Neurodegenerative diseases are characterized by progressive neuron loss and brain atrophy. While conventional studies focused on neuronal death as the primary cause of these diseases, accumulating evidence suggests that impaired neurogenesis, particularly the dysfunction of adult neural stem cells (NSCs), may also contribute significantly to disease pathogenesis. Adult neurogenesis occurs primarily in two adult NSC niches. These specialized niches are enriched with complex cytokine networks, neuronal activity, and non-cellular components such as the extracellular matrix. Understanding the regulation of NSCs in the adult brain and how their dysregulation exacerbates neurodegeneration provides novel insights into therapeutic strategies. This review proposes that dysfunction of the NSC microenvironment, rather than neuronal death alone, may drive neurodegeneration, and that restoring this microenvironment offers a novel research direction of stem cell-based therapies.

Strontium (Sr)-based nanofibers have gained great attention in biomedical and tissue engineering applications due to their unique ability to combine nanoscale structural features with the biological activity of Sr ions (Sr2+). Nanofibers offer a versatile platform to harness these properties owing to their high surface area, tunable porosity, and mechanical strength. The incorporation of Sr2+ ions further enhances their bio-functionality and offers a cost-effective alternative to growth factor-based strategies. Sr2+ ions could stimulate the production of growth factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), thereby promoting neovascularization, while also enhancing osteogenesis by mimicking calcium's physiological role, inducing mesenchymal stem cell differentiation, and stimulating extracellular matrix mineralization. This review summarizes recent advances in the fabrication techniques such as electrospinning, assisted-electrospinning, and non-electrospinning, including the design, control composition, morphology, and functionality of Sr-based nanofibers. The mechanisms governing Sr2+ ions interactions with cells and tissues are discussed, along with in vitro and in vivo biological outcomes. Our bibliometric analysis shows that Sr-based nanofibers have been most extensively investigated in bone tissue engineering, followed by applications in drug delivery and tumor therapy, with fewer studies exploring skin and cartilage regeneration. This review highlights the advantages and disadvantages of every fabrication strategy, discusses biomedical applications of Sr-based nanofibers, and outlines challenges and future directions for their clinical translation.

Advances in transcriptomic technologies have progressively transformed the questions we can ask and answer about muscle stem cells (MuSCs) during aging. Early microarray and bulk RNA sequencing studies established foundational population-level signatures of aged MuSCs, including attenuation of myogenic and metabolic programs as well as induction of inflammatory and stress-associated transcription. However, these averaged readouts obscured cell-to-cell variability and rare functional states. The transition to single-cell and single-nucleus RNA sequencing marked a turning point by resolving MuSC heterogeneity and revealing that MuSC aging is not purely stochastic. Instead, aged MuSC pools show reproducible changes in state composition, delayed or altered myogenic lineage progression, and selective vulnerability of specific functional subsets. Emerging spatial transcriptomic approaches, although still limited by sensitivity and cell-type discrimination in muscle, are beginning to place these MuSC states into their native tissue context, directly linking transcriptional states, niche organization, and age-associated remodeling. In parallel, integrative multi-omic designs that pair transcriptomics with chromatin accessibility and metabolic measurements have strengthened mechanistic connections among age-associated gene programs, epigenetic remodeling, and metabolic state shifts. Finally, computational frameworks - including trajectory inference, dynamic modeling, and machine learning - are increasingly applied to high-dimensional transcriptomic data to predict aging trajectories and identify candidate rejuvenation targets. In this Perspective, we trace the evolution of transcriptomic technologies through the lens of MuSC aging and highlight how increasing resolution has reframed core models of MuSC decline and plasticity.

Cell therapy for neurodegenerative diseases (NDs) is considered a promising strategy to halt disease progression. Currently, most clinically applied cells are derived from two-dimensional (2D) cultures. However, 2D-cultured mesenchymal stem cells (MSCs) are prone to aging and functional deterioration after multiple passages, and the availability of neural precursor cells for cell replacement therapy remains limited. In contrast, three-dimensional (3D) cell cultures have garnered significant attention due to their unique 3D spatial interactions. The unique spatial architecture of 3D culture not only enhances cell-cell and cell-extracellular matrix (ECM) interactions in MSC spheroids, thereby preserving MSCs properties, but also facilitates developmental processes of brain organoids derived from pluripotent stem cells, including embryogenesis, morphogenesis, and organogenesis. This review highlights the therapeutic ability of 3D-cultured MSC spheroids and brain organoids for NDs and summarizes advanced engineering platforms for their production. Future research should integrate the strengths of both technologies by establishing standardized quality control systems and scalable production processes to harness the microenvironmental modulation capacity of MSC spheroids and the precise cell replacement ability of brain organoids, ultimately advancing personalized therapies for NDs.

Regenerative medicine is evolving exponentially due to the wide range of therapeutic applications of mesenchymal stromal cells (MSCs), including wound healing. Although the translation of tissue-derived primary MSCs (tMSCs) into clinical practice remains scarce despite preclinical success. The primary causes are donor-associated and batch-to-batch variations, replicative senescence, and the inability of large-scale manufacturing. Recent studies show that the induced MSCs (iMSCs) derived from reprogrammed induced pluripotent stem cells (iPSCs) offer distinct advantages over conventional tMSCs. This review aims to provide a comprehensive comparative analysis of the cellular characteristics, secretome composition (including growth factors, cytokines, and exosome cargo), regenerative capacities, and therapeutic potentials of tMSCs and iMSCs, with a specific focus on their applications in wound healing and tissue regeneration. The iMSCs surpass tMSCs by providing superior regenerative, immunomodulatory, and angiogenic benefits, along with unmatched consistency and scalability. iMSCs and their derivatives have exhibited remarkable capacities to promote angiogenesis, ECM production, re-epithelialization, tissue regeneration, and scarless wound healing in diabetic, cutaneous, mucosal, and burn wounds. These advantages position iMSCs as a next-generation cell therapy for managing both acute and chronic wounds, promising improved clinical outcomes and broader applicability.

Stem cells from human exfoliated deciduous teeth (SHED) and their derivatives have emerged as promising therapeutic agents for treating immune-mediated inflammatory diseases (IMIDs). IMIDs are characterized by dysregulated immune responses, leading to chronic inflammation and tissue damage. The current treatment landscape for IMIDs faces challenges, including the complexity of disease mechanisms and the limitations of existing therapies, which frequently fail to achieve long-term remission and are often associated with significant side effects. Consequently, there is a pressing need for innovative therapies that not only alleviate symptoms but also address the underlying immune dysfunction and promote the repair of damaged tissues. In this context, SHED and their derivatives offer a dual therapeutic advantage by harnessing both immunomodulatory and regenerative capacities. Research highlighted in this review demonstrates the therapeutic potential of SHED and their derivatives in multiple IMIDs, such as systemic lupus erythematosus, Sjögren's syndrome, multiple sclerosis, and rheumatoid arthritis. Critically, the aim of this review is not only to synthesize recent progress in SHED research for IMID treatment but also to highlight the strategic significance of innovative therapies emerging from the intersection of regenerative medicine and immunology.

Glioblastoma (GBM) is the most malignant primary central nervous system tumor in adults, with strong invasiveness, high recurrence, and poor prognosis. Natural killer (NK) cells, innate immune cells that eliminate glioma stem cells without MHC matching, show promise for GBM immunotherapy, but their efficacy is limited by GBM's immunosuppressive tumor microenvironment (TME), especially via protein post-translational modifications (PTMs). This review summarizes seven key PTMs' (phosphorylation, acetylation, glycosylation, methylation, ubiquitination, SUMOylation, lactylation) dual regulation on NK cell therapy: physiological PTMs enhance NK cytotoxicity, targeting, and persistence; aberrant PTMs block NK activation, induce exhaustion, and promote GBM immune escape. It also analyzes bottlenecks (insufficient NK activity/persistence, GBM's PTM-mediated escape) and breakthroughs (PTM-targeted small molecules like TAK-981, CRISPR-edited NK cells, combination therapies). Future directions include BBB precision delivery, PTM-guided personalized therapy, and PTM crosstalk research, aiming to advance NK therapy's clinical translation for GBM.

Haematopoiesis has long been a paradigm for understanding how human genetic variation can influence physiology in health and disease, ranging from the genetic characterization of Mendelian blood diseases to population-scale genomic studies of blood cell phenotypes and diseases. More recently, advances in single-cell genomics and variant-to-function mapping are enabling mechanistic insights into how genetic variation shapes blood cell development. Alongside inherited variation, the characterization of somatic mutations accumulating in haematopoietic stem cells during the lifespan has revealed clonal haematopoiesis as a ubiquitous evolutionary process, with heterogeneous clonal expansions impacting haematopoietic function and disease risk. Insights from genetic studies of haematopoiesis are translating into therapeutic applications, transforming treatment for monogenic blood disorders and promising broader applications. As methods continue to advance, haematopoiesis will remain central to understanding how genetic variation influences human biology, disease susceptibility and therapeutic response.

Neural stem cells (NSCs) persist throughout adulthood and contribute to circuit maintenance through controlled neurogenesis and trophic, metabolic, and immunomodulatory signaling. However, across neurological and psychiatric disorders, NSCs are not passive bystanders but direct targets of disease pathology and active participants in its progression. Evidence from stroke, Alzheimer's disease, Parkinson's disease, epilepsy, depression, anxiety, bipolar disorder, autism spectrum disorder, and schizophrenia shows that pathogenic conditions, such as neuroinflammation, oxidative and metabolic stress, and hypothalamic-pituitary-adrenal axis dysregulation disrupt intrinsic NSC programs. These insults suppress NSC activation, impair lineage commitment, and alter the NSC secretome in ways that exacerbate synaptic dysfunction and network instability. Despite interest in NSC-based transplantation, structural replacement remains constrained by poor survival, migration, long-range integration, and safety considerations. In contrast, paracrine mechanisms and extracellular vesicles drive more consistent functional benefits by suppressing neuroinflammation, protecting vulnerable neurons, restoring neurovascular integrity, and modulating immune and metabolic homeostasis. NSCs with gene editing, bioengineered scaffolds, extracellular matrix-mimetic hydrogels, and exosome-based delivery offer renewed translational potential. By repositioning NSCs as both vulnerable targets and mechanistic drivers of disease rather than secondary responders, this review reframes shared pathological processes across brain disorders and highlights NSCs as a tractable entry point for therapeutic intervention and circuit repair.

Framed as the "geography" of skeletal stem cells (SSCs), this review aims to synthesize how developmental stages and local niche cues determine SSC identity and function. Ultimately, it seeks to provide a comprehensive conceptual basis for understanding skeletal development and regeneration.

Cell therapy remains an attractive therapeutic option for the numerous genetic and non-genetic maladies affecting skeletal muscle. Since skeletal muscle is the largest tissue in the body, delivery has been notoriously challenging, but there have been significant advances, with several ongoing clinical trials of allogeneic and autologous cell transplantation aiming to replace diseased skeletal muscle with healthy and functional myofibers and muscle stem cells. Paracrine cellular approaches intended to enhance regeneration are also ongoing. In this review, we will provide an overview of the progress and current status of these different approaches, and discuss the forecast for future phases as well as the hurdles that need to be circumvented for the widespread application of cell therapy for skeletal muscle disorders.

Sarcomas and carcinomas represent approximately 1% and 80% of all cancer diagnoses, respectively. Despite their very different prevalence, both tumor types share a critical dependence on mitochondrial functions for metabolic adaptation, survival and progression. Mitochondria act as cellular powerhouses by generating ATP through oxidative phosphorylation; however, their roles extend far beyond energy production. These organelles are central hubs of biosynthetic and catabolic pathways, including the tricarboxylic acid cycle, glutaminolysis, lipid metabolism, branched-chain amino acid catabolism and gluconeogenesis. Moreover, they play a key role in regulating various forms of programmed cell death, such as apoptosis, necroptosis, ferroptosis and pyroptosis. In this review, we provide a comprehensive overview on the contribution of mitochondria to tumor cell metabolism specifically in sarcomas and carcinomas. We describe how mitochondrial DNA-encoded proteins influence tumorigenesis and how mitochondria support cancer stem cell maintenance. We also discuss the therapeutic potential of targeting mitochondrial pathways, highlighting clinical trials and emerging strategies. The available evidence suggests that sarcoma cells might be more responsive to mitochondrial-targeted therapies due to their higher mitochondrial content and activity compared with carcinomas. Lastly, we bring some evidence of the involvement of mitochondria in the tumor microenvironment and discuss the implication of this finding for cancer immunotherapy. Altogether, these insights emphasize the importance of mitochondria as central regulators of cancer cell fate and promising therapeutic targets.

By virtue of their intrinsic immunomodulatory properties, mesenchymal stromal cells (MSCs) represent a promising therapeutic tool for immune-related disorders. Research findings support that MSCs are involved in complex inflammatory pathologies by interacting with local immune cells. In addition to their immunomodulation ability, MSCs also contribute to cell-mediated tissue regeneration due to their potential for multilineage differentiation. However, despite their accessibility, clinical translation of MSCs faces challenges, including their inherent heterogeneity, transient therapeutic effects, and microenvironment-dependent functionality. This review provides an overview of current advances in MSC-based therapies for immune-related disorders, emphasizing Phase III and IV clinical trials and therapies approved by global regulatory agencies. Additionally, we highlight innovative engineering strategies designed to address the limitations of MSCs while enhancing their immunomodulatory capabilities. These approaches include: (1) cell pre-treatment and genetic modification to improve therapeutic efficacy; (2) biomaterial-mediated delivery systems for targeted sites; (3) MSC-derived extracellular vesicle (EV)-based therapeutics to amplify paracrine signaling; (4) induced pluripotent stem cell (iPSC)-derived MSCs to overcome donor variability. By integrating these methodologies with ongoing clinical approaches, this review underscores the potential of engineered MSC immunomodulation in addressing inflammatory pathologies, bridging the gap between basic research and clinical application.

The periodontium hosts diverse populations of mesenchymal stem and progenitor cells that are essential for maintaining homeostasis and driving regeneration. These include cells derived from the periodontal ligament, gingiva, and apical papilla. In health and disease, the fate and function of these stem cell populations are shaped by their microenvironment, particularly by inflammatory signals and their resolution. Chronic inflammation, such as that observed in periodontitis, disrupts the regenerative capabilities, impairing stem cell function and biasing differentiation pathways. Inflammation resolution is an active, instructive process that can restore stem cell plasticity and re-establish regenerative potential. Specialized pro-resolving lipid mediators and immune-regulatory cell types play a central role in this reprogramming. We explore how inflammation and its resolution actively shape the behavior of multiple stem cell compartments in the periodontium, highlight the emerging role of spatially organized immunoregulation, and discuss how these insights may be leveraged to develop regenerative therapies for oral and mucosal tissues. We focused on how inflammatory and resolution signals modulate osteogenic programs in periodontal MSCs and contrast these responses with those in bone marrow-derived MSCs, highlighting source-dependent differences in inflammatory susceptibility and regenerative potential.

The impaired healing of diabetic wounds is closely associated with a persistent inflammatory response, wherein macrophages, as crucial immune effector cells in the local wound microenvironment, play a vital role in maintaining inflammatory equilibrium. Increasing evidence indicates that lactate, a product of glycolysis, is now recognized as a novel regulator of macrophage function by influencing gene transcription through protein lactylation on histone and non-histone substrates. This review seeks to outline the impact of chronic inflammation on macrophage phenotype (metabolism and polarization) and to clarify how subsequent protein lactylation alters macrophage biology, thereby impacting the progression of chronic inflammatory conditions such as diabetic wounds. These findings collectively provide new insights into the pathogenesis of impaired diabetic wound healing and underscore the potential of targeting protein lactylation as a therapeutic approach against chronic inflammation.

Decellularized extracellular matrices (dECMs) have gained increasing attention in regenerative dentistry due to their ability to replicate aspects of the native cellular microenvironment while reducing immunogenicity. Dental-derived stem cells exhibit regenerative and immunomodulatory properties, making them promising candidates for tissue repair when combined with biologically derived scaffolds such as dECMs.

Radical prostatectomy (RP) is a highly effective treatment for localized prostate cancer; unfortunately, post-prostatectomy urinary incontinence (UI) remains a prevalent and distressing complication, significantly diminishing patients' quality of life. Current therapeutic options often provide incomplete continence restoration and may lead to substantial morbidity. This review examines the rapidly advancing field of regenerative medicine, specifically focusing on stem cell and exosome-based therapies as innovative approaches to address post-RP UI. We go deeper into the unique pathophysiology of male post-prostatectomy UI, distinguishing it from other forms of UI, and present the compelling biological rationale for these regenerative interventions. Highlighting advancements from 2014 to 2025, we explore recent preclinical and clinical progress in this domain. Furthermore, we critically assess the persistent challenges crucial for widespread clinical application, including optimizing cell dose and source, ensuring long-term efficacy and safety, and interpreting complex regulatory environments. By bridging the understanding of sex-related differences between females and males in UI and tackling the specific challenges of male post-RP incontinence, this review emphasizes that while promising, the journey from laboratory bench to bedside for these innovative therapies demands rigorous scientific inquiry and collaborative efforts.