Growing evidence implicates early metabolic dysfunctions in retinal ganglion cells (RGCs) as a contributor to both high- and normal-tension glaucoma, yet no approved therapy directly protects RGCs to preserve vision. We aimed at identifying a safe, druggable neuroprotective strategy that restores RGC metabolic homeostasis for glaucoma therapy.

Successful autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (NDMM) patients relies on the efficient mobilization of hematopoietic stem cells following induction therapy. While the efficacy of etoposide for stem cell mobilization has been demonstrated in numerous studies, a randomized comparison of the efficacy of cyclophosphamide versus etoposide has previously been lacking. This randomized, open-label, multicenter trial enrolled NDMM patients eligible for ASCT. The inclusion criteria were patients with a diagnosis of NDMM who required stem cell mobilization prior to ASCT. Patients were randomly assigned to receive either high-dose etoposide (VP16; 1.2 g/m2) or high-dose cyclophosphamide (CTX; 3.0 g/m2) before mobilization. Granulocyte colony-stimulating factor (G-CSF) was administered after chemotherapy to promote stem cell mobilization. The primary endpoint was the proportion of patients achieving CD34 + cell counts ≥ 2 × 10⁶/kg and ≥ 5 × 10⁶/kg. A total of 62 patients were enrolled, with 31 patients in each group. The VP16 group significantly outperformed the CTX group in CD34 + cell collection across all thresholds: ≥2 × 10⁶/kg (100% vs. 77%, p = 0.011), ≥ 5 × 10⁶/kg (90% vs. 55%, p = 0.002), and ≥ 8 × 10⁶/kg (71% vs. 32.3%, p = 0.023). The VP16 group also showed superior success rates in the first apheresis session and achieved higher CD34 + percentages in the collection. Additionally, the VP16 group required fewer apheresis sessions, fewer platelet transfusions, and experienced less nausea during the mobilization period. High-dose etoposide (1.2 g/m2) demonstrated superior efficacy and safety compared to high-dose cyclophosphamide (3.0 g/m2) for stem cell mobilization in NDMM patients. Based on these findings, etoposide may be considered a more effective and safer option for stem cell mobilization in clinical practice.The clinical trial was registered on 24/08/2022 (clinical trial identifier NCT05517213).

In this study, we demonstrate that cytoskeletal state at the onset of directed differentiation impacts the exit of human pluripotent stem cells (hPSCs) from pluripotency and downstream lineage specification. In particular, depolymerizing F-actin with latrunculin A (latA) during the first 24 h of definitive endoderm formation facilitates efficient loss of pluripotency and alters Activin/Nodal, BMP, c-Jun, and WNT signaling dynamics. These signaling changes influence downstream patterning of the gut tube, leading to improved pancreatic progenitor identity and decreased expression of markers associated with other endodermal lineages. Continued differentiation generates islets containing a higher percentage of β cells that exhibit improved maturation, insulin secretion, and ability to reverse hyperglycemia. Furthermore, this latA treatment reduces enterochromaffin cells in the final cell population and corrects differentiations from hPSC lines that otherwise fail to consistently produce pancreatic islets, highlighting the importance of cytoskeletal signaling at the onset of directed differentiation.

Glioblastoma (GBM) is an aggressive primary brain tumor marked by a poor prognosis and limited effectiveness of current therapies, which are often accompanied by substantial recurrence rates. To address this challenge, we developed BM03, an engineered mesenchymal stem cell (MSC) line specifically designed for glioblastoma therapy. BM03 is structured to enhance migration to GBM sites and deliver targeted, multimodal gene-based therapies.

Not available.

Repairing large-scale craniomaxillofacial bone defects is hindered by a limited availability of stem-cell sources and a low osteogenic efficiency. To address these challenges, Fe3O4 nanoparticles were modified with methacrylic anhydride (MAA), which helped to introduce photopolymerizable methacryloyl groups, resulting in MAA-Fe3O4 nanoparticles that exhibit excellent magnetic properties and colloidal stability. These nanoparticles were incorporated into gelatin methacryloyl (GelMA) and covalently crosslinked to form an injectable, photocurable GelMA-Fe3O4 magnetic composite hydrogel. This hydrogel provided a three-dimensional culture microenvironment for human dental follicle stem cells (hDFSCs), and upon encapsulation, osteogenesis was significantly enhanced under a 100 mT static magnetic field (SMF). In vitro, GelMA-Fe3O4 hydrogels demonstrated increased porosity and improved mechanical properties, thereby significantly promoting hDFSCs proliferation, adhesion and spreading. Additionally, under SMF exposure, the expression of osteogenesis-related genes and proteins, including alkaline phosphatase (ALP), Runx2, Col-I and OPN, was significantly upregulated. In a rat calvarial defect model, bone mineralization centers with multi-site distribution were observed in the GelMA-Fe3O4 + SMF group as early as 4 weeks postoperatively, leading to high-quality defect repair. The limitations of traditional 'peripheral-to-center' unidirectional repair were overcome by this model of synchronous multi-site osteogenesis, maximizing bone regeneration with a minimal number of stem cells and providing an efficient, controllable tissue-engineering strategy for the clinical treatment of craniomaxillofacial bone defects.

Volumetric Muscle Loss presents a critical challenge involving the traumatic or surgical loss of over 20% of skeletal muscle mass by overwhelming the body's natural regenerative capacity. It causes functional decline of skeletal muscles leading to reduced quality of life. Current surgical interventions, such as autograft and allograft muscle transfers, often fall short of restoring full mobility frequently causing donor site morbidity and graft failure. The objective of this manuscript is to discuss the role of emerging regenerative strategies focusing on restoring muscle structure and regenerative microenvironment. Recent advances emphasize on extracellular matrix-based therapies that promote myogenesis and vascularization because of their ability to replicate the native structural as well as biochemical attributes leading to muscle fiber regeneration and innervation. Further, incorporation of growth factors like vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1), or stem cells in the scaffolds help to recapitulate the complex structure and signaling of extracellular matrix promoting accelerated healing and recovery as observed in pre-clinical trials. However, despite of positive outcomes, there are challenges like immunogenicity, issues with batch to batch reproducibility, which hinder scalability and translation. Interdisciplinary collaboration between biomaterials science, tissue engineering, and clinical research can serve as solution to resolve this critical issue and will be helpful to advance these technologies potentially shifting the approach of VML therapeutic management from palliative to curative.

Adult zebrafish exhibit full recovery following spinal cord injury. Transient expansion of stem cell-like progenitors is thought to underlie their regenerative capacity. Yet, our understanding of the identities and contributions of the crucial stem cell populations that direct spontaneous neural repair remains limited. Moreover, while most neural regeneration research is centered on promoting proliferative repair, the regulatory mechanisms that reinstate quiescence post-repair are unknown. Here, we determined the molecular identities and cellular contributions of sox2+ progenitors during spinal cord repair. Genetic lineage tracing shows zebrafish spinal progenitors, while quiescent in uninjured tissues, self-renew and differentiate into neurons and glia after injury. By single-cell sequencing, sox2 + cells are heterogeneous and biased towards neuronal or glial fates in both homeostatic and regenerating tissues. By screening for transcription factors that are differentially expressed in acute versus chronic spinal cord injury, we find the Bach1 transcription factors control transient progenitor cell activation by acting as dual activators and repressors of sox2 expression. This study elucidates the molecular diversity and contributions of sox2 expressing cells during spinal cord repair and identifies a transcriptional regulatory switch by which progenitor cells expand after injury and restore quiescence after regeneration is completed.

m6A is the predominant internal RNA modification in eukaryotic cells and is distinguished by its abundance and evolutionary conservation. This epigenetic mechanism is dynamically controlled by a coordinated system of writer, eraser, and reader proteins. This sophisticated posttranscriptional regulatory mechanism precisely controls gene expression by influencing RNA metabolism, including its stability, translation, and splicing. Recent advances have revealed the functions of m6A in female reproductive cancers, early embryonic development, and stem cell differentiation. However, its functional roles and molecular mechanisms throughout pregnancy and in related disorders remain incompletely understood, which, to some extent, limits its clinical translation. This review systematically outlines the core regulators of m6A, advanced detection technologies, and its regulatory network across the continuum of pregnancy. Given the immunological parallels between the maternal-foetal interface and the tumour microenvironment, we discuss the possible function of m6A modifications in regulating the maternal-foetal immune microenvironment. The aims of this review were to elucidate the m6A regulatory network across gestation and evaluate its potential as a source of diagnostic biomarkers and therapeutic targets for pregnancy-related pathologies.

Cancer stem cells (CSC) can sustain tumor growth and therapeutic resistance in part through their contribution to vasculogenic mimicry (VM) in ovarian cancers. Pharmacological targeting of CSC-associated transcriptional programs could represent a promising strategy to overcome recurrence and metastasis. While preclinical studies show caffeic acid phenethyl ester (CAPE), a plant-derived metabolite, can sensitize tumors to chemotherapy and radiotherapy, little is known about its anti-VM properties.

Chronic cigarette smoke (CS) disrupts epithelial homeostasis, fuels persistent inflammation, and impairs alveolar repair-hallmarks of COPD with few disease-modifying options. Extracellular vesicles (EVs) from human umbilical cord mesenchymal stem cells (hUC-MSCs) are emerging as cell-free modulators of regeneration, yet their impact on the CS-injured alveolus and alveolar type-2 (AT2) stem/progenitor programs remains unclear. We used a preclinical model of chronic CS exposure coupled with organoid-guided analyses to test whether hUC-MSC-derived EVs can restore epithelial regeneration while tempering injury-associated inflammation and remodeling. Following CS injury, animals received vehicle, hUC-MSCs, or purified hUC-MSC EVs; lungs were evaluated histologically (airway/parenchymal inflammation, emphysema-like change), by Masson's trichrome (collagen deposition), and functionally using ex vivo epithelial organoids (organoid number/size, architecture, and AT2/AT1 marker balance). Transcriptomic profiling of organoid-derived RNA mapped pathway-level changes. CS induced robust immune-cell infiltration, increased collagen, and abnormal organoid phenotypes consistent with dysregulated progenitor activity. Post-injury EV treatment reduced inflammatory infiltrates and collagen, normalized organoid number and size, and restored AT2/AT1 lineage balance toward naïve patterns. At the molecular level, EVs dampened injury-upregulated circuits (including IL-17, PI3K-AKT-mTOR, MAPK, oxidative-stress and matrix-remodeling signatures) and enriched pathways associated with epithelial homeostasis and barrier integrity. Together, these data position hUC-MSC EVs as precision modulators of the injured alveolar niche that rebalance inflammation and re-engage endogenous regenerative programs. The organoid-guided, multi-scale readouts provide mechanistic insight and a translational rationale for EV-based regenerative therapeutics in smoke-induced lung injury and, by extension, COPD.

Hard-to-soft tissue interfaces, such as bone-tendon or bone-ligament junctions, remain a challenge to treat. Low healing success rates stem from the complexities at the interface, creating an urgent need for better models to elucidate the properties that enable these junctions to withstand complex mechanical loads and to function as hubs for crosstalk among different cell populations.

Oncolytic viruses (OVs) are widely studied for their ability to lyse cancer cells and prime immune responses; however, the immune consequences triggered by OVs remain incompletely understood. Here, we discover that oncolytic VSVΔ51 treatment suppresses the T cell receptor signaling of tumor-infiltrating T cells. Mechanistically, VSVΔ51-infected cancer cells upregulate PCSK9 secretion, which triggers lysosomal degradation of major histocompatibility complex (MHC)-I in bystander cells. PCSK9 inhibition synergizes with VSVΔ51 treatment to suppress tumor growth in multiple colorectal cancer models and induce complete regression in a microsatellite-stable (MSS) tumor model. This combination fosters stem-like CD8+ T cells and establishes anti-tumor memory. Engineered VSVΔ51 expressing anti-PCSK9 single-chain variable fragments improves intra-tumor viral replication, sustains anti-tumor CD8+ T cell memory, and enhances anti-PD-1 therapy efficacy. Our results identify the role of PCSK9 in the immunosuppressive feedback following viral infection and propose a strategy for engineered oncolytic virotherapy.

Orofacial and limb muscles differ in embryonic origin and regenerative capacity. Neuromuscular junction (NMJ) regeneration is critical for muscle restoration both histologically and functionally. The relative potential of orofacial and limb muscles to form postsynaptic apparatuses remains elusive. While the role of fibro-adipogenic progenitors (FAPs) in NMJ regeneration has been discussed in limb muscles, it remains unexplored in orofacial muscles.

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by loss of fragile X messenger ribonucleoprotein (FMRP). In most cases, this results from a CGG expansion exceeding 200 repeats in the 5' untranslated region of the fragile X messenger ribonucleoprotein 1 (FMR1) gene, known as the "full mutation". While the trinucleotide expansion has long been thought to induce epigenetic silencing of this locus, studies have shown that many males with a full mutation still express FMR1 mRNA. However, these individuals produce little to no FMRP protein, due to mechanisms that remain unclear. Mis-splicing of FMR1 transcripts with an expanded CGG tract has recently been proposed as a potential mechanism underlying the absence of FMRP in FXS tissues despite the presence of gene transcripts.

The Jiangquan black pigs, a new breed of swine obtained by introducing traits from Duroc pigs into Yimeng black pigs, exhibits fast growth rates and high meat quality. To understand how daily weight gain influences muscle development in this breed, we analyzed longissimus dorsi muscle cell subpopulations from Jiangquan black pigs using snRNA and bulk RNA sequencing. Thirteen distinct cell types (e.g., muscle stem cells, satellite cells, fibroblasts) were identified, and marker genes (PAX7, MYOD, MYOG) were found to exhibit stage-specific expression during differentiation. Pseudotime analysis revealed the differentiation trajectories of these cell populations, while cell cycle analysis uncovered the higher mitotic activity in satellite cells of the fast-growth versus slow-growth groups. Furthermore, cell communication analysis highlighted the interactions between muscle cells and other cell types. Finally, intergroup analysis revealed that 2,466 and 2,597 genes were differentially expressed in muscle stem cells and muscle satellite cells, respectively. These genes were enriched in disease-related pathways. This study provides a single-cell resolution atlas of porcine muscle development, offering insights into the genetic regulation of growth and potential targets for breeding optimization.