The motor symptoms of Parkinson's disease are linked to age-dependent degeneration of dopamine neurons. Traditionally, the loss of these neurons has been thought to stem mainly from cell-autonomous cellular dysfunctions. However, there is growing evidence suggesting that it could result from complex interactions between cell-autonomous and noncell-autonomous mechanisms. This review article examines evidence for cell-autonomous mechanisms linked to mitochondrial, lysosomal, or proteasomal perturbations and for noncell-autonomous processes arising from glial and peripheral immune cells. We discuss how these pathways can converge to create chronic cellular stress and trigger cell death mechanisms. Beyond highlighting apoptosis as a key mode of degeneration, we consider the contribution of other mechanisms, including pyroptosis and ferroptosis. Understanding the relative dominance of these mechanisms across disease stages and patient subgroups could help guide the development of mechanism-based neuroprotective strategies.

Fanconi anemia (FA) is a rare genetic disorder characterized by genomic instability, bone marrow failure, physical abnormalities, and increased cancer susceptibility. Growing evidence suggests that. FA may represent a progeroid syndrome, displaying features of accelerated aging at the cellular and molecular levels. This review examines the cellular and molecular characteristics of FA in the context of the established hallmarks of aging, supporting the hypothesis that FA constitutes a premature aging disorder. The hallmarks of aging, classified as primary, antagonistic, and integrative, are highly interconnected and mutually influential. FA cells exhibit primary hallmarks such as; genomic instability, telomere attrition, epigenetic alterations, and dysregulated autophagy. Antagonistic hallmarks, including cellular senescence, mitochondrial dysfunction, and altered; nutrient sensing, are also evident. Integrative hallmarks, such as stem cell exhaustion, altered; intercellular communication, chronic inflammation, and dysbiosis, arise as downstream consequences of the accumulated primary and antagonistic damage. The presence of these hallmarks, together with the early onset of clinical manifestations such as bone marrow failure, cancer, and premature menopause, strongly supports the notion that FA involves accelerated aging. Although patients with FA lacks the overt physical features typical of other progeroid syndromes, its clinical, cellular, and molecular abnormalities demonstrate a strong association with age-related decline, making FA a valuable model of premature aging. Despite limited experimental evidence directly demonstrating accelerated aging, this review highlights the molecular mechanisms linking FA and aging and identifies understudied areas that warrant further investigation.

Myelodysplastic Neoplasms (MDS) are a group of clonal hematopoietic malignancies originating from hematopoietic stem cells. Their pathogenesis involves not only genetic abnormalities in hematopoietic cells but is also closely associated with functional dysregulation of the bone marrow microenvironment (BMME). In MDS, both the heterogeneous cellular populations and non-cellular components of the BMME exhibit significant dysfunction. Aberrant BMME components drive the initiation and progression of the disease through complex intercellular interactions. In-depth research into its pathological features and molecular mechanisms is of great significance for developing effective targeted therapeutic strategies. In recent years, novel treatment strategies based on BMME regulation have made significant progress, including immunomodulators, epigenetic regulators, molecularly targeted drugs, and cell therapies, providing new insights for improving the clinical outcomes of MDS patients. This article systematically reviews the pathological features of the BMME in MDS and its key molecular mechanisms in disease development, and discusses the latest clinical research advances in BMME-targeted therapies.

Hematopoietic stem and progenitor cells (HSPCs), including multipotent progenitors (MPPs), sustain lifelong blood production by integrating intrinsic metabolic and epigenetic mechanisms with extrinsic cues from the bone marrow (BM) niche. Epigenetic mechanisms interact with metabolic pathways to establish a coordinated network that supports HSPC maintenance and differentiation. Spatially defined signals within BM niches shape HSPC metabolic and epigenetic states and govern lineage specification. Herein, we review recent advances on the bidirectional relationship between metabolism and epigenetics in HSPCs, emphasizing how both intrinsic and niche-derived factors regulate fate decisions under steady-state and pathological conditions. Particular attention is given to the CXCL12/CXCR4 signaling axis, a central regulator of HSPC retention, migration, and quiescence, and its emerging role in orchestrating metabolic and epigenetic mechanisms. Integrating intrinsic regulatory networks with dynamic extrinsic signals provide a conceptual framework for understanding HSPC fate and may uncover strategies for regenerative medicine and hematological disease therapy.

Carcinogenesis and acquisition of multidrug resistance within established cancers are both multistep evolutionary processes in which stem cells play a role. This perspective will briefly review two corresponding theoretical constructs under development. Efficiency of carcinogenesis (EOC) considers multistep carcinogenesis and predicts the effect of differing dynamics on the efficiency of generating a transformed founder cell. EOC has been applied to evaluation of the role of genetic instability in carcinogenesis. Dynamic precision medicine (DPM) is a method for providing personalized treatment sequences for cancer while explicitly considering intracancer subclonal heterogeneity and evolutionary dynamics (growth and evolutionary rates). It adapts therapy frequently and proactively by anticipating the kinetics of multidrug resistance prior to its detection, and prioritizing its prevention. Simulations suggest potential to substantially increase survival and cure rates across a broad range of clinical presentations. Both of these problems implicate very small subclones within stem cell and/or differentiated compartments, and evolution may occur over months to years. We describe novel experimental technologies for quantifying longitudinal dynamics of very large numbers of cells for prolonged periods, allowing detection and tracking of rare events and their evolution over time. We further highlight two potential applications. In Fanconi anemia, optimal treatment sequences for minimizing bone marrow failure while not increasing the risk of leukemia may be designed using EOC and DPM and tested in laboratory models. In refractory acute myeloid leukemia, high throughput molecular characterization and drug sensitivity screening of subclones is showing clinical promise, and may be further optimized with DPM.

To evaluate the potential of tumor-suppressor microRNAs delivered via exosomes, especially those from human dental pulp stem cells, as a targeted therapy for oral cancer and to examine recent strategies that improve their delivery and clinical application. Although extensive preclinical evidence supports the anticancer functions of TS-miRNAs, the robustness and reproducibility of their effects vary substantially across experimental models. Exosome-based delivery has emerged as a biologically attractive strategy to improve miRNA stability, targeting specificity, and therapeutic efficacy.

Engineered cell therapies are transforming precision medicine by enabling real-time, context-responsive interventions that act upon disease-specific cues. Inspired by the success of CAR-T cells in oncology, next-generation platforms are being developed using diverse immune cells and stem cells to address a broader spectrum of diseases. These living therapeutics harness synthetic gene circuits to induce targeted cytotoxicity, to modulate the secretion of effector proteins or to coordinate both functions in response to endogenous signals or externally delivered molecular and physical triggers. Ex vivo engineering of autologous cells remains the norm, but challenges in scalability, cost and accessibility are fuelling efforts towards allogeneic products and in vivo reprogramming. Advances in targeted delivery - using viral vectors, mRNA-loaded nanoparticles and virus-like particles - are expanding the toolkit for direct programming of cells within the body. This Review discusses emerging strategies for engineering human cells with therapeutic functions, highlighting modular control systems, delivery innovations and the translational hurdles that lie ahead.

Metastases cause most cancer-related deaths, underscoring the need for therapies targeting metastatic stages, including the tumor microenvironment. Yet translating biological insights into treatments remains difficult. Preclinical metastasis research largely relies on rodent models, which have species-specific limitations and are incompatible with large-scale perturbation screens in a human context. Human organoids aim to emulate organ microenvironments in vitro and, when cocultured with cancer cells, can provide complementary models. These 'chimeroids' may enable scalable studies of cancer-microenvironment interactions and support genetic and pharmacological screens to discover new targets, offering insights into the final, often lethal step of metastasis-tissue colonization. This review summarizes advances in stem cell-derived organoid models for organs frequently affected by solid tumor metastases, including the brain, lung, liver, and bone, and evaluates their ability to recreate physiologically relevant niches for studying cancer cell adaptation and colonization.

Adipose stromal and progenitor cells (ASPCs) represent the largest cell population in human white adipose tissue (WAT). Despite their abundance, ASPC heterogeneity remains less well characterized compared to adipocytes or immune cells. Recent single-cell transcriptome studies provide unprecedented resolution of ASPC diversity and function. This review summarizes state-of-the-art approaches, including high-resolution single-cell methods, classical lineage and functional assays, to define ASPC populations. By systematically comparing recent datasets, we identify evidence for at least eight distinct ASPC-subtypes, which demonstrate specific marker genes and putative functional diversity. Along the adipogenic trajectory, these include uncommitted multipotent progenitors, intermediate and committed preadipocytes, and premature adipocytes. Additional populations comprise specialized anti-adipogenic, profibrotic, inflammatory, and fibroblast-like ASPCs. Other cell types are not consistently detected across studies, reflecting both biological and methodological variability, and the need for further validation studies. Better understanding of ASPC heterogeneity may improve the clinical assessment of metabolic disorders and support their treatment. We further discuss subtype-specific (dys)functions linked to fibrosis, inflammation and impaired adipogenesis and describe their increased abundance in metabolic disease. Together, this review integrates current knowledge on ASPC heterogeneity and highlights its clinical relevance, aiming to provide a unified framework for future studies on WAT remodeling and metabolic dysfunction.

Neurodegenerative diseases are a major and growing global health burden. Their pathogenesis is complex, and effective therapies remain limited. Gene editing and stem cell-based strategies are reshaping the therapeutic landscape. However, the field has not been systematically examined through bibliometric analysis.

Interferon-gamma (IFN-γ) is a central mediator of immune-driven bone marrow failure (BMF) in acquired aplastic anemia (AA). Persistent IFN-γ signaling alters the bone marrow microenvironment by activating the JAK-STAT1 pathway, which results in immunological imbalance, inflammatory amplification, and depletion of hematopoietic stem and progenitor cells (HSPCs). IFN-γ disturbs HSPC quiescence and self-renewal, interferes with thrombopoietin (TPO)-c-Mpl communication, and stimulates cytotoxic T-cell-dominant immunological responses. Simultaneously, IFN-γ destabilizes local immunological homeostasis by disrupting immune crosstalk through the IDO1 axis and regulatory T-cell (Treg) malfunction. In addition to discussing new therapeutic methods, such as Treg-based therapies and JAK inhibition, as prospective precision approaches for AA, this review incorporates current mechanistic insights into IFN-γ-driven cellular interactions inside the bone marrow niche.

Stress urinary incontinence (SUI), characterized by involuntary urine leakage, significantly impairs quality of life and often stems from urethral sphincter insufficiency. While conventional treatments offer relief for many, they have limitations or may be unsuitable for certain patient populations. Regenerative medicine offers a transformative approach by focusing on the restoration of damaged tissue integrity and physiological function.

Pulmonary fibrosis (PF) is a chronic and progressive interstitial lung disease characterized by excessive extracellular matrix (ECM) deposition and remodeling of lung structures. Currently, no effective clinical treatments exist to reverse or halt the progression of PF. Consequently, there is an urgent need to identify novel therapeutic strategies for this complex disease. Stem cells, renowned for their self-renewal and multipotent differentiation capabilities, have garnered considerable attention for their potential therapeutic applications, particularly in regenerative medicine. The primary stem cell types investigated for PF treatment include mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSCs), and lung progenitor cells. Preclinical studies have demonstrated that these stem cells can reduce inflammation, modulate immune responses, and promote the repair of damaged lung tissue. Although stem cell transplantation shows promise in PF treatment, challenges such as safety, quality control, and therapeutic efficacy remain unresolved. Recent studies have highlighted that stem cells interact with and modify their transplanted environment, influencing their structural properties and chemical composition. These interactions strongly influence stem cell survival, phenotype, and therapeutic efficacy. Understanding these dynamics will inform the development of new strategies to improve the effectiveness of stem cell therapies for PF.

Regulatory T cells (Tregs) represent a distinct T cell subpopulation crucial for preserving immune homeostasis. Their primary function is to facilitate self-tolerance and suppress other immune responses, achieved through multifaceted mechanisms, including the secretion of extracellular vesicles (EVs) such as exosomes, which effectively modulate the activity of other innate and adaptive immune cells. Treg-derived extracellular vesicles (Treg-EVs) are minute, membrane-bound vesicles containing specific biological molecules, comprising proteins, nucleic acids, and lipids. Upon transfer to target cells, these molecules exert diverse effects on immune responses. The Treg-mediated immune suppression process encompasses several contact-dependent and contact-independent mechanisms. These encompass the expression of various inhibitory receptors, such as CTLA-4, PD-1, CD39, and CD73, which serve to regulate the immune response. Furthermore, Tregs exhibit the capacity to directly eliminate target cells through the expression of perforin and granzyme B. Additionally, Tregs produce immunosuppressive cytokines that play a pivotal role in maintaining immune system equilibrium. Studying the impact of Treg-derived exosomes on the immune system in cancer is crucial for advancing cancer research and treatment. Understanding these interactions is vital for unraveling the potential implications for cancer development and progression.

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterized by the destruction of pancreatic β-cells and the subsequent loss of insulin production. The regeneration of pancreatic β-cells from induced pluripotent stem cells (iPSCs) represents a promising therapeutic approach for restoring β-cell function in T1DM patients. However, ensuring the safety, functionality, and genetic stability of iPSC-derived β-cells is crucial for their clinical application. To address this challenge, a comprehensive literature review was conducted using PubMed/MEDLINE, Web of Science, and Scopus databases to identify relevant studies published up to October 2025. It included an analysis of key regulatory documents from the U.S. Food and Drug Administration (FDA), the European Medicines Agency on Advanced Therapy Medicinal Products (EMA ATMP), and the International Organization for Standardization (ISO). This article proposes a comprehensive quality control (QC) strategy for differentiating iPSCs into pancreatic β-cells, emphasizing a tiered approach with multiple checkpoints throughout the process. The strategy integrates advanced molecular and functional assays to evaluate cell identity, viability, stability, and microbiological safety. The proposed QC framework allows for continuous monitoring, early detection of potential issues, and real-time adjustments to optimize the differentiation process. The flexibility of this approach ensures its adaptation to emerging scientific advancements and regulatory requirements. This integrated and adaptable QC strategy enhances the likelihood of success in generating functional β-cells, laying a solid foundation for the clinical application of iPSC-derived β-cell therapies and offering hope for effective, long-term treatments for T1DM.

Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR associated protein 9 (CRISPR/Cas9) technology has become a revolutionary tool in medicine, offering substantial potential for treating a wide range of diseases, including hematological disorders, cancers, genetic conditions, and ophthalmological diseases. This systematic review evaluates the efficacy, safety, and applicability of CRISPR/Cas9 in clinical trials. A comprehensive search of the PubMed, Scopus, Web of Science, and Cochrane databases was conducted. All studies, up to November 2024, meeting the eligibility criteria assessing the application of CRISPR for the treatment of diseases were included. A quality assessment of the included studies was conducted using the Cochrane risk of bias tool. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement for systematic reviews and meta-analyses was followed, and a total of 17 studies were included. This systematic review of CRISPR/Cas9 technology focused on its effectiveness and safety across various diseases. In nonmalignant hematological disorders, CRISPR successfully treated β-thalassemia and sickle cell disease, resulting in high transfusion independence and the elimination of disease crises. In malignant hematological disorders, B-cell acute lymphoblastic leukemia, CRISPR-engineered chimeric antigen receptor T (CAR-T) cells achieved an 83.3% complete remission rate. Furthermore, CRISPR-based CAR-T cells showed promising results in B-cell non-Hodgkin's lymphoma. In oncology, lung cancer and other solid tumors are among the diseases that have been safely engineered using CRISPR gene editing technology. For genetic disorders, CRISPR improved vision in retinal degeneration and reduced symptoms in hereditary angioedema and transthyretin amyloidosis with mild side effects. The results demonstrated CRISPR's potential across a wide range of conditions. In conclusion, the findings underscore the potential role of CRISPR/Cas9 technology across a wide range of diseases. However, challenges remain, including optimizing delivery systems, minimizing off-target effects, addressing immunogenicity concerns, and ethical considerations.

Islet cell transplantation holds great promise for restoring glycemic control in patients with type 1 diabetes. However, its long-term efficacy remains limited due to poor islet survival, immune rejection, and insufficient vascularization. Mesenchymal stem cells (MSCs) have emerged as potent biological adjuvants capable of addressing these challenges through a range of molecular mechanisms. MSCs secrete a variety of growth factors, immunoregulatory and pro-angiogenic molecules that enhance viability of islet cells, modulate the immune response, promote neo-angiogenesis and enhance islet engraftment. In addition, MSC-derived exosomes (MSC-Exos) have been identified as key mediators, delivering regulatory microRNAs and proteins that replicate many of the beneficial effects of MSCs in a cell-free format. MSC-Exos act as small RNA carriers and immunomodulators, promoting islet survival and functional integration. Understanding the molecular interplay between MSCs, their exosomes, and the islet microenvironment provides crucial insights for the development of advanced co-transplantation strategies. Accordingly, in this review article, we summarized current knowledge about molecular mechanisms that are responsible for MSC-dependent improvement of islet cell transplantation and we highlighted the translational potential of MSC and MSC-Exos-based approaches in improving islet graft outcomes for type 1 diabetes.

Tumor dormancy is a fundamental phenomenon in cancer biology, characterized by malignant cells that remain viable but non-proliferative, thereby frequently evading detection and treatment. This review examines the intricate role of the tumor microenvironment (TME) in regulating tumor cell dormancy. The TME encompasses a diverse array of components, including immune cells, extracellular matrix proteins, and soluble factors, all of which contribute to a dynamic interplay that influences tumor cell behavior. Key mechanisms involved in the maintenance of dormancy include immune surveillance, where immune cells can either suppress or promote tumor growth, and extracellular matrix interactions that provide structural support and biochemical signals essential for quiescence. Additionally, microenvironmental conditions such as hypoxia and acidosis impose selective pressures that can favor dormant states over active proliferation. Emerging therapeutic strategies are being explored to target dormant tumor cells, including the use of mesenchymal stem cell therapies, which may modulate the TME to either awaken dormant cells for targeted treatment or maintain their quiescent state to prevent recurrence. Understanding the TME's influence on tumor dormancy not only enhances our comprehension of cancer progression but also opens avenues for innovative treatments aimed at improving patient outcomes by mitigating the risks of recurrence and metastasis. This article aims to provide a comprehensive overview of the current knowledge on TME-mediated tumor dormancy and highlight promising therapeutic strategies for future research.