Chimeric antigen receptor (CAR) T cells have demonstrated remarkable ability to render multiple relapsed and refractory patients into a deep and often durable remission. Since initial FDA approval of tisagenlecleucel in 2017, real-world data have shown the benefit of this therapy, even among historically complex populations, such as infants, children with Down syndrome, and those with extramedullary leukemia. Despite the success of CAR T cell therapy, nearly half of patients tend to show relapsed disease, demanding ongoing advancements. Furthermore, the incorporation of the bispecific T cell engager, blinatumomab, into B cell acute lymphoblastic leukemia (B-ALL) therapy has fundamentally shifted the treatment paradigm, calling for a reevaluation of the optimal application of CAR T cells. In this review, we describe the current usage of CAR T cells in children, adolescents, and young adults (CAYAs) with B-ALL and discuss anticipated changes to CAR T cell therapy and post-infusion management. Upfront use of blinatumomab will require novel approaches to relapsed disease, including the use of CAR T cells earlier in therapy. Limited durability of the currently approved CAR T cells will require novel constructs along with improved toxicity mitigation and refinements in post-CAR disease surveillance and therapy. While CAR T cells have made an incredible impact on the field, there is much work due to improve outcomes for CAYAs with B-ALL.

Cancer stem cells (CSCs) are a self-renewing population often linked to tumor initiation, metastasis, relapse, and resistance to therapy. While bulk tumor cells are often dependent on glycolysis, CSCs demonstrate metabolic plasticity can switch between glycolysis and OXPHOS (oxidative phosphorylation) depending on context. Mitochondria buffer against stress and allow for a metabolic reprogramming towards apoptosis evasiveness, making mitochondrial function crucial to CSC survival. The acquisition of stem-like traits coincides with the rewiring of mitochondrial metabolism, as newly emerging CSCs intermittently upregulate respiration, ROS detoxification, and metabolic plasticity to satisfy cellular demands. Several regulators converge on this mitochondrial metabolism axis. For instance, the co-activator peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) and partner estrogen-related receptor α (ERRα) promote mitochondria biogenesis and OXPHOS while promoting tumor sphere formation and expression of stemness genes. Conversely, knockdown of PGC-1α reduces sphere formation and stemness. Similarly, a crucial process - mitophagy via AMP-activated protein kinase (AMPK) and related kinases regulate organelle turnover and quality control to promote CSC viability against stress. Mitochondrial dynamics (fission/fusion) also decides the fate of CSCs. The CSC metabolism is further influenced by the tumor microenvironment (TME). Hypoxia-inducible transcription factors, along with tumor stromal signals such as CAF-derived metabolites induce metabolic rewiring and strengthen antioxidant defenses in CSCs, thereby making it easier for CSCs to survive in unfavourable niches. The abundance of mitochondrial DNA and basal respiratory activity has been linked to CSC features such as increased ATP, stem cell markers and chemoresistance. Over the past few years, significant progress has been made in targeting mitochondrial metabolism of CSCs, yet is still a developing area with tremendous therapeutic scope. More research is required to identify mitochondrial vulnerabilities that are specific to therapy and then translate those findings into effective, precision-based cancer treatments. In this review, we try to provide a comprehensive overview of mitochondrial metabolism in regulating behaviour of CSCs, origin and characteristics of CSCs, the metabolic reprogramming for OXPHOS and glycolytic flexibility, molecular regulators of mitochondrial function, mitochondrial dynamics in stemness pathways and how the TME regulates these processes. We also review novel diagnostic techniques and therapies that target mitochondrial vulnerabilities to eliminate CSCs and provide better clinical outcomes.

Nanozymes are a class of nanomaterial-based catalysts with enzyme-like functionalities. They exhibit excellent physicochemical properties and stable catalytic activity in both in vivo and in vitro environments, demonstrating immense potential for biomedical applications. Autoimmune diseases arise from the immune system's erroneous attack on self-tissues or cells, affecting individuals across all age groups. Current therapies primarily rely on immunosuppressive drugs, which may control disease progression or alleviate symptoms but often fail to achieve a cure. Long-term use of these drugs is associated with significant side effects, imposing substantial health burdens on patients. Oxidative stress, driven by excessive reactive oxygen species (ROS) production or dysfunctional antioxidant defense systems, is a key mechanism underlying many autoimmune diseases. Excessive ROS accumulation exacerbates cellular damage and inflammatory responses, accelerating disease progression. Nanozymes, with their enzyme-mimicking catalytic capabilities, are ideal tools for modulating ROS levels, offering promising applications in the prevention and treatment of autoimmune diseases. Furthermore, by regulating the ROS microenvironment, nanozymes may enhance the proliferation, differentiation, and regenerative capacity of stem cells, further amplifying their therapeutic potential. This review comprehensively explores recent advancements in nanozymes for biomedical applications, focusing on their roles in oxidative stress modulation and mesenchymal stem cell (MSC)-based therapies. It aims to provide innovative insights and solutions for future clinical strategies.

Inhalation-induced lung injury, caused by harmful factors like chemical fumes and dust, leads to acute and chronic inflammation and fibrosis. Traditional treatments, such as mechanical ventilation and anti-inflammatory drugs, can relieve symptoms but fail to promote tissue regeneration. Stem cells and their extracellular vesicles (EVs) offer new treatment possibilities due to their anti-inflammatory and regenerative properties. However, the specific pathological environment of these lung injuries limits the effectiveness and targeting of EVs, challenging their clinical use. This review outlines stem cell EVs' mechanisms in treating inhalation-induced lung injury, examines recent engineering advancements, and addresses challenges in moving from research to clinical application. It highlights the importance of interdisciplinary collaboration in carrier design, production, and regulation, offering a theoretical foundation for developing precision EV-based treatments.

Polycystic ovary syndrome (PCOS) is a major health concern for women of reproductive age and a leading cause of infertility and metabolic dysfunction. Current treatments mainly involve lifestyle modification and pharmacological therapies, such as oral contraceptives and metformin, and may also include laparoscopic ovarian drilling (LOD), acupuncture, and probiotic interventions. Although these approaches can be effective, they often produce adverse effects and show a high relapse rate after discontinuation. This review summarizes recent advances in exosome-based therapies as emerging strategies for PCOS. Exosomes derived from adipose-derived mesenchymal stem cells, menstrual blood-derived stem cells, bone marrow mesenchymal stem cells, brown adipocytes, and human umbilical cord-derived mesenchymal stem cells have demonstrated therapeutic potential. As nanosized extracellular vesicles carrying bioactive molecules, exosomes exhibit strong targeting capacity and low immunogenicity. We discuss the mechanisms by which exosomes may ameliorate PCOS, including suppression of chronic low-grade inflammation, enhancement of mitochondrial function, inhibition of apoptosis, modulation of angiogenesis, and improvement of metabolic disturbances. However, translating these promising findings into clinical practice faces significant challenges. The main obstacles include lack of standardization, high production costs, and limited clinical data to confirm safety and efficacy. Addressing these issues could pave the way for mechanism-based, personalized exosome treatments and offer new approaches for managing PCOS.

Plant-derived exosome-like nanoparticles (PDENs) have demonstrated unique advantages in the prevention and treatment of osteoporosis and osteoarthritis in recent years. This review systematically summarizes the biological properties of PDENs, methods for their isolation and purification, molecular composition, and their mechanisms of action in bone and joint tissue repair. Current evidence indicates that PDENs can maintain bone homeostasis by promoting the proliferation and differentiation of osteoblasts, inhibiting osteoclast activity, modulating osteogenic differentiation of mesenchymal stem cells, and stimulating angiogenesis. In the context of osteoarthritis, PDENs enhance joint repair by facilitating chondrocyte regeneration, modulating inflammatory responses, and improving extracellular matrix metabolism. Despite the promising therapeutic potential of PDENs in the treatment of bone- and joint-related diseases, challenges remain regarding their precise mechanisms of action, standardization of preparation, and clinical translation. Future research should focus on elucidating the underlying mechanisms, establishing robust quality control methodologies, and conducting comprehensive preclinical evaluations to pave the way for their clinical application.

This study aimed to critically review the current evidence on the anticancer potential of the cell-derived secretome, with emphasis on mesenchymal stem/stromal cell (MSC) products, and to provide a realistic translational roadmap.

The thyroid gland is an endocrine organ responsible for production of triiodothyronine and thyroxine, essential hormones that regulate human metabolism. A wide range of conditions can impair its function, leading to potential life-threatening consequences such as myxedema coma. The standard treatment for hypothyroidism is lifelong levothyroxine supplementation, which, despite being a significant therapeutic breakthrough, has notable limitations and does not fully restore quality of life for many patients. Biomimetic thyroid gland has emerged as a promising alternative treatment strategy for patients with hypothyroidism. Most research to date has focused on generating thyroid organoids from primary thyroid cells or stem cells. However, there is growing interest in other approaches, including the use of biomaterials, bioreactors, and 3D bioprinting as potential alternatives or supplementary technologies to the organoids. While in vitro and preclinical studies have shown encouraging results, clinical application of biomimetic thyroid gland requires further studies in several key areas, including long-term functional validation, studies on large animal models, immunological compatibility and scaffold biodegradation, and absence of standardized good manufacturing practice (GMP)-compliant production protocols.

The mammary gland serves as a pivotal model for studying stem cell dynamics and breast cancer, the most prevalent malignancy worldwide. Developing a long-term organoid culture system to study the normal physiology and pathophysiology of mammary glands in vitro is of paramount importance. However, current organoid systems lack the morphological and functional fidelity required to model its complex physiology. Here we present a detailed Protocol to establish a long-term, dynamic three-dimensional culture system for mouse mammary organoids, which we call 'mini-glands', that recapitulates in vivo morphogenesis and functional cycles. This method uses basal stem cells to generate organoids through sequential phases: sphere formation, polarity induction, symmetry breaking, branching morphogenesis and pseudoestrous cycle simulation. The resulting 'mini-glands' replicate the natural gland's branched architecture and undergo developmental stages mimicking puberty, pregnancy, lactation and involution. Furthermore, the system enables lineage tracing of cell fate transitions and oncogenic transformation studies via genetic manipulation. By bridging the gap between in vitro models and in vivo complexity, this platform advances studies in mammary gland biology, breast cancer initiation and therapeutic screening. The Protocol can be readily performed by researchers with basic experience in mammalian cell culture and requires no specialized instrumentation. A full culture cycle typically takes ~2 weeks to produce mature, highly branched 'mini-glands'.

The placenta is an essential organ that supports fetal development during pregnancy. The establishment of human trophoblast stem cells has enhanced our understanding of placental development; however, their limited diversity constrains our ability to capture interindividual variation. Patient-specific trophoblast stem cells (pTSCs), derived from induced pluripotent stem cells, fibroblasts, cytotrophoblasts, or chorionic villus tissue, retain the unique genetic and epigenetic backgrounds of individual patients. Notably, chorionic villus-derived trophoblast stem cells can be obtained without terminating a pregnancy, allowing for integration with prospective clinical data. pTSCs, therefore, provide powerful platforms to investigate the pathogenesis of placental disorders, assess individual risk, and advance personalized therapeutic strategies. This review highlights recent advances in pTSC derivation and discusses their potential applications.

To optimize nutrient absorption and protect against physical, chemical, and microbial threats, the small intestine undergoes extensive remodeling during embryogenesis and postnatal development to establish peristalsis, expand absorptive surface area, and modulate epithelial turnover. Each developmental stage demands precise spatiotemporal regulation of cell fate specification and positioning while simultaneously coordinating cell shape changes to drive organogenesis. This chapter examines mammalian small intestinal morphogenesis from late embryogenesis through postnatal maturation, highlighting the interplay between epithelial-mesenchymal signaling, intrinsic actomyosin dynamics, and external mechanical forces in gut tube elongation, smooth muscle patterning, villus morphogenesis, and crypt formation. Once the crypt-villus axis is established, epithelial cells employ dynamic extracellular matrix interactions and cytoskeletal reorganization to migrate toward the villus tip, where they are extruded to maintain high turnover. Insights from animal models and in vitro organoid systems reveal how tissue architecture not only emerges from but reinforces epithelial maturation and functional specialization.

Adult stem cells maintain homeostatic tissue turnover or remain quiescent until tissue injury in a manner dependent on signaling cues from their niche. How stem cells physically interact with niche cells, and whether stem cells possess morphologies that optimize niche recognition and signal reception, is understudied. Here, we discuss several different adult stem cell types in Drosophila and mice that display distinctive morphologies, notably several types of cellular protrusions. Such protrusions function in multiple ways, including: (1) ensuring that the signaling range of ligands secreted by niche cells is restricted only to the stem cell; (2) allowing stem cells to interact simultaneously with multiple, spatially separated, niche cell types; and (3) acting as dynamic sensors of the niche. The in vivo morphology of many adult stem cell types is not well established, and it is likely that cellular protrusions are employed as a means of niche interaction by a variety of such stem cells.

Asymmetric cell division is an evolutionarily conserved mechanism to create cellular diversity. Stem cells utilize this division mode to recreate the stem cell while forming differentiating sibling cells at the same time. Fly neural stem cells, also called neuroblasts, are an ideal system to investigate the mechanisms and functions of asymmetric cell division under physiological conditions. Neuroblasts are intrinsically polarized, containing a molecularly defined apical and basal cell cortex. The proteins associated with the basal cell membrane segregate into a smaller, differentiating ganglion mother cell, which turns off neural stem cell genes and induces differentiation genes. The precise spatiotemporal regulation of the actomyosin and microtubule cytoskeleton are instrumental in neuroblast polarization, spindle orientation and division orientation, cell size asymmetry, and cell fate segregation. This chapter will provide an overview of cytoskeletal dynamics and the underlying regulatory mechanisms during neural stem cell divisions in the developing Drosophila nervous system.

Injuries and degenerative diseases of the human nervous system result in irreversible functional loss, reflecting the limited regenerative capacity of the central nervous system and the slow repair rate of the peripheral nervous system. Progress has been hindered by the lack of human-relevant experimental models that accurately capture the cellular diversity, long axonal architecture, and species-specific regulatory mechanisms underlying neural injury and repair. Human induced pluripotent stem cells (iPSCs) have emerged as a transformative platform to bridge this gap, enabling the generation of diverse neuronal and glial subtypes, reconstruction of complex neural circuits, and modeling of injury and regeneration in a human-specific context. In this review, we discuss the recent advances in the use of human iPSC-derived systems to study neural repair, spanning two-dimensional cultures, three-dimensional organoids and assembloids, microengineered axon injury platforms, and in vivo transplantation models. We highlight how these approaches have revealed key intracellular regulators of neurite growth, clarified the impact of disease-associated mutations on axonal integrity, and enabled high-throughput screening of neuroprotective and pro-regenerative compounds. We further discuss the role of iPSC-derived glial cells, Schwann cells, and neuromuscular junction models in elucidating axon-glia interactions, remyelination, and circuit-level repair mechanisms. Together, human iPSC-based models offer unprecedented insight into the cellular and molecular determinants of human neural regeneration, thereby overcoming the limitations of animal systems. While challenges remain in standardization, maturation, and clinical translation, these platforms are redefining regenerative neuroscience and hold promise for the development of patient-specific therapies aimed at restoring function after nervous system injury.

Vitiligo is an autoimmune depigmenting disorder characterized by selective melanocyte loss and a chronic relapsing course. Increasing evidence supports a network model in which immune activation, cellular stress responses, and microenvironmental imbalance converge to drive disease activity and repigmentation stability. Interferon-γ-driven JAK/STAT signaling induces chemokines such as CXCL10 and promotes CXCR3-dependent recruitment of cytotoxic T cells, reinforcing melanocyte-directed inflammation. In parallel, impaired Nrf2-mediated antioxidant defenses and enhanced lipid peroxidation lower melanocyte resilience and may predispose to ferroptosis, highlighting regulatory nodes including SLC3A2, SIRT7, and GPX4 as potential stress-adaptation regulators. Persistence and recurrence are increasingly linked to IL-15-supported tissue-resident memory T (TRM) cells and inflammatory microenvironments that can suppress hair follicle melanocyte stem cell function, thereby destabilizing repigmentation. Therapeutically, topical and systemic JAK inhibitors have demonstrated clinically meaningful repigmentation benefits, while emerging strategies targeting immune memory (e.g., IL-15/TRM pathways) and restoring the repigmentation niche-through Wnt/β-catenin, AhR-related pathways, and antioxidant/anti-ferroptosis programs-may improve durability and reduce relapse. Future progress will require biomarker-guided stratification and well-designed randomized trials to define temporal combination regimens that block dominant inflammatory hubs during active disease and reinforce melanocyte resilience during maintenance.

Mesenchymal stem cells (MSCs) have been proposed as treatments for degenerative diseases, but clinical outcomes have been inconsistent. Here, we reviewed the ClinicalTrials.gov database and identified ~1,600 trials associated with MSC-based therapies; osteoarthritis (OA) and spinal cord injury (SCI) were most frequently investigated, but the reporting of results was consistently low (<7%). We next searched the PubMed database and identified 26 OA and 16 SCI published trials, which included studies from one or both databases. Our analysis identified a common set of factors that influenced therapeutic efficacy in both diseases, including MSC source, donor type, dose/route & frequency of administration, and patient variation. Of these, three factors were significant for improving efficacy. MSC quality is affected by age of the donor, and this is especially important when treating older OA patients with autologous MSCs. Phase of the disease is important, and both OA and SCI may benefit from early treatment, since MSCs can ameliorate inflammation and initiate tissue repair. MSC source is critical as allogenic MSCs are no longer considered "immune privileged", and autologous cells can differentiate and repair damaged tissue without immune interference. The results of this narrative literature review suggest that establishing a personal autologous MSC bank may be an essential component for achieving success with MSC-based therapies, since MSCs from this repository could be deployed early, ameliorate inflammation, and initiate repair of damaged tissues.

The availability of identification markers is a major expectation in the field of stem and progenitor cell biology, whether to decipher the hierarchy of these cellular compartments or to isolate these cells for use in tissue reconstruction and regeneration approaches. Epithelial hair follicle stem cells (HFSCs) constitute a well-established model of multipotent tissue stem cells. Knowledge of relevant HFSC phenotypes is crucial for their identification and manipulation for therapeutics, including hair regeneration in patients with alopecia and skin engineering after injury. In this review, we provide a detailed review of murine and human HFSC markers, drawing upon traditional studies that identify classic HFSC markers and highlighting single-cell RNA-sequencing studies that have greatly expanded our knowledge of HFSCs. Recently defined HFSC subsets with distinct marker expression, microRNAs that qualify as cycle-specific HFSC markers, and HFSC marker changes with aging are all discussed.

The meniscus is a fibrocartilaginous tissue essential for load distribution, shock absorption, and knee joint stability, yet its intrinsic healing potential is limited, particularly in the avascular inner zone. Conventional treatments such as partial meniscectomy, repair, or transplantation often fail to restore long-term biomechanical and biological function, underscoring the need for regenerative strategies. Meniscus tissue engineering (TE) has emerged as a promising approach that combines biomaterial scaffolds with stem cells to recreate the structural and functional complexity of the native tissue. This narrative review summarizes recent advances in scaffold design and cell-based therapies for meniscus repair. Natural materials such as collagen, alginate, and silk fibroin provide biocompatibility and bioactivity but lack sufficient mechanical strength, whereas synthetic polymers including PGA, PLA, PLGA, and polyurethane offer tunable degradation and structural reinforcement but are biologically inert. Composite scaffolds that integrate these material classes-through multiphase, gradient, or layered designs-represent a promising strategy to replicate zonal heterogeneity and anisotropic mechanics. On the cellular side, bone marrow-, adipose-, and synovium-derived mesenchymal stem cells have demonstrated potential for zone-specific regeneration, while induced pluripotent stem cells present opportunities for patient-specific therapies but remain limited by safety concerns. Advances in cell seeding strategies, including dynamic perfusion and 3D bioprinting, have further improved scaffold-cell integration. Finally, emerging technologies such as 3D/4D printing, smart responsive biomaterials, controlled drug delivery, dynamic bioreactors, and AI-assisted scaffold design provide new opportunities to overcome persistent challenges of vascularization, mechanical anisotropy, and clinical translation. While significant obstacles remain, the convergence of materials science, stem cell biology, advanced fabrication, and computational modeling offers a promising roadmap toward clinically viable meniscus regeneration.

Over the past decade, organoid research has made transformative advances, emerging as a powerful platform to address key limitations of traditional biomedical models. Although animal systems remain indispensable for studying disease mechanisms, their limited ability to accurately recapitulate human-specific physiology and pathophysiology has contributed to the high failure rate of drug candidates during clinical translation. The emergence of three-dimensional (3D) organoid systems, such as brain and cardiac organoids derived from stem cells, represents a major technological breakthrough. These self-organizing multicellular constructs closely mimic key architectural, cellular, and functional features of native human tissues, enabling more physiologically relevant modeling of complex neurological and cardiovascular disorders. Beyond fundamental biological investigations, brain and cardiac organoids have demonstrated substantial utility in drug screening, toxicity assessment, and precision medicine approaches, including patient-specific disease modeling and therapeutic response prediction. This review highlights recent progress in brain and cardiac organoid technologies, discusses their applications in translational and regenerative medicine, and evaluates their current limitations and future directions in disease modeling and drug discovery.