and CD8+ T cells via β2-adrenergic signaling. Disrupting this axis restores antitumor immunity, nominating β-blockers and neural modulation as promising therapies.

The molecular mechanisms linking immune cell signaling to osteoclastogenesis remain incompletely defined. Here, we identify an Annexin A1 (AnxA1)-Dectin-1 axis as a key driver of osteoclast differentiation. Dectin-1 (CLEC7A), a myeloid C-type lectin receptor best known for β-glucan recognition, is shown to bind the endogenous ligand AnxA1 on pre-osteoclasts, thereby promoting their maturation. In Dectin-1 deficient mice, reduced osteoclast numbers resulted in increased bone volume, whereas β-glucan-induced Dectin-1 activation enhanced osteoclastogenesis. Within the bone marrow niche, AnxA1 was abundantly expressed on B220+ B cells, and γ-irradiation markedly increased its surface translocation both in vitro and in vivo. γ-irradiated B220+ B cells exhibited strong Dectin-1 binding capacity and robustly stimulated osteoclast differentiation in a Dectin-1-dependent manner. These findings establish the AnxA1-Dectin-1 interaction as a critical immune-skeletal communication pathway, revealing a mechanism by which radiation exposed immune cells can accelerate bone resorption. Targeting this axis offers a potential strategy to mitigate radiation-induced bone degradation and preserve skeletal homeostasis.

Several protocols for generating oligodendrocytes (OLs) from human pluripotent stem cells have been reported. However, they are limited by long culture duration, intensive handling, and low yield of mature OLs. Transcription factor-based strategies have improved efficiency, but OLIG2 and SOX10, key regulators of oligodendrocyte precursor cells (OPCs), also promote alternative neural fates. Here, we developed a Tet-inducible system to control SOX10 and OLIG2 expression, including that of a phosphorylation-deficient OLIG2 mutant (S147A). Co-expression of SOX10 and OLIG2 enhanced OPC induction, confirmed by O4 positivity and transcriptomic profiling. Interestingly, only a brief induction of SOX10 + OLIG2(S147A) (2-5 days) efficiently yielded myelin basic protein positive OLs within 25 days, reaching approximately 20% of total cells. In contrast, sustained doxycycline-mediated expression of SOX10 and OLIG2(S147A) favored OPC proliferation and delayed OL maturation. These findings highlight the importance of temporal control of transcription factor activity in accelerating OL differentiation and provide a practical platform for disease modeling and regenerative applications.

Failure of remyelination is a major determinant of progressive neurological decline in demyelinating disorders of the central nervous system. Although endogenous repair mechanisms are activated following injury, the generation of fully functional myelinating oligodendrocytes is frequently insufficient to restore long-term tissue integrity. In addition to oligodendrocyte progenitor cells, neural stem cells (NSCs) residing in adult neurogenic niches represent a potential endogenous source of oligodendroglial regeneration. However, promoting effective remyelination from NSCs requires more than stimulating lineage commitment, as progenitor fate and maturation are tightly regulated by lesion-specific microenvironmental cues. Over the past decades, a wide range of experimental models-including reductionist in vitro systems, organoid platforms, toxin-induced or immune-mediated demyelination in vivo models-have provided important mechanistic insights into NSCs activation and oligodendroglial differentiation. Yet, no single model fully captures the complexity of chronic human pathology, highlighting significant translational limitations. Moreover, inflammatory signaling, glial reactivity, and extracellular matrix remodeling critically influence whether enhanced oligodendrogenesis results in effective remyelination. In this review, we analyze current experimental frameworks used to investigate NSCs-driven oligodendrogenesis and discuss how microenvironmental regulation shapes regenerative outcomes. We further examine emerging therapeutic strategies aimed at modulating endogenous NSCs and their niche, including pharmacological approaches, cell-based interventions, and nanotechnology-based platforms. By integrating experimental and translational perspectives, we propose that successful remyelination requires coordinated modulation of both progenitor competence and lesion microenvironment.

Regenerative medicine for stroke patients has been attracting attention. However, the effects of rehabilitation after the cell transplantation have not been fully elucidated. The purpose of the present study was to investigate whether intensive gait-focused rehabilitation using a robotic orthosis after regenerative medicine improved gait function and induced plastic changes in cortical networks. The present study was conducted in a retrospective cohort study. We selected seven chronic stroke patients, those who had undergone adipose-derived mesenchymal stem cells (MSC) transplantation therapy after the onset of stroke and had been receiving adequate subsequent gait rehabilitation with a robot for more than 2 months. During hospitalization, each patient received at least 2 h of rehabilitation, including robotic-assisted gait training more than five times per week. As the assessments, gait performance and M1 seed-based resting state-functional connectivity (rs-FC) obtained by a magnetoencephalography were compared before and after hospitalization. After rehabilitation, cadence and spatial gait symmetry ratio were significantly improved, and a significant negative correlation was found between the changes in the gait symmetry ratio and the time from transplant to rehabilitation. Seed-based rs-FC in the beta band between the lesioned M1 and multiple brain regions (e.g., both frontal areas, ipsilateral postcentral gyrus) was significantly decreased after the rehabilitation. Significant negative correlations were also observed between the changes in the gait symmetry ratio and the changes in lesioned M1 seed-based rs-FC in the paracentral gyrus and regions associated with the default mode network. It was revealed that intensive gait-focused rehabilitation using a robotic orthosis improved gait function and induced plastic changes in the cortical networks. The improvements were significantly correlated with the timing of the start of rehabilitation after MSC transplantation.

The development of multicellular organisms relies on controlled cell divisions and differentiation that generate specific cell types of functional tissues and organs. Control of the cell cycle and its checkpoints are tightly intertwined with the maintenance of stem cells, cell fate acquisition and cellular reprogramming. This Review focuses on cell cycle-mediated control of plant development and regeneration, where cell division and differentiation occur in the absence of cell migration. We examine two systems - the root apical meristem and leaf epidermis (stomata) - and explore how master-regulatory transcription factors directly impact the cell cycle to achieve differentiation of specific cell types, as well as how epigenetic machineries guide or constrain such processes. We further emphasize the importance of G1 cell cycle phase duration and G2/M checkpoints for stem cell differentiation and regeneration. By synthesizing recent discoveries, we aim to highlight cell cycle regulation that underpins both robustness and plasticity of plant development and regeneration. Such knowledge will ultimately enhance our understanding of the commonalities and uniqueness of cell cycle regulation between plants and metazoans.

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Single-cell passaging of induced pluripotent stem cells (iPSCs) has historically been discredited, as it may risk mutations. Here, however, in combination with Rho kinase inhibition and based on stringent quality control, we successfully validate a corresponding iPSC banking process under Good Manufacturing Practice (GMP) conditions. The underlying culture system features enhanced consistency, sustains genomic integrity in the resulting cell lines, and enables excellent priming for gene editing and directed differentiation. The process, as well as the resulting GMP iPSC lines, will provide a robust foundation for clinical manufacturing.

Globally, third leading cause of cancer-related deaths is contributed by Hepatocellular carcinoma (HCC). Chronic hepatitis B virus infection is one of the seminal etiological drivers of HCC. Hepatitis B viral DNA integration, host genomic instability, persistent inflammatory responses and the oncogenic activity of the viral oncoprotein Hepatitis B virus X (HBx), contribute to the hepatocarcinogenesis. Emerging evidences indicate that epigenetic dysregulation plays a seminal role in linking viral persistence in the liver tissue to its malignant transformation. In HBV-infected hepatocytes, aberrant DNA methylation, histone modifications, and dysregulated non-coding RNAs reprogram transcriptional networks that activate oncogenic pathways, promote proliferative signaling, and sustain cancer stem cell-like phenotypes driving HCC progression. The epigenetic modifications in the infected, malignant hepatic cells can influence the tumor microenvironment, contributing to the infiltration of exhausted cytotoxic T lymphocytes with elevated PD-1 and Tim-3 expression. Further, the T lymphocytes exhibit reduced proliferative capacity, impaired cytokine secretion, and diminished cytotoxic activity. In the clinical perspective, long-term nucleotide analogue therapy causes viral suppression and attenuation of inflammation, thereby reducing HCC progression by 40-80%. Despite the extensive T-cell exhaustion, HBV-associated HCC (HBV-HCC) is responsive to immune checkpoint blockade, as highlighted in the CheckMate-040 trial. Emerging therapeutic strategies combine anti-viral agents with immune checkpoint inhibitors, epi-drugs and HBsAg-directed TCR-engineered T cells. These clinical approaches aim to simultaneously restore antitumor immune responses as well as neutralize the viral oncogenic drivers, offering promising avenues for improved management of HBV-induced HCC.

Employing a comprehensive strategy that integrated network pharmacology, molecular docking, and in vitro experimental techniques, this study examined the effect of neohesperidin on the proliferation and osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) upon lipopolysaccharide (LPS)-induced inflammatory conditions.

Volumetric Musculoskeletal Trauma (VMST), which is characterized by volumetric muscle loss accompanied by bone injury, poses a significant challenge to regenerative medicine. While current therapies primarily focus on the individual regeneration of muscle or bone, there is no systematic and integrated treatment strategy. In this study, we developed a CuMBG-PA, a copper-doped nanozyme based on mesoporous bioactive glass (MBG) and procyanidin (PA), for integrated muscle and bone repair of VMST. CuMBG-PA self-assembles into a stable polyphenol network via Cu-PA coordination bonds, enhancing PA stability and reactive oxygen species-scavenging capacity. In vitro and in vivo experiments demonstrated that CuMBG-PA promoted osteogenesis and myogenesis while exhibiting high biocompatibility and antibacterial activity. Single-cell RNA-sequencing results revealed that CuMBG-PA synergistically induces stem cell differentiation and promotes tissue repair through multiple myoskeletal shared metabolic pathways. Mechanistically, CuMBG-PA exerts its beneficial effects by increasing the number of Proteoglycan 4 (Prg4) + fibro/adipogenic progenitor cells (FAPs), which highly express fibronectin and insulin-like growth factor. In addition, PRG4 regulates immune cells, removes overactivated muscle satellite cells, reduces muscle fibrosis, and promotes functional recovery during regeneration. In summary, this work demonstrates that the novel self-assembled CuMBG-PA nanozyme represents a potential biomaterial-based strategy for integrated muscle and bone repair in VMST.

Patients with polycystic ovary syndrome (PCOS) are at an elevated risk of depression, yet the underlying mechanisms remain elusive. Emerging evidence implicates the gut-brain axis and systemic lipid homeostasis alterations as potential key contributors. We profiled untargeted plasma lipidomes of PCOS patients with and without comorbid depression (PCOS-DP) and integrated these data with our prior gut microbial and host transcriptomic datasets to construct multi-omics interaction networks. The causal role of the candidate gut microbial was preliminary explored in a germ-free PCOS mouse model using fecal microbiota transplantation, followed by behavioral phenotyping and ELISA-based protein quantification. We identified a distinct plasma lipidomic signature differentiating PCOS-DP from PCOS alone, characterized primarily by the downregulation of 26 lipid species. Most of these altered lipids were triacylglycerols (TAGs) enriched with FA18:1 and FA18:2, whose levels correlated with coagulation dysfunction. Multi-omics network analysis revealed significant interconnections between depression-associated gut microbiota (including Bacteroides eggerthii), specific altered lipids such as TAG (60:12/FA22:6), and host genes involved in inflammation (e.g., IL22, NLRP7), metabolism, and neural processes. Animal validation demonstrated that B. eggerthii colonization in PCOS mice specifically exacerbated anhedonia and hyperlocomotion, alongside modulating plasma IL-22 expression, suggesting its context-dependent neurobehavioral effect role. This study delineates a TAG-downregulated lipid signature with diagnostic potential and reveals a novel "gut microbiota-lipid-host gene" interaction network underpinning PCOS-DP, with B. eggerthii as a key microbial modulator of neurobehavioral phenotypes in the context of PCOS. These findings provide new pathophysiological insights and highlights potential diagnostic biomarkers for PCOS-DP.

Repairing large-scale craniomaxillofacial bone defects is hindered by a limited availability of stem-cell sources and a low osteogenic efficiency. To address these challenges, Fe3O4 nanoparticles were modified with methacrylic anhydride (MAA), which helped to introduce photopolymerizable methacryloyl groups, resulting in MAA-Fe3O4 nanoparticles that exhibit excellent magnetic properties and colloidal stability. These nanoparticles were incorporated into gelatin methacryloyl (GelMA) and covalently crosslinked to form an injectable, photocurable GelMA-Fe3O4 magnetic composite hydrogel. This hydrogel provided a three-dimensional culture microenvironment for human dental follicle stem cells (hDFSCs), and upon encapsulation, osteogenesis was significantly enhanced under a 100 mT static magnetic field (SMF). In vitro, GelMA-Fe3O4 hydrogels demonstrated increased porosity and improved mechanical properties, thereby significantly promoting hDFSCs proliferation, adhesion and spreading. Additionally, under SMF exposure, the expression of osteogenesis-related genes and proteins, including alkaline phosphatase (ALP), Runx2, Col-I and OPN, was significantly upregulated. In a rat calvarial defect model, bone mineralization centers with multi-site distribution were observed in the GelMA-Fe3O4 + SMF group as early as 4 weeks postoperatively, leading to high-quality defect repair. The limitations of traditional 'peripheral-to-center' unidirectional repair were overcome by this model of synchronous multi-site osteogenesis, maximizing bone regeneration with a minimal number of stem cells and providing an efficient, controllable tissue-engineering strategy for the clinical treatment of craniomaxillofacial bone defects.

Volumetric Muscle Loss presents a critical challenge involving the traumatic or surgical loss of over 20% of skeletal muscle mass by overwhelming the body's natural regenerative capacity. It causes functional decline of skeletal muscles leading to reduced quality of life. Current surgical interventions, such as autograft and allograft muscle transfers, often fall short of restoring full mobility frequently causing donor site morbidity and graft failure. The objective of this manuscript is to discuss the role of emerging regenerative strategies focusing on restoring muscle structure and regenerative microenvironment. Recent advances emphasize on extracellular matrix-based therapies that promote myogenesis and vascularization because of their ability to replicate the native structural as well as biochemical attributes leading to muscle fiber regeneration and innervation. Further, incorporation of growth factors like vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1), or stem cells in the scaffolds help to recapitulate the complex structure and signaling of extracellular matrix promoting accelerated healing and recovery as observed in pre-clinical trials. However, despite of positive outcomes, there are challenges like immunogenicity, issues with batch to batch reproducibility, which hinder scalability and translation. Interdisciplinary collaboration between biomaterials science, tissue engineering, and clinical research can serve as solution to resolve this critical issue and will be helpful to advance these technologies potentially shifting the approach of VML therapeutic management from palliative to curative.

Adult zebrafish exhibit full recovery following spinal cord injury. Transient expansion of stem cell-like progenitors is thought to underlie their regenerative capacity. Yet, our understanding of the identities and contributions of the crucial stem cell populations that direct spontaneous neural repair remains limited. Moreover, while most neural regeneration research is centered on promoting proliferative repair, the regulatory mechanisms that reinstate quiescence post-repair are unknown. Here, we determined the molecular identities and cellular contributions of sox2+ progenitors during spinal cord repair. Genetic lineage tracing shows zebrafish spinal progenitors, while quiescent in uninjured tissues, self-renew and differentiate into neurons and glia after injury. By single-cell sequencing, sox2 + cells are heterogeneous and biased towards neuronal or glial fates in both homeostatic and regenerating tissues. By screening for transcription factors that are differentially expressed in acute versus chronic spinal cord injury, we find the Bach1 transcription factors control transient progenitor cell activation by acting as dual activators and repressors of sox2 expression. This study elucidates the molecular diversity and contributions of sox2 expressing cells during spinal cord repair and identifies a transcriptional regulatory switch by which progenitor cells expand after injury and restore quiescence after regeneration is completed.

Recent genetic discoveries in congenital hyperinsulinism (HI) and advances in sequencing technology suggest that the diagnostic yield may be improved by rescreening in people with genetically unsolved HI.