The spleen is the largest secondary lymphoid organ in humans. Beyond its classical role in clearance of senescent erythrocytes, it functions as a pivotal node in systemic immune surveillance. Emerging evidence indicates that tumor can remotely remodel splenic niches through a spectrum of soluble mediators, thereby accelerating tumor initiation and progression. Tumor-derived signals divert splenic hematopoietic stem and progenitor cells (HSPCs) toward myeloid- and erythroid-biased extramedullary hematopoiesis (EMH), expanding myeloid-derived suppressor cells (MDSCs) and erythroid progenitor cells (EPCs) that collectively foster immune evasion and metastatic cascades. Consequently, splenic resident immune cells, stromal cells and EMH-related pathways have surfaced as actionable therapeutic targets. In parallel, bidirectional crosstalk between the autonomic nervous system and splenic immunity fine-tunes homeostasis, systemic inflammation and antitumor responses-fueling rising interest in splenic neuromodulation as a therapeutic strategy. In addition, spleen-targeted nanoplatforms are emerging as promising tools to deliver immunomodulatory payloads with improved precision. Nonetheless, inherent structural and functional disparities between human and murine spleens complicate clinical translation of pre-clinical findings. This review provides a concise overview of human lymphoid organs and their functions, with a particular focus on splenic anatomy, cellular composition, and neural regulation. It further delineates tumor-induced splenic rewiring and discusses the prospects of exploiting the spleen as both a biomarker and a therapeutic target in oncology.

Extracellular vesicles (EVs) are defined as key nanoscale messengers that mediate intercellular communication, demonstrating immense potential in tissue repair and regenerative medicine. As the only organ in mammals capable of complete, cyclical regeneration, deer antlers provide EVs with exceptional regenerative bioactivity. This paper systematically reviews and prospectively discusses the research field of deer antler-derived EVs. We first outline their isolation strategies and characteristic functional subtypes, then focus on elucidating their multi-level molecular mechanisms driving tissue repair: at the cellular level, they directly regulate stem cell proliferation and lineage differentiation; at the microenvironmental level, they effectively remodel the immune ecology of injured areas by reprogramming immune cells and coordinating cytokine networks, thereby creating favorable conditions for regeneration. At the molecular level, they precisely regulate core signaling pathways, including the Wnt/β-catenin, NF-κB, miR-21-5p/STAT3, and TGF-β pathways. Finally, this paper prospectively explores cutting-edge developments in the field, including enhancing vesicle targeting and drug-loading capacity through engineering strategies, constructing controlled-release delivery systems based on smart materials, and developing precision therapies tailored to specific pathological microenvironments. This review aims to elucidate the biomedical potential of deer antler extracellular vesicles as regenerative nanomedicines for promoting tissue repair.

Persistent Ag exposure in tumors, chronic infections, and autoimmune diseases progressively drive CD8+ T cell dysfunction-a process known as T cell exhaustion. During this process, progenitor exhausted CD8+ T (Tpex) cells represent an early subset with stem cell-like properties and serve as key mediators of immune checkpoint blockade responses. Despite their longevity and proliferative capacity, Tpex cells display limited cytotoxicity. Upon sustained TCR stimulation, they differentiate into exhausted CD8+ T (Tex) cells that express high levels of granzyme B and contribute critically to tumor elimination. Accumulating evidence indicates that Tex cells are functionally heterogeneous, as defined by diverse surface markers and transcriptional programs, and their states are further shaped by tissue- and context-specific cues within the tumor or inflammatory microenvironment. Such extrinsic signals can compromise CD8+ T cell function and limit the efficacy of anti-PD-1 therapy. A comprehensive understanding of this heterogeneity, integrating both intrinsic transcriptional regulation and extrinsic modulatory signals, is crucial for developing more effective immunotherapeutic strategies. Finally, T cell exhaustion should not be viewed solely as a pathological endpoint but also as an adaptive mechanism that restrains immunopathology, underscoring its context-dependent roles across cancer, infection, and autoimmunity.

Gastrointestinal (GI) tumors remain a leading cause of global cancer mortality, with late-stage diagnosis and metastatic dissemination posing major clinical challenges. This review synthesizes current understanding of the intricate interplay between immune regulation, neural signaling, and tumor microenvironment dynamics in GI malignancies. We highlight how chronic inflammation, driven by pathogens like H. pylori or inflammatory bowel disease, establishes a pro-tumorigenic milieu through cytokine networks (IL-1β, TNF-α, IL-6) and Wnt/β-catenin signaling, while neural components (serotonergic, cholinergic, and peptidergic pathways) actively participate in cancer progression via neurotrophic factors and neurotransmitter-mediated crosstalk. Emerging evidence reveals that colorectal cancer stem cells exploit neuronal signaling (particularly 5-HT/Wnt activation) for self-renewal, and that perineural invasion serves as a critical metastatic route. The dual role of immune cells is explored, with macrophages (M1/M2 polarization), T cells, and neutrophils exhibiting both tumor-suppressive and pro-metastatic functions depending on context. We evaluate recent therapeutic advances including immune checkpoint inhibitors, CAR T-cell therapies, and neural-targeted approaches, while addressing limitations such as chemoresistance and immune-related adverse events. The potential of microbiota modulation and nanotechnology for precision therapy is discussed. By integrating molecular mechanisms with clinical observations, this work proposes that combinatorial strategies targeting immuno-neural axes may overcome current treatment barriers, emphasizing the need for early detection and personalized approaches in GI oncology.

Lung development is a complex and precisely regulated process of continuously branching morphogenesis, the core of which lies in the directed differentiation of diverse cell types and the dynamic intercellular interaction network. This review systematically delineates the differentiation pathways of major cellular lineages during pulmonary development, with a particular focus on the dual functions of epithelial cells as the core regulatory hub of the microenvironment. These cells not only dominate the spatial patterning of lung branching morphogenesis but also orchestrate the developmental fates of key cell types through multiple signaling cues. Furthermore, this review discusses the regenerative properties of lung-resident stem cells and the interaction patterns between various cell types and epithelial cells. These insights not only provide an important theoretical framework for elucidating the molecular regulatory network of lung development but also offer novel ideas for the optimization of strategies in lung regenerative medicine and the precision intervention for lung-related diseases.

Spina bifida is a neural tube defect (NTD) that arises when the neural tube fails to close properly during early development. This review focuses on myelomeningocele (MMC), the most common severe form of spina bifida, which often leads to motor and sensory impairments, including lower limb weakness or paralysis, as well as renal, urological, orthopedic, developmental, and psychosocial challenges. We explore the etiology, pathogenesis, prevention, diagnosis, and management of spina bifida, with a special emphasis on in-utero surgical repair. Over the past several decades, researchers and clinicians have made remarkable strides across all stages of care from prevention to postnatal outcomes. Widespread use of folic acid supplementation has significantly reduced the number of new cases. Advances in prenatal imaging and diagnostics now allow for earlier and more accurate detection, enabling timely intervention. In-utero surgical techniques continue to evolve, with innovative hybrid approaches that combine the strengths of open and minimally invasive methods. The momentum in this field shows no sign of slowing. Promising developments in stem cell therapy, biomaterials, robotic-assisted surgery, 3D printing, and enhanced imaging are redefining treatment goals in spina bifida. With each advance, clinicians gain better tools to improve outcomes for both mother and child, minimizing risks and maximizing long-term health and quality of life for both patients.

Acute myeloid leukemia (AML) is caused by uncontrolled proliferation and impaired differentiation of hematopoietic stem and progenitor cells. Historically, research has emphasized the role of protein-coding genes in the development of AML. However, with the human genome project revealing that 98% of the transcriptome consists of non-protein-coding RNAs, recent studies have explored how the large classes of noncoding RNAs (ncRNAs) contribute to AML. Although there are many types of ncRNAs, much attention has been placed on understanding the function of long ncRNAs (lncRNAs) and small ncRNAs known as microRNAs (miRNAs). lncRNAs are >200 nucleotides, whereas mature miRNAs are typically 18 to 25 nucleotides. lncRNAs are involved in miRNA and protein sequestration and act as transcriptional and translational regulators, whereas miRNAs facilitate mRNA degradation and translational inhibition. In addition to lncRNAs and miRNAs, two additional types of ncRNAs, namely small nucleolar RNAs (snoRNAs) and circular RNAs (circRNAs), have recently garnered attention for their roles in AML. Here, we discuss how these four distinct classes of ncRNAs may aid in disease diagnosis and prognosis as well as the mechanisms by which their dysregulation contributes to AML.

Osteoarthritis (OA) is a highly prevalent degenerative joint disease whose complex pathological microenvironment and limited cartilage self-repair capacity have resulted in the absence of therapeutic approaches capable of simultaneously achieving structural reconstruction and functional recovery. Current clinical strategies face significant limitations, as conventional pharmacological treatments can only alleviate symptoms with accompanying systemic side effects, while surgical interventions often encounter challenges such as inadequate mechanical properties of repaired tissues and long-term degeneration. The precise functionalization of injectable hydrogels represents a key strategy for cartilage regeneration and the core challenge lies in integrating multiple material properties to design on-demand delivery platforms that can dynamically respond to complex pathological microenvironments in vivo. This review systematically elaborates on precision customization strategies for injectable hydrogels based on OA pathological mechanisms, focusing on how hydrogel design responds to pathological signals in the joint microenvironment to achieve on-demand and precise regulation of therapeutic agents including drugs, cells and genes. Beginning with cartilage structure and injury mechanisms, this article analyzes the limitations of existing pharmacological and surgical repair methods, then, elaborate on the multifunctional platform role of hydrogels in cartilage tissue engineering, including recent advances in mechanical design, drug loading/release behavior, inflammation regulation, stem cell delivery and gene-activated repair. Finally, it outlines challenges and future directions for smart hydrogels in cartilage regenerative medicine, aiming to provide a theoretical framework and technical pathway for integrating materials science with clinical medicine.

Radial glia are a specialized population of neural progenitor cells that persist throughout embryogenesis and into adulthood. Throughout this period, radial glia reside in a highly dynamic microenvironment that influences various biological decisions that govern typical cortical development. Subsequently, radial glia must fine-tune their responses to numerous environmental cues throughout development. The establishment of the cortical vasculature coincides with neurogenesis and dramatically alters the radial glia microenvironment by increasing oxygen and metabolite delivery. In addition, a synergistic spatial relationship between radial glia and endothelial cells regulates multiple aspects of radial glial biology. Here, we discuss crosstalk between radial glia and the cortical vasculature/endothelial cells throughout development, including the influence of extrinsic angiogenic processes and our growing understanding of the intricate spatial relationships between radial glia and endothelial cells.

This article offers an in-depth review of the design and modeling of 3D-printed hip prostheses, emphasizing the integration of regenerative medicine, especially in the context of custom Rapidly Destructive Osteoarthritis implants. It traces the history of Total hip arthroplasty and current implant materials, along with recent advances in tissue engineering strategies and biofunctionalization methods to enhance biological integration. Computational processes are examined, including segmentation, image processing, computer-aided design, finite element analysis, and CAE simulations. It also discusses techniques in additive manufacturing that control porosity and stiffness, as well as strategies for recruiting host stem cells. The overall performance of existing THA approaches, combined with reliance on outdated surgical workflows and the complexity of clinical standards, creates challenges for the adoption of innovative implant research and limits broader application. International standards (ISO/ASTM), regional regulations (MDR, FDA), ethical considerations, and professional design guidelines are crucial components of this review, guiding safety, reproducibility, and the clinical impact of next-generation THA solutions. Finally, this review proposes a novel 'regenerative design' paradigm. Distinct from traditional biointegration methods, this framework integrates patient-specific imaging, mechanobiology-based architecture optimization, and biologically calibrated simulation to direct endogenous cell recruitment and vascularized healing explicitly.

The 38 currently registered clinical trials with the keyword "adult neurogenesis" indicate growing interest in new neurons as a target for intervention. Today, we have strong evidence that adult neurogenesis is involved in hippocampal function and can contribute to brain functions in health and disease. Neurogenesis research can now ask new questions, such as (1) the identity of stem cells and their input integration for initiating neurogenesis, (2) the nature of the neurogenic niche and neurogenesis without stem cell activity, (3) the complex functionality beyond the hippocampus, and (4) evolutionary and computational theory, including neurogenic neural networks for artificial intelligence.

Twenty years have passed since the first demonstration of mouse induced pluripotent stem cells (iPSCs). What began as an unexpected observation in Kyoto quickly transformed stem cell biology and regenerative medicine worldwide. Over the past two decades, we have gained profound insights into the molecular mechanisms underlying cellular reprogramming and pluripotency. The technology has continued to evolve-becoming safer, more efficient, and more versatile. Today, iPSCs serve as a foundation for wide-ranging applications, from disease modeling and drug discovery to regenerative therapies and rejuvenation research. In this review, I reflect on the scientific journey of iPSCs, highlight key milestones in our understanding of reprogramming, and discuss the expanding clinical and societal impact of iPSCs.

Ischemic heart disease, which leads to the loss of functional myocardium, remains the leading cause of death in late adulthood. Epicardial patches have emerged as a promising adjunctive strategy for myocardial repair. However, owing to the thick epicardial barrier (epicardial adipose tissue), only a select few approaches have demonstrated reduced scarring and improved heart function in large animal models and early-stage human trials. In this opinion article, we examine the different mechanisms and approaches to overcome the epicardial barrier. We further discuss key design and material considerations to improve safety and efficacy in clinical applications. Finally, we provide a summary of current regulatory and clinical challenges, together with proposed future research directions and foci in the translation of epicardial patches.

Clonal hematopoiesis (CH) refers to the expansion of hematopoietic stem and progenitor cells carrying somatic mutations and is increasingly identified in oncology through cell-free DNA testing. Once regarded mostly as a precursor to myeloid neoplasms and a contributor to cardiovascular disease, CH is now recognized as a major determinant of clinical outcomes in patients with cancer. Specific anticancer agents selectively promote the expansion of clones with DNA damage response gene mutations, particularly those with TP53 or PPM1D mutations, which are strongly associated with myeloid neoplasms post cytotoxic therapy (MN-pCT). The extent of clonal growth varies with treatment and, in some cases, may regress once therapy is withdrawn. In addition to therapy-driven clonal selection, inflammatory stress accelerates clonal expansion, creating a self-reinforcing cycle that contributes to atherosclerosis and other inflammation-associated complications. In oncology, CH-derived immune cells can infiltrate the tumor microenvironment and remodel local immunity, influencing tumor growth and treatment response. This tissue-infiltrating form of CH, termed tumor-infiltrating CH, has been associated with inferior survival in some cancer cohorts. Together, these findings establish CH as both a clinical challenge and an opportunity in modern oncology. Dedicated CH clinics and molecular tumor boards are emerging to address its implications for risk stratification, treatment selection, and survivorship care. This review examines the biology and clinical impact of CH in oncology, including its mutational spectrum, clonal evolution, role in MN-pCT, effects on inflammation and the tumor microenvironment, and emerging strategies for risk assessment and patient management.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a dismal 5‑year survival rate of ~9%, primarily due to late diagnosis, aggressive metastasis and profound resistance to conventional therapies. Epithelial‑mesenchymal transition (EMT) has been identified as a pivotal driver of these malignant phenotypes, facilitating early invasion, dissemination and treatment failure. The present review systematically elaborated on the multidimensional mechanisms underlying EMT in PDAC, emphasizing its operation as a spectrum of hybrid epithelial/mesenchymal states rather than a binary switch. Key molecular mechanisms include the activation of core transcription factors (such as Snail, ZEB, Twist), intricate crosstalk within the tumor microenvironment (such as transforming growth factor-β and hepatocyte growth factor signaling from stromal cells) and dynamic epigenetic reprogramming. Furthermore, EMT critically contributes to the acquisition of cancer stem cell properties and enhances the survival and colonization of circulating tumor cells. The present review also outlined emerging translational strategies targeting EMT‑related pathways, highlighting agents such as STNM01 that have entered early-phase clinical trials. By synthesizing unprecedented insights into EMT's plastic spectrum states and subtype‑specific regulatory networks, this work establishes a paradigm‑shifting framework for advancing EMT‑targeted therapies; offering transformative potential to overcome PDAC's historical therapeutic barriers and substantially improve patient survival outcomes. By synthesizing current insights from molecular pathways to therapeutic applications, the present review confirmed EMT as a promising therapeutic target and provides a strategic framework for advancing PDAC treatment, with the ultimate goal of improving clinical outcomes.

Growing evidence has supported the potential method of umbilical cord mesenchymal stem cell (UCMSC) therapy for diabetic foot and lower extremity peripheral artery disease (PAD), but their results are not consistent. Thus, the authors conducted the first meta-analysis concerning the safety and efficacy of UCMSC treatment in diabetic foot patients. 8 English and Chinese databases were searched to identify randomized controlled trials regarding UCMSC therapy in diabetic foot patients. Two independent investigators carried out literature inclusion, data extraction, and quality assessment. Meta-analysis was performed using ReviewManager 5.4.1., 6 RCT studies involving 380 patients were included. Primary endpoints included ulcer healing, transcutaneous oxygen pressure (TcPO2), ankle-brachial index (ABI), and intermittent claudication. Compared with conventional treatment, patients who accepted UCMSC therapy had a better ulcer healing rate (Odds Ratio (OR) = 2.88 [1.20-6.91]), TcPO2 (standardized mean difference (SMD) = 1.39, [0.01-2.77]), and ABI improvement (SMD=1.22 [0.30-2.13]). Moreover, they also experienced significantly better improvements in pain amelioration, skin temperature, and ulcer area reduction. Whereas, intermittent claudication cannot be ameliorated by UCMSC therapy (SMD=0.83 [-0.45-2.10]). Additionally, neovascularization, examined by angiography, was significantly promoted after UCMSC administration. Moreover, two studies recorded adverse events during follow-up, which were considered to be transient, minor, and regional. The present meta-analysis validated that UCMSC treatment enhances diabetic foot ulcer healing and circulation recovery, and has a promising safety profile, though limited by incomplete reporting. Larger-sample multicenter randomized controlled trials and longer-term follow-up are urgently needed to further explore the safety and efficacy of UCMSC treatment in diabetic foot patients. The meta-analysis was prospectively registered on PROSPERO.

Lentiviral vectors (LVs) have revolutionized gene therapy by enabling stable gene integration into dividing and non-dividing cells, addressing critical challenges in treating genetic disorders. The transition from second to third-generation LVs has increased biosafety by minimizing the risk of replication-competent lentiviruses and expanded their clinical applicability. Despite significant advancements, producing high-titer functional LVs, particularly at an industrial scale, remains a considerable challenge due to the need for enhanced scalability, cost-efficiency, and effectiveness. This Review delves into cutting-edge innovations in LV production, from optimized transient transfection in various cell lines to the development of stable producer cell lines. Stable producer cell lines offer unparalleled scalability but face challenges related to viral protein cytotoxicity. Inducible systems have emerged as pivotal tools for addressing these problems, allowing for precise gene expression and controlled production. Additionally, advancements in bioprocess engineering, ranging from optimized culture conditions, including pH and media composition, to novel bioreactor technologies like structured fixed-bed systems, continue to redefine industrial-scale LV production. These breakthroughs, coupled with the analysis of costs and efficiencies of various methodologies, can further illustrate the potential for large-scale LV production and facilitate widespread therapeutic applications.

Introduction: Spinal cord injury (SCI) is among the most severe medical conditions, with profound impacts on global healthcare systems. SCI results in temporary or permanent loss of spinal cord function and is associated with high incidence rates, substantial economic burden, significant disability, and a low average age of onset. Astrogliosis and neuroinflammation play central roles in secondary injury and limit functional recovery. This systematic review examines pathophysiology, mechanisms of recovery, and emerging clinical treatment strategies for SCI. Methods: A comprehensive literature search was conducted across multiple databases, including PubMed, Scopus, and Web of Science, to identify relevant studies on SCI classification, pathophysiology, and treatment approaches, with a particular focus on Exosome and low level Laser therapy. The search included articles published up to September 2024, and key data were extracted for analysis. Results: A total of 141 studies met the inclusion criteria. The pathogenesis of SCI involves an initial mechanical injury followed by a secondary cascade of molecular and cellular events that exacerbate tissue damage. Current treatment options primarily provide supportive care for patients with lifelong disabilities. Pharmacological interventions focus on neuroprotection, employing medications and therapeutic agents tailored to modulate degenerative processes. Non-pharmacological approaches, including growth factors, Low level laser therapy, cultured cells, and vitamins, offer additional therapeutic benefits. Laser therapy integration into SCI treatment is increasingly studied due to its anti‑inflammatory, neuroprotective, and analgesic effects. Exosome therapies have shown significant neuroprotective and neuroregenerative potential by addressing multiple pathological mechanisms in SCI. Conclusion: A promising future direction lies in combining conventional pharmacological and surgical strategies with emerging therapies, particularly exosome therapy and LLLT, offers a promising approach to mitigate secondary injury, modulate astrogliosis, and enhance recovery in SCI patients. Comprehensive therapeutic strategies integrating pharmacological and non-pharmacological approaches with cutting-edge cell therapies hold significant promise for improving outcomes in SCI treatment.