Cochlear supporting cells are glia-like cells critical for development, homeostasis, and regeneration. In the neonatal mouse cochlea, inner phalangeal cells (IPhCs), a supporting cell subtype surrounding inner hair cells, are uniquely regenerated by greater epithelial ridge (GER) cells. Here, we used fate-mapping and single-cell transcriptomic analysis to show that GER cells both mitotically and non-mitotically regenerate IPhCs. Mechanisms of regeneration are spatially distinct, with non-mitotic regeneration found throughout the cochlear spiral and mitotic regeneration restricted to the apical and middle turns. By profiling the regenerating cochlea at four time points, we revealed a damage-induced loss of medial-to-lateral specialization of GER cells. Moreover, in silico analysis predicted distinct lineages and associated pathways where mitotic and non-mitotic IPhC progenitors emerge in the lateral GER. Finally, inhibiting proliferation eliminated mitotic IPhC regeneration while sparing non-mitotic regeneration in vitro. Together, our study reveals dual mechanisms and molecular targets governing supporting cell regeneration.

Osteosarcoma is the most prevalent primary bone cancer affecting children and adolescents, characterized by its high invasiveness and the challenges in treatment posed by multidrug resistance. Cancer stem cells significantly contribute to poor clinical outcomes; however, current targeted therapies remain limited in their effectiveness. In this study, we developed a novel dual-responsive nanomedicine designed to target the microenvironment of osteosarcoma cancer stem cells (OCSCs) and osteosarcoma itself, which selectively releases all-trans retinoic acid and paclitaxel, termed mPCDAP. Our findings indicate that mPCDAP rapidly releases all-trans retinoic acid to suppress stemness under conditions of elevated glutathione, subsequently increasing intracellular reactive oxygen species levels in tumor cells. This mechanism further facilitates the release of paclitaxel under conditions of highly reactive oxygen species, thereby inducing apoptosis in osteosarcoma cells. Additionally, mPCDAP was effectively internalized by both osteosarcoma cells and OCSCs, with in vitro and in vivo results demonstrating significant synergistic antitumor effects, promoting apoptosis and markedly reducing tumor stemness. This study presents a novel approach and promising prospects for targeted therapy of osteosarcoma and OCSCs.

In this study, we aimed to construct an injectable hydrogel composed of gelatin methacryloyl/hyaluronic acid (GelMA-HA) and combine it with lyophilized concentrated growth factors (CGF) and dental pulp stem cells (DPSC) to promote the process of periodontal regeneration. We confirmed that bioactive lyophilized CGF can be anchored to hydrogels by Schiff base imine bonding, thereby achieving effective sustained release of various growth factors in the inflammatory microenvironment of periodontal bone destruction. Meanwhile, this hydrogel can provide a 3D cell growth microenvironment to improve the survival rate of dental pulp stem cells. GelMA-HA-CGF-DPSCs exhibit remarkable ability to promote cell proliferation and differentiation as well as excellent biocompatibility. In vitro experiments demonstrated that this system can increase alkaline phosphatase activity, enhance osteogenic mineralization capacity, and significantly upregulate the expression of osteogenesis-related genes and proteins. In the rat alveolar bone defect model, the experimental group significantly facilitated regeneration of periodontal bone. These findings suggest that this injectable composite material has the potential to overcome the limitations of CGF applications and stem cell injections. Specifically, through the chemotactic effects of growth factors and intercellular interactions, endogenous stem cells can also attract endogenous stem cells. Serving as a scaffold structure, it creates an osteogenic microenvironment and provides a space for bone regeneration. Moreover, its injectability and fluidity can achieve minimally invasive periodontal treatment in a noninvasive manner. The findings of this study are expected to provide valuable insights and references for the clinical translational repair treatment of periodontal bone defects caused by periodontitis.

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.

Glioblastoma (GBM) is the highly lethal intracranial tumor characterized by low survival rates and high recurrence, partly attributable to the challenges posed by the blood-brain barrier (BBB). To enhance therapeutic efficacy, the Exo-U2-Dox complex was engineered by functionalizing mesenchymal stem cell (MSC)-derived exosomes with the GBM-targeting aptamer U2 and integrating them with doxorubicin (DOX). This complex is designed to augment the sensitivity of GBM to chemo-radiotherapy. Here, it is found that Exo-U2 effectively accumulates in GBM-bearing mice, thereby inhibiting tumor progression. When administered in conjunction with DOX and radiation, Exo-U2-Dox increases DNA damage in GBM cells, and diminishes invasiveness. Mechanistically, Exo-U2 targets and inhibits the autophosphorylation of Epidermal growth factor receptor variant Ⅲ (EGFRvⅢ) in GBM cells, thereby activating the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome-mediated pyroptosis pathway, which leads to increased expression of Gasdermin D (GSDMD) and Cysteine-aspartic acid protease-1 (caspase-1), ultimately suppressing GBM cell proliferation, migration, and invasion. Furthermore, the combination of Exo-U2 with X-ray treatment inhibits the expression of p53-binding protein 1 (53BP1), reduces phosphorylation of the Ataxia-Telangiectasia Mutated/Checkpoint kinase 2 (ATM/Chk2) pathway, resulting in the accumulation of DNA damage. Collectively, these findings underscore the potential of aptamer-functionalized exosomes in conjunction with DOX as a promising strategy for GBM treatment. This approach not only broadens the therapeutic applications of DOX but also provides a novel direction for targeted GBM therapies.

Treatment-resistant schizophrenia (TRS) affects 20%-30% of individuals diagnosed with schizophrenia and is effectively managed with clozapine. However, the molecular and cellular mechanisms that underlie its efficacy remain largely unclear. We previously generated induced pluripotent stem cell (iPSC) lines from a unique pair of monozygotic twins with TRS. One twin responded to clozapine (CLZ-res), while the other did not (CLZ-non-res). Building on our previous study of these twins, we included healthy controls and focused on the early developmental stages of neuronal differentiation. To investigate the phenotypic differences in the developmental stages of neural cells between patient-derived cells, we differentiated each iPSC line-from both patients and healthy individuals-into neural stem cells (NSCs) and subsequently induced the differentiation of NSCs into neurons. Our results demonstrated that NSCs derived from patients' iPSC lines exhibited impaired neuronal differentiation, with a more pronounced reduction in differentiation observed in CLZ-non-res cells than in CLZ-res cells. RNA sequencing analysis revealed significant differences in the expression of genes involved in neuronal development between CLZ-res and CLZ-non-res cells. These findings suggest that the differences in neuronal development may contribute to the variability in clozapine responsiveness. Although this study is limited to a single twin pair, this unique human model provides valuable insights into the molecular and cellular mechanisms underlying differential clozapine responses, offering a promising framework for the development of effective treatments for patients with TRS.

Juvenile systemic sclerosis (jSSc) is a rare, chronic, autoimmune disease in children/adolescents and is associated with significant morbidity, skin thickening/hardening (scleroderma), organ toxicity and sub-optimal therapeutic options. In this report, autologous stem cell transplantation is associated with clinical improvement in a 17-year-old with refractory jSSc.

Fibrinogen is a blood-derived protein involved in coagulation and can make its way into the central nervous system (CNS) following breakdown of the blood-brain barrier. This molecule has been implicated in multiple sclerosis (MS), a disease marked by inflammation and demyelination in the CNS. However, the effect of this molecule has not been studied on human myelinating cells. This study examines how fibrinogen influences human oligodendrocyte (OL) lineage cells at various stages of development. Using induced pluripotent stem cell-derived (iPSC) OL precursors and human primary OLs, we examined the effects of fibrinogen on cell differentiation, viability, and myelination-related function. Here we show the differential effect of fibrinogen, based on OL-lineage stage. While fibrinogen induced aberrant differentiation of early lineage OLs, by inhibiting their maturation and inducing an astrocytic phenotype, on mature OLs fibrinogen was found to promote myelination capacity, as shown by ensheathment assays as well as on the RNA level. These effects were associated with the activation of bone morphogenetic protein (BMP) signaling, both in early and mature OLs. We further found BMP signaling enrichment in OLs to be correlated with the inflammatory activity of an MS lesion and confirmed fibrinogen deposition on OLs in situ. Unlike previous rodent studies, these findings indicate that fibrinogen has a lineage-dependent effect, where it may be inhibitory earlier in the lineage while promoting OL function in later stages. Understanding this dual role will provide insight into remyelination failure in MS and highlights the importance of timing and target in future therapeutic strategies.

Glioblastoma (GBM) is the most prevalent primary malignant tumor of the adult central nervous system, characterized by pronounced vascularity that facilitates tumor proliferation, invasion, and progression. Although anti-angiogenic therapy has emerged as a potential treatment strategy for GBM, currently available anti-angiogenic agents, such as bevacizumab targeting VEGF, have demonstrated limited efficacy in improving patient survival. This underscores the urgent need for novel therapeutic targets and strategies. In this study, we identified that the expression of maternally expressed gene 3 (MEG3), a tumor-suppressive long non-coding RNA (lncRNA), is negatively correlated with patient prognosis. Spatial transcriptomics sequencing and RT-qPCR analyses revealed that MEG3 is highly expressed in glioma stem cells (GSCs). In vitro tube formation assays further demonstrated that MEG3 in GSCs promotes angiogenesis in human brain microvascular endothelial cells (HBMECs). Transcriptome sequencing identified VGF nerve growth factor inducible (VGF), a secreted pro-angiogenic protein, as a downstream target, and showed that MEG3 regulates the pro-angiogenic activity of GSCs by modulating VGF expression. RNA pull-down assays revealed that MEG3 binds to far upstream element-binding protein 1 (FUBP3), which also regulates VGF expression. In vivo, knockdown of MEG3 significantly extended survival in orthotopic xenograft models of GSCs. Immunohistochemical analysis of mouse tumor tissues showed a corresponding reduction in VGF levels and microvessel density following MEG3 knockdown. In conclusion, this study demonstrates that MEG3 in GSCs promotes GBM angiogenesis through a FUBP3-dependent induction of VGF expression, highlighting MEG3 as a potential therapeutic target for anti-angiogenic intervention in GBM.

Tuberculosis (TB) remains a major global public health challenge, with drug-resistant tuberculosis (DR-TB) presenting a serious threat to TB management. Conventional treatment faces challenges such as significant drug toxicity, frequent emergence of drug resistance, and compromised host immune microenvironment. These limitations, particularly in DR-TB cases, often lead to poor treatment outcomes and heightened recurrence rates, underscoring the need for complementary strategies. Cell-based host-directed therapy (HDT) emerges as a novel therapeutic strategy that may complement conventional drugs by directly modulating pathological immune responses and facilitating the repair of damaged tissue. This narrative review synthesizes preclinical and clinical data on cell therapy for TB. We focus on two distinct strategic approaches: (1) mesenchymal stem cell (MSC)-based therapies, which primarily exert immunomodulatory and tissue-repair functions, and (2) T cell-based adoptive cell therapies (ACTs), which are designed to enhance antimicrobial immunity directly. Current evidence, while promising, predominantly remains in the early exploratory stages or lacks robust evidence-based support. To facilitate successful translation, future research should focus on standardizing cell products, conducting comprehensive safety assessments and implementing more rigorous clinical trials. This review critically assesses the therapeutic potential and translational challenges of cell therapy for TB.

Circadian rhythms are endogenous, transcription-translation feedback loops that align cellular activities with the 24-h light-dark cycle. Stem-cell populations across tissues exhibit circadian oscillations that influence their self-renewal, proliferation, and differentiation. Key developmental pathways (Wnt/β-catenin, Notch, and Hedgehog) are increasingly recognized as both regulators and targets of circadian machinery.

Acute liver failure (ALF) is a life-threatening syndrome characterized by rapid deterioration of liver function, resulting in high mortality and posing a substantial global health burden. Human embryonic stem cells (hESCs) possess unlimited self-renewal capacity and pluripotent differentiation potential. Transplantation of hESC-derived hepatocyte-like cells (HPLCs) represents a promising therapeutic strategy for ALF.

Craniofacial bone regeneration remains a major clinical challenge, yet the identity of orofacial mesenchymal stem/stromal cells (OMSCs) has not been fully elucidated. Here, we performed single-cell RNA sequencing (scRNA-seq) on mouse orofacial bone and identified multiple stromal cell clusters. Cell-cell communication mapping and trajectory inference uncovered the heterogeneity of OMSCs and functional divergence among subpopulations. We identified a previously unrecognized population, Smmhc-expressing mesenchymal stem/stromal cells (MSCs), at the earliest stage of the progenitor lineage trajectory. In vivo lineage tracing demonstrated that Smmhc+ MSCs are multipotent, giving rise to osteoblasts, osteocytes, periodontal ligament (PDL) cells, and dental pulp cells. Targeted ablation of Smmhc+ MSCs using SmmhcCreER;iDTR mouse model led to impaired orofacial bone development and disrupted orofacial tissue homeostasis, characterized by reduced osteogenic differentiation and non-cell autonomous reduction of bone resorption. Collectively, this study establishes a cellular atlas of OMSCs and identifies Smmhc+ MSCs as a functionally indispensable subset for craniofacial bone homeostasis, orchestrating the dynamic balance between osteogenesis and bone resorption within the orofacial skeletal niche.

Deficiency of adenosine deaminase 2 (DADA2) causes a complex phenotype of autoinflammation and immunodeficiency. Bone marrow failure is often refractory to treatment with tumour necrosis factor-alpha (TNF-alpha) inhibitors and additional treatment options are needed. However, the pathomechanisms underlying the disease remain incompletely understood. The aim of this study was to examine the viability and metabolic profile of ADA2-deficient cells and to characterise the activity of different cell death pathways to advance the mechanistic understanding of DADA2. By flow cytometry and western blot, we showed that ADA2-/- U-937 cells and PBMCs from DADA2 patients showed significantly elevated levels of cell death compared with cells expressing wild-type ADA2. Viability of ADA2-deficient cells was not improved by inhibitors of apoptosis, necroptosis, pyroptosis and ferroptosis. Blocking of TNF-alpha, type I interferon and STING signalling as well as reintroduction of wild-type ADA2 protein did not rescue the cell death phenotype in vitro. ADA2-deficient cells had an aberrant morphology with increased cell size and granularity and were impaired in their proliferative capacity. To identify the cause of the impaired viability, we performed 13C glucose tracer metabolomics experiments which revealed disturbances in the pentose phosphate pathway of ADA2-deficient cells. This tended to be associated with increased exposure to intracellular reactive oxygen species that was attenuated in the PBMCs of a DADA2 patient measured after successful hematopoietic stem cell transplantation. Collectively, our findings established increased levels of cell death as a possible pathomechanism of DADA2 and showed that the absence of ADA2 leads to an impairment of the pentose phosphate pathway which may account for the cellular vulnerability of ADA2-deficient cells.

Systemic sclerosis (SSc) is an autoimmune disease that transitions from vasculopathy as an initiating pathogenic event to tissue fibrosis. The mechanisms of these transitions remain, however, poorly understood, mainly because complex multicellular human models of SSc vasculopathy are lacking. We aimed to develop a complex multicellular human model of SSc vasculopathy and use it to investigate the mechanisms underlying this process.

Bone marrow contains abundant free fatty acids (FFA). Abnormal accumulation of FFAs can be triggered by pathological or physiologic conditions such as hyperlipidemia, diabetes mellitus, and menopause, leading to osteoporosis. Excess FFAs impair bone homeostasis by promoting osteoclast-mediated bone resorption and inhibiting the proliferation and differentiation of osteoblasts. C-type lectin domain family 11 member A (Clec11a) is an osteogenic growth factor that can protect islet proliferation and function against lipotoxicity. However, there is a lack of research on the function of Clec11a under bone marrow lipotoxic conditions. Here, we demonstrate that Clec11a counteracts the lipotoxicity-induced osteogenic inhibition and facilitates the proliferation and differentiation of osteoblasts. Clec11a effectively reverses palmitic acid(PA)-induced suppression of osteoblast proliferation and osteogenic differentiation, alleviates oxidative stress, and maintains mitochondrial homeostasis. Mechanistically, these protective effects of Clec11a depend on the SIRT3-SOD2 signaling axis, as the SIRT3 inhibitor 3-TYP abolishes its effects in both MC3T3-E1 cells and mouse bone marrow mesenchymal stem cells. Collectively, our findings reveal that Clec11a protects osteoblasts from PA-induced damage through regulation of the SIRT3-SOD2 signaling axis, providing mechanistic insights into bone impairment under lipotoxic conditions.

Chronic diabetic ulcers present a persistent challenge due to delayed wound healing. At the wound site, oxidative stress impairs stem cell survival and differentiation, accelerates senescence, and impairs autophagy. RLIM was identified as a critical regulator in human umbilical cord mesenchymal stem cells (hUCMSCs), where oxidative stress-induced RLIM upregulation leads to MDM2 degradation and stabilization of p53. Functionally, RLIM upregulation under oxidative stress inhibited autophagy, induced cellular senescence, and significantly impaired angiogenesis, cell migration, and immunomodulatory functions, ultimately hindering diabetic wound healing in vivo. These results highlight the RLIM-MDM2-p53 signaling axis as a pivotal pathway governing stem cell senescence and function under oxidative stress, offering promising therapeutic targets to enhance stem cell-based approaches for diabetic wound repair.

The African spiny mouse (Acomys dimidiatus) is a unique mammalian model capable of scarless tissue regeneration, extending to the nervous system. Unlike conventional rodents, Acomys show significantly higher levels of adult brain stem cells, enhanced functional plasticity after brain injury, and the ability to regenerate and regain function following severe spinal cord damage. While the regenerative capacity of the Acomys central nervous system (CNS) is only beginning to be explored, existing studies have already challenged the long-standing dogma that adult mammals are incapable of CNS recovery after injury. This review provides a critical overview on the current knowledge of Acomys nervous system biology, from development to repair. We summarize the known cellular and mechanistic insights and highlight the current outstanding questions and research priorities. Understanding how Acomys achieves CNS functional recovery, an ability unmatched by any other known mammal, may ultimately guide strategies to enhance repair in nonregenerative mammals, including humans.