Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by the degeneration of dopaminergic neurons in the midbrain. While PD is typically considered a disorder primarily affecting the central nervous system, there is mounting evidence of cellular dysfunction and PD pathology occurring in the peripheral nervous system, likely preceding central manifestations. In this context, it has become increasingly evident that dysregulation of both the central and the peripheral immune system plays a key role in PD pathogenesis and progression. In this narrative review, we describe and discuss the methodological approaches employed in human studies to investigate immune responses in PD pathogenesis and progression, their main findings and the potential to unveil novel therapeutic avenues. In particular, we present methodologies employed in and insights gained from human genetic studies, techniques utilized to investigate neuroinflammatory processes in post-mortem and living human brains, to investigate the blood-brain barrier, as well as the involvement of peripheral T cells and innate immune cells. Additionally, we elucidate methodologies utilized to explore the roles of mitochondrial dysfunction and infectious diseases in PD. Finally, we address the causes behind conflicting findings in the published literature, which may stem from disparities in sample ascertainment schemes, immunological protocols, and analysis designs. Given these challenges, it becomes imperative to develop methodological guidelines to enhance the validity of immunological studies in PD and facilitate their translation into clinical medicine.

Over the past decade, tremendous progress has been made in using organoids-three-dimensional, miniature organ-like structures-to model tissues and organs in vitro, including both regenerative tissues (which contain tissue-residing stem/progenitor cells) and largely non-regenerative tissues, such as the brain. Organoids resemble the tissues from which they are derived in many aspects of structure, function, and organization. As a result, organoid models have been utilized in a variety of fields for cell studies. Many well-written reviews have provided in-depth descriptions of organoid models for various systems. In this article, we review the establishment and application of tissue stem/progenitor cell-derived organoid models relevant to chemosensory cell studies (taste and smell), and discuss the limitations and future directions of using these models to study chemosensation.

Natural killer (NK) cell‑based immunotherapy has emerged as a transformative approach for cancer treatment However, its widespread clinical application faces several challenges, such as donor variability, limited scalability and functional heterogeneity of primary NK cells. Additionally, issues including in vivo persistence, resistance to tumor microenvironment and safety concerns related to genomic instability further hinder its clinical application. Induced pluripotent stem cell (iPSC)‑derived NK cells offer a promising solution. They provide high homogeneity and quality control, genetic engineering flexibility and inexhaustible cell source. This present review highlighted the unique advantages of iPSC‑ NK cells, including clonal uniformity, enhanced cytotoxicity and suitability for large‑scale production, positioning them as an ideal 'off‑the‑shelf' therapeutic platform. It discussed the biological properties of iPSC‑derived NK cells, advances in differentiation protocols and strategies to augment their anti‑tumor efficacy through genetic engineering, such as chimeric antigen receptor integration and cytokine optimization. Despite these advantages, several challenges remain, including the need to optimize differentiation efficiency, ensure the safety of gene editing (such as off‑target effects) and improve the in vivo migration and infiltration abilities. With technological advances and clinical validation, this present review aimed to guide future research toward overcoming these barriers to clinical implementation. Ultimately, it is expected that iPSC‑NK will become a core means of next‑generation immunotherapy, promoting the combination of personalized and inclusive cancer treatment.

VEXAS SYNDROME. VEXAS (Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a recently described autoinflammatory syndrome, mostly affecting men above 50 years, caused by somatic mutation in the X-linked UBA1 gene. Patients present a broad spectrum of inflammatory manifestations (fever, neutrophilic dermatosis, chondritis, pulmonary infiltrates, ocular inflammation, venous thrombosis) with hematological involvement (macrocytic anemia, thrombocytopenia, vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow) which are responsible for significant morbidity and mortality. The therapeutic management is currently poorly codified, and based on two main approaches: controlling inflammatory symptoms by using corticosteroids, JAK inhibitors or tocilizumab, or targeting the UBA1-mutated hematopoietic population using azacitidine or allogeneic hematopoietic stem cell transplantation.

Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by the loss of dopaminergic neurons in the substantia nigra that leads to reduced dopamine levels and impaired motor function. Current treatments only provide temporary symptom relief without addressing the underlying neuronal loss. A promising new approach for treating PD is stem cell therapy, particularly induced pluripotent stem cells and human pluripotent stem cells. They have the ability to differentiate into various neural cells, offering potential for neuronal replacement and restoration of brain function. Induced pluripotent stem cells are derived from reprogramming adult cells and present advantages such as genetic compatibility and reduced immune rejection, overcoming ethical concerns associated with embryonic stem cells. Preclinical studies show promising results, demonstrating that stem cells can differentiate into dopaminergic neurons and improve motor function in animal models. These advancements pave the way for clinical trials and potential long-term solutions for patients with PD. This review highlighted the significance of stem cell therapy in neuroregeneration and addressed preclinical successes, challenges in long-term safety, and ethical considerations, with the hope of revolutionizing PD treatment and improving patient outcomes.

Mesenchymal stem cells (MSCs) have a paracrine impact and may regenerate a variety of tissues. This represents a new prospect in cell-based stroke treatment. Several in vitro and in vivo investigations have demonstrated the neuroprotective and neurogenesis properties of MSCs and their secretome.

Patient-derived organoids (PDOs) are tridimensional cultures derived from the stem component of a tissue. They preserve the genetic and phenotypic characteristics of the tissue of origin, and represent valuable in vitro models for drug screening, biomarker discovery, cell therapy and genetic modification. Importantly, PDOs reproduce the tumor behavior and can predict therapeutic responses, making them relevant for clinical applications for personalized therapies. PDOs may also be used for studying the interactions between cancer cells and the tumor microenvironment (TME). These interactions are driven by biochemical factors released by the cells, and biomechanical events such as the remodeling of the extracellular matrix (ECM). In recent years, it has become evident that the interactions between cancer cells and the TME have an impact on tumor development and on the efficacy of cancer therapy Therefore, targeting both tumor cells and the TME may improve patient response to treatment. Most PDO culture protocols are limited to epithelial cells. However, recent advances such as use of decellularized ECM (dECM) scaffolds have allowed for the development of in vivo-like environments that host diverse cell types, both normal and pathological, in a tridimensional (3D) manner that closely mimics the complexity of the TME. dECM-based models effectively replicate the interactions between tumor cells, ECM and the microenvironment, are easy to analyze and adaptable for drug testing. By incorporating TME components and therapeutic agents, these models offer an advanced platform for preclinical testing.

The engineered extracellular vesicles (EVs) derived from pluripotent stem cells (PSCs) are a new concept in regenerative medicine. These vesicles are secreted from the embryonic stem cells as well as the induced PSCs (iPSCs) and are involved in the transfer of bioactive molecules required for cell signaling. This review describes the possibilities for their use in the modification of therapeutic approaches in regenerative medicine and targeted therapies. PSCs can differentiate into various cell types that can be useful for tissue engineering or to generate models of diseases in a dish. Compared to cell therapies, engineered EVs are characterized by lower immunogenicity, higher targetability, and improved stability. Some of the applications are angiogenic, tissue restorative, immunomodulatory, and gene therapies for the treatment of certain diseases. iPSC-derived engineered EVs find application in regenerative medicine, drug delivery systems, diagnostics of diseases, and hydrogel systems. In regenerative medicine, they can promote the restoration of cardiac, bone, cartilage, and corneal tissues. Engineered EVs are also employed in drug targeting to particular sites as well as in the diagnosis of diseases based on biomarkers and improving image contrast. Hydrogels that contain EVs provide a depot-based delivery system to slowly release drugs in a controlled manner that enhances tissue repair. Thus, the results described above demonstrate the potential of engineered PSC-EVs for various biomedical applications. Future work will be directed toward expanding the knowledge of engineered PSC-EVs and their possibilities to create new therapeutic approaches based on the functions of these vesicles.

Sciatic nerve injury, affecting the longest and thickest nerve in the human body, often leads to severe pain, weakness, and impaired motor function in the lower extremities. Despite the peripheral nervous system's inherent capacity for some degree of regeneration, complete recovery remains elusive, necessitating advanced therapeutic approaches. This review explores two promising modalities electrical stimulation (ES) and platelet-rich plasma (PRP) that have shown the potential to enhance nerve repair and functional recovery. ES, through techniques such as transcutaneous electrical nerve stimulation (TENS), neuromuscular electrical stimulation (NMES), and direct current stimulation (DCS), facilitates neuronal regeneration by guiding axonal growth, releasing neurotrophic factors, and promoting synaptic plasticity. PRP, derived from autologous blood, is rich in growth factors such as Platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and nerve growth factor (NGF), which are essential for nerve regeneration, angiogenesis, and reducing inflammation. Clinical evidence supports the efficacy of ES and PRP in promoting nerve regeneration and functional recovery (Figure 1). However, further research is needed to optimize their application and understand their long-term outcomes. This review highlights the potential of these therapies to capitalize on their actions, potentially creating a robust regenerative milieu. Further research is needed to optimize treatment procedures and validate their efficacy and safety in humans.

Intervertebral disc (IVD) herniation is a leading cause of lower back pain, with symptoms ranging from tingling to disability. Discectomy, as the most common treatment, relieves pain and reduces inflammation, but the unrevealed defect in annulus fibrosus (AF) inevitably increases the risk of herniation as high as 21%. Repair and regeneration of AF are crucial to prevent herniation and recreate healthy IVD. Mechanical repair strategies, including suture, annulus closure device, and AF patch, often fall short in material-tissue integration and tissue regeneration. Recent developments in tissue engineering integrate biological science and material engineering, mainly through hybrid hydrogels and synthetic polymer scaffolds, showing promising effects on AF repair and regeneration. This review outlines various repair strategies and their limitations. It emphasizes the need for a holistic approach considering material selection, scaffold design, and incorporating cytokines or stem cells to improve AF repair outcomes. First, advancements in electrospinning, 3D printing, and porosity engineering will be discussed to enhance the integration of scaffolds with surrounding tissue to mimic a natural AF environment. Second, the benefits of adding cells or biofactors will be reviewed to strengthen cellular interactions, migration, and differentiation of stem cells. Finally, future research will be proposed to develop innovative, multifunctional scaffolds that complement personalized medicine while also considering the impact of mechanical stimulation and scaffold porosity on cell behavior and drug delivery for more efficient repair effects.

Cancer immunotherapy, which boosts the immune system to recognize and attack malignant cells, has revolutionized traditional cancer treatment paradigms. Approaches such as chimeric antigen receptor T cell (CAR-T) therapy and immune checkpoint inhibitors (ICIs) have demonstrated promising therapeutic outcomes, leading to the approval of numerous immuno-oncology agents by the US Food and Drug Administration (FDA) over the past few decades. Immuno-oncology agents, mainly based on conventional full-length antibodies or their derivatives, are widely used in cancer immunotherapy. However, their large size, unwanted immunogenicity, poor solubility, complex molecular architectures, and limited tumor penetration pose significant challenges that must be addressed. Nanobodies, which are single-domain antibody fragments originating from the variable regions of camelid heavy-chain immunoglobulins, represent the smallest known antigen-binding fragments. In addition to their small size (~ 15 kDa), nanobodies possess a range of advantageous properties, including high stability, strong specificity and affinity for target antigens, low immunogenicity, and cost-effective production. Nonetheless, their short serum half-life and lack of Fc-mediated functions may limit efficacy, which can be addressed by Fc fusion, albumin binding, or multivalent construct design. These properties enable nanobodies to support multifunctional constructs, such as bispecific CARs, nanobody-secreting CARs, dual ICI-containing molecules, and trispecific immune cell-engaging antibodies. In recent years, a growing number of nanobody-based immuno-oncology agents have progressed into preclinical and clinical trials, with several products approved by the US FDA and China's National Medical Products Administration for cancer therapy. In this review, we explore the unique properties of nanobodies and provide a comprehensive summary of recent preclinical and clinical advancements in nanobody-based immuno-oncology agents, with a focus on their applications in CAR-T cells, ICIs, and immune cell-engaging antibodies. Through their unique capacity to integrate innovative molecular engineering with translational clinical development, nanobody-based therapeutics are poised to revolutionize current paradigms in cancer immunotherapy.

Systems biology offers a view of the cell as an input-output device: a biochemical network (or cellular "processor") that interprets cues from the microenvironment to drive cell fate. Advancements in single-cell technologies are unlocking the cellular black box, revealing heterogeneity in seemingly homogeneous cell populations. But are these differences technical variability or biology? In this review, we explore this question through a systems biology lens, offering a framework for conceptualizing heterogeneity from the cell's perspective and summarizing systems and synthetic biology tools for capturing heterogeneity. While cellular inputs shape the probability of attaining particular fates, each cell spins a stochastic "wheel of fate." Applying this framework, we explore heterogeneity in two case studies: human pluripotent stem cell (hPSC) culture and beta cell differentiation. Looking forward, we discuss how a systems approach to heterogeneity may enable more predictable outcomes in stem cell research, with broad implications for developmental biology and regenerative medicine.

AIM Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important treatment for blood disease, and ocular graft-versus-host disease (oGVHD) is a common complication that significantly affects the quality of life of patients. Currently, the risk factors for oGVHD are still controversial.Methods To provide a scientific foundation for the prevention of oGVHD in patients undergoing allo-HSCT, studies on the factors influencing the development of oGVHD were searched in PubMed, Embase, Web of Science, Sino Med, the Cochrane Library, CIKI, the Wanfang Database, and the VIP Database from database construction to May 2024.Results Seventeen studies included 4,501 patients who received allo-HSCT, of which 1,526 were diagnosed with oGVHD, involving 22 factors. The overall prevalence of oGVHD was 37.8%.[95% CI (0.294, 0.463)].The prevalence of oGVHD based on the diagnostic criteria recommended by the National Institutes of Health was 46.7% [95% CI (0.390, 0.545)], that of the International Chronic oGVHD Group was 33.7% [95% CI (0.167, 0.506)], and that of self-defined diagnostic criteria was 32.0% [95% CI (0.184, 0.457)]. According to the meta-analysis, elderly patients [OR=1.10, 95% CI (1.00, 1.20)], female donors [OR=1.48, 95% CI (1.20, 1.83)], matched-relative donors (MRD) [OR=1.50, 95% CI (1.22, 1.83)], peripheral hematopoietic stem cells (PBSCs) [OR=1.81, 95% CI (1.38, 2.39)], acute graft-versus-host disease (aGVHD) [OR=1.74, 95% CI (1.29, 2.35)], chronic graft-versus-host disease (cGVHD) [OR=3.04, 95% CI (1.82, 5.08)], oral [OR=13.83, 95% CI (5.09, 37.56)] and skin graft-versus-host disease (GVHD) [OR=5.55, 95% CI (2.41,12.79)] were risk factors for the development of oGVHD (P < 0.0 5).Conclusion According to our systematic review and meta-analysis, the factors listed above are associated with oGVHD and can serve as early warning signs for clinicians in identifying high-risk populations eligible for early intervention and treatment.

Myogenic regulatory factors, including myoblast determination protein 1 (MyoD1 or MyoD) and myogenic factor 5 (Myf5), crucially regulate skeletal muscle lineage specification and development. Although MyoD and Myf5 exhibit overlapping functions during embryogenesis, their roles significantly diverge in adult muscles. Single MyoD knockout analysis revealed that MyoD uniquely regulates adult muscle regeneration, considerably influencing delayed myogenic differentiation, enhancing self-renewal, and modulating apoptosis resistance. These findings highlight fundamental differences between embryonic and adult myogenesis. Recent advances in single-cell technologies have revealed the heterogeneity of MyoD expression among adult muscle stem cells (MuSCs), thereby elucidating its diverse functional roles during muscle regeneration. Furthermore, MyoD has been implicated in the regulation of myofiber type specification and plasticity in mature skeletal muscles. Overall, these findings suggest that MyoD serves as a key orchestrator in cellular, functional, and pathological processes in adult skeletal muscle across multiple contexts. Although previous reviews have extensively addressed the role of MyoD in embryonic muscle development, the available literature lacks a focused discussion on its multifaceted functions in adult MuSCs, mature myofibers, and the aging process. In this review, we aimed to bridge this gap by integrating recent discoveries and offering novel insights into the dynamic roles of MyoD in adult skeletal muscles; the information discussed in this review has potential therapeutic implications in muscle regeneration, disease management, and combating age-related muscle decline.

Neonatal hypoxia-ischemia is a leading cause of neonatal death in both developed and developing countries. The consequences of hypoxic-ischemic injury affect the rest of the child's life, often resulting in intellectual or motor disability that persists into adulthood. To date, therapeutic hypothermia (TH) appears to be the only available intervention aimed at limiting brain injury and is recognized as the "gold standard" in neonatal intensive care. The basic mechanisms of neuroprotection achieved by temporal cooling involve the reduction of free radical activity, suppression of the inflammatory response after reperfusion and increased neuronal cell survival. However, the protective effects of hypothermia need to be enhanced by additional therapies that can enhance neuroprotection and support neuroregenerative processes. The components derived from the umbilical cord are thought to confer the above-mentioned beneficial effects. This review summarizes the clinical trials based on stem cell transplantation or umbilical cord milking and presents their effects when supported by official data. The great promise associated with the application of stem cells to neonates suffering from perinatal asphyxia is discussed in the context of the results of their clinical use.

Neurons are post-mitotic cells that are not replaced once lost, leading to the need for neuronal replacement therapies for central nervous system (CNS) repair. The generation of induced pluripotent stem cell (iPSC) derived human neurons is relatively advanced, with the capacity to generate pure and validated populations of different neuronal subtypes as clinical grade cells ready for engraftment. Clinical trials using human-derived embryonic stem cells (hESC) and iPSC-derived neurons are underway. As an alternative approach, the ability to target in vivo resident non-neuronal cells with reprogramming factors to induce replacement neurons has been demonstrated. The ability to engineer a defined population of resident replacement neurons that retain their cytoarchitectural location may permit an additional, more focused therapeutic strategy for specific circuits that could complement the bulk engraftment of ex vivo stem cell-derived replacement neurons. This mini-review summarizes and compares these two strategies and offers a perspective on the steps needed to advance recruitment as a complementary therapeutic strategy.

Bone Morphogenetic Proteins might be the most prospective in glioma treatment because of the facts that they can differentiate glioma cells, inhibit tumor growth and manage glioma stem cells. Its clinical application is hindered by several challenges, including limited permeability across the blood-brain barrier, which impedes effective delivery to the central nervous system; high susceptibility to enzymatic degradation, which compromises stability and therapeutic efficacy; and nonselective binding, which reduces specificity and may result in unintended off-target effects. This review systematically covers the advanced BMP delivery systems such as nanoparticles, smart carriers, gene therapy, and exosome-based system. Hydrogels, scaffolds, and microspheres' local delivery methods are also discussed as prospective options. The in vitro studies reveal that BMPs are effective and using in vivo glioma models there is also evidence of the effectiveness of BMPs. In addition, new clinical trials reveal concern with safety, tolerability, and therapeutic effects of BMPs, especially their combination with chemotherapy and immunotherapy. BMP specificity and therapeutic performance are further optimized by Personalized medicine and CRISPR/Cas engineering. However, regulatory barriers and product commercialization are challenging issues. This review highlights the need for novel approaches and advanced technologies to address the challenges associated with BMP delivery, aiming to establish BMP-based therapies as an effective treatment strategy for glioma.

Diabetes mellitus often results in vascular complications, significantly impacting patients' well-being. This review focuses on the role of immune cells in these complications, examining their mechanisms, biomarkers, and treatment strategies. Immune cells, including macrophages, T cells, and B cells, contribute to the development of both macrovascular and microvascular complications by secreting inflammatory factors and modulating immune responses. For instance, in diabetic coronary artery disease, macrophages form foam cells and promote inflammation, whereas in diabetic nephropathy, an imbalance in T-cell subsets exacerbates the condition. Novel immune-related biomarkers, such as soluble cytokine receptors and specific microRNAs, offer new avenues for early diagnosis and monitoring. Current treatments focus on inflammation and oxidative stress, while emerging therapies, including stem cell treatment and precision medicine, show promise but also present challenges. This review systematically summarizes and analyzes pertinent research. Its significance lies in synthesizing current research findings, identifying knowledge gaps, and providing guidance for future basic research and clinical practice. By elucidating the critical role of immune cells in diabetic vascular complications, it aids in the development of new therapeutic targets and more effective treatment strategies. Moreover, the exploration of novel biomarkers opens up the possibility of early disease intervention, and the review of the current treatment landscape and challenges encourages clinicians to make more rational treatment decisions. Overall, the aim is to enhance patients' prognoses, alleviate the medical burden, and advance progress in diabetes treatment.

Temozolomide (TMZ) remains the cornerstone chemotherapy for glioma, yet intrinsic and acquired resistance mechanisms significantly limit its clinical effectiveness. This review summarizes the multifaceted molecular pathways contributing to TMZ resistance, including enhanced DNA repair mechanisms such as O6-methylguanine-DNA methyltransferase (MGMT), mismatch repair (MMR), and base excision repair (BER). Additional resistance factors include genetic mutations that affect the drug response, dysregulated non-coding RNAs (miRNAs, lncRNAs, and circRNAs), glioma stem cells (GSCs), cytoprotective autophagy, an immunosuppressive tumor microenvironment (TME), altered signaling pathways, and active drug efflux transporters. Recent advancements to overcome these resistance mechanisms, including enhancing TMZ bioavailability through nanoparticle-based delivery systems and the inhibition of efflux transporters, have been explored. Novel therapeutic approaches that target DNA repair pathways and manipulate autophagy are highlighted. Immunotherapeutic interventions reversing immune suppression and metabolic strategies targeting tumor metabolism offer additional avenues. Emerging therapies such as CRISPR-based gene editing, phytochemical combinations, repurposed drugs, and novel TMZ analogs designed to bypass MGMT-mediated resistance are also discussed. This review highlights current developments and identifies emerging areas, with the goals of enhancing clinical outcomes and prolonging survival for glioma patients.

Cord blood, which is rich in hematopoietic stem/progenitor cells, is now an important cell source for allogeneic hematopoietic cell transplantation (HCT). Although cord blood transplantation (CBT) was initially only performed in pediatric patients due to the limited number of cells, it now accounts for around 30% of allogeneic HCT for adults in Japan. It has overcome the shortage of donors caused by the declining birthrate and aging population. Although the greatest disadvantage of CBT is the high incidence of Engraftment failure, it has been shown that even in HLA-incompatible recipients, graft-versus-host disease (GVHD) is less frequent and less severe in CBT, whereas the graft-versus-leukemia (GVL) effect is stronger. CBT in Japan differs from that in other countries in that a single-unit is used in adult patients, and CBT is actively performed in elderly patients and patients with advanced hematopoietic disease. Based on the Japanese analysis, the usefulness of intensified conditioning regimen, the survival-improving effect on mild acute or chronic GVHD, and the strong GVL effect are all characteristic of CBT, which is an important source of cells for allogeneic HCT.