Stem cell-derived insulin-producing cells (Ins-PCs) hold great promise for diabetes treatment. Placenta-derived multipotent stem cells (PMSCs) are considered an ideal source of Ins-PC generation due to their immunomodulatory and differentiation properties. However, the cellular and molecular pathways underlying PMSC differentiation to Ins-PCs have not been fully elucidated. In this study, PMSCs were isolated from human placenta and successfully differentiated into Ins-PCs using miRNA-181a mimics. Differentiated Ins-PCs produced a significant amount of insulin and upregulation of C-peptide, insulin, and MAFA expression, compared to undifferentiated control PMSCs. RNA sequencing and LC-MS/MS were performed to uncover the pathways involved in the Ins-PC differentiation process. RNA sequencing revealed the transcriptional landscape of PMSC-derived Ins-PC differentiation. Pathway analysis identified important pathways involved in the differentiation process, including Notch and Wnt/ß-catenin, and so forth. Proteomics analysis further affirmed the presence of key insulin pathway-related proteins involved in the differentiation of PMSCs into Ins-PCs, including LEPR, STC2, MAP2K2, and so forth. Moreover, integrated transcriptomic and proteomic analyses further highlighted LEPR as a potential key regulator for Ins-PC differentiation. These findings demonstrated the feasibility of generating Ins-PCs from PMSCs and identified potential signaling pathways and regulators underlying Ins-PC differentiation, supporting PMSCs as a promising stem cell source of cell-based therapy for diabetes treatment.

Steroid-refractory acute graft-versus-host disease (SR-aGVHD), a severe complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) lacking standard second-line therapy, was studied in a retrospective analysis of 95 patients (2019-2024) at Third Hospital of Shanxi Medical University. We compared umbilical cord mesenchymal stem cells (UC-MSCs) plus standard care (n = 44) vs. standard care alone (n = 51). UC-MSCs were infused intravenously at 1-3 × 106 cells/kg with three infusions per patient. The MSC group had higher complete response (CR) rates than non-MSC group: 84.1% vs. 58.8% for grade II-IV SR-aGVHD (p = 0.007) and 54.5% vs. 31.4% for grade III-IV SR-aGVHD (p = 0.034) at week 4. Liver and gut CR rates improved by 31.8% and 28.1%, respectively. Multivariate analysis identified age ≥35 years, grade IV aGVHD, and hemoglobin ≤90 g/L as independent adverse prognostic factors. After median follow-up of 27 months, overall survival (OS) did not differ (HR = 1.04, p = 0.911). UC-MSCs improve early SR-aGVHD remission; prognostic factors enable risk stratification.

Cytokines mediating epithelial and immune cell interactions modulate mucosal healing-a process that goes awry with chronic inflammation as in inflammatory bowel disease. TNFSF13 is a cytokine important for B cell maturation and function, but roles for epithelial TNFSF13 and putative contribution to inflammatory bowel disease are poorly understood. We evaluated functional consequences of a novel monoallelic TNFSF13 variant using biopsies, tissue-derived colonoids and induced pluripotent stem cell (iPSC)-derived colon organoids. TNFSF13 variant colonoids exhibited a >50% reduction in secreted TNFSF13, increased epithelial proliferation, and reduced apoptosis, which was confirmed in iPSC-derived colon organoids. Single cell RNA-sequencing and flow cytometry suggested FAS as the predominant colonic epithelial receptor for TNFSF13, which was confirmed by co-immunoprecipitation and binding assays. Imaging mass cytometry revealed an increase in epithelial-associated B cells in TNFSF13 variant colon tissue sections. Finally, TNFSF13 variant colonoids co-cultured with memory B cells demonstrated a reduction in immunoglobulin-producing plasma cells compared to control colonoid cocultures. Our findings support a role for epithelial TNFSF13 as a regulator of colonic epithelial growth and epithelial crosstalk with B cells.

Cellular senescence in osteogenic mesenchymal cells contributes to age-related bone loss. The bone marrow hosts myeloid cells, the precursors of immune cells, as well as mesenchymal cells, which give rise to osteoblasts and osteocytes. The senotype and senolytic response of bone marrow cells, particularly hematopoietic cells, in age-related bone loss is unclear. In this issue, Doolittle et al. showed that of all immune cells, myeloid cells had the strongest senescence profile, yet the relative level of senescence remained lower than that of mesenchymal stromal cells. Mesenchymal cells displayed a profound senotype, rendering them susceptible to senolytic clearance protecting against bone loss. By contrast, selective clearance of p16+ myeloid cells was not long-lasting and, hence, did not fully protect against age-related bone loss. These findings underscore the challenges of developing senolytic strategies for tissues with mixed senotypes, such as bone.

Cellular senescence plays a critical role in the pathogenesis and progression of osteoarthritis (OA), contributing to articular cartilage degradation, chronic inflammation, and joint function impairment. Mesenchymal stem cells/stromal cells (MSCs) and their derivatives have emerged as potential targets for novel therapeutic strategies against cell senescence in OA, as they exert anti-aging effects in repairing damaged cartilage through multiple mechanisms-including regulating age-related signaling pathways, reducing the secretion of pro-inflammatory cytokines, and improving mitochondrial function.

Telocytes (TCs) have recently emerged as novel components of the skeletal muscle interstitium. They are distinguished from other stromal cells by their immunophenotypic profiles and, especially, unique ultrastructural traits. Specifically, TCs feature a small cell body and very long, thin telopodes with a moniliform appearance conferred by the alternation of slender segments (podomers) and small dilated portions (podoms). Experimental evidence suggests that, as part of the skeletal muscle stem cell niche, TCs may be involved in orchestrating satellite cell activation and myogenic differentiation through both direct physical interactions and paracrine signaling. Yet, further in-depth research is needed to uncover specific immunophenotypic signatures for skeletal muscle TCs within the niche, as well as to identify the signaling pathways by which they influence neighboring satellite cells and, possibly, other cellular components of the niche. In the present review, particular emphasis is placed on the putative strategic role of TCs in maintaining skeletal muscle tissue homeostasis, their involvement in muscle pathological alterations, and, most importantly, their possible role in the coordination of the regenerative response following injury. In perspective, the promising therapeutic potential of TC-based strategies to enhance skeletal muscle tissue repair/regeneration and restrain post-injury fibrosis is also discussed.

β-thalassemia is an inherited blood disorder characterized by chronic anemia, ineffective erythropoiesis, and in its most severe form, lifelong transfusion dependence. The standard of care for transfusion-dependent thalassemia (TDT) is regular red blood cell transfusions to relieve the anemia and suppress ineffective erythropoiesis and iron chelation therapy to mitigate morbidity and mortality related to iron overload. Allogeneic hematopoietic stem cell transplantation is a curative option but is only available to patients with an appropriate donor and carries risks of graft-versus-host disease and other transplant-related morbidity. In recent years, the therapeutic landscape for TDT has changed dramatically with the approval of two autologous gene therapies in the United States: betibeglogene autotemcel (beti-cel) and exagamglogene autotemcel (exa-cel). Clinical trials for both gene therapies have demonstrated high rates of sustained transfusion independence for both pediatric and adult age groups. However, despite these advances, challenges remain. Gene therapy requires myeloablative busulfan-based conditioning chemotherapy, which carries the risk of short- and long-term toxicities. Furthermore, centralized manufacturing and high treatment costs are likely to limit access to gene therapy. In this review, we discuss the available clinical trial and real-world data for beti-cel and exa-cel. We describe how gene therapy fits into the current treatment landscape and introduce areas of ongoing investigation to improve access to transformative therapy for TDT.

Myocardial infarction (MI), a lethal coronary artery disease primarily triggered by atherothrombosis or an imbalance in myocardial oxygen supply and demand, stands as a leading cause of mortality worldwide. Promoting angiogenesis is recognized as an effective therapeutic strategy for MI, a process highly dependent on the functional status of endothelial cells (ECs). Small extracellular vesicles (sEVs), which are membrane-bound vesicles secreted by cells and enriched with bioactive molecules including proteins, lipids, and RNAs, are ubiquitously present in the secretome of diverse cell types such as stem cells, immune cells, and cardiac cells. Studies have confirmed that sEVs can deliver specific "cargo" such as miRNAs and cytokines via paracrine or endocrine pathways, activating key downstream signaling cascades. This effectively promotes EC proliferation, migration, and tube formation, thereby enhancing angiogenic capacity and ultimately mitigating pathological cardiac remodeling while improving prognosis post-MI. This review focuses on sEVs derived from various cellular sources, systematically summarizing their roles in promoting angiogenesis and the latest research advances in regulating EC function, aiming to provide novel insights for the effective treatment of MI.

The regeneration of large bone defects remains a major clinical challenge due to the lack of stable and effective osteoinductive signals. Although extracellular vesicles have shown promising potential for cell-free bone regeneration, their application is largely constrained by complex purification and embedding into scaffolds. Migrasomes, newly identified organelles with the extracellular matrix affinity, represent a promising yet underexplored avenue for cell-free tissue engineering. Here, we report a migrasome-enriched bioactive layer as a functional osteoinductive interface for cell-free bone regeneration. We demonstrated that osteoprogenitor stem cells (OPSCs) derived from human cortical bone exhibit robust osteogenic capacity and, upon osteogenic induction, promote the release and deposition of migrasomes together with calcium on culture surfaces. Utilizing these characteristics, we developed an in situ deposition strategy where OPSCs are preseeded on biphasic calcium phosphate (BCP) scaffolds, induced to mineralize, followed by decellularization. This process robustly preserves a native, osteogenic migrasome layer on the scaffold without the need for vesicle isolation or chemical conjugation. The resulting migrasome-functionalized scaffolds markedly up-regulated osteogenic gene expression and promoted bone regeneration in a murine calvarial defect model. Altogether, these findings validate migrasomes as a potent, endogenous signaling platform for bone tissue engineering. Moreover, our new paradigm for cell-free biomaterials employing cellular secretomes opens a new frontier in regenerative medicine, where the transient activity of cells is permanently captured to direct tissue repair.

Familial adenomatous polyposis (FAP) is characterized by hundreds of colorectal adenomas that inevitably progress into carcinomas. This study focused on the heterogeneity during the polyposis progression to identify new targets and signatures for therapeutic development.

[This corrects the article DOI: 10.3892/ol.2019.10992.].

Type 2 diabetes mellitus (T2DM) is a risk factor for breast cancer (BC) development and recurrence due to multifactorial mechanisms, including the generation of glycated proteins under hyperglycemic conditions. Emerging evidence indicates that hyperglycemia promotes the formation and expansion of BC stem-like cells (BCSC), contributing to worse outcomes in patients with T2DM. To support early detection and personalized therapy, there is an urgent need to identify novel biomarkers that specifically target BCSCs in patients with T2DM. The present study examined the effects of glycated albumin (GA) on the cellular functions of KAIMRC1, a naturally immortalized BCSC line derived from invasive ductal carcinoma (IDC), the primary breast carcinoma developed in patients with T2DM. Cells were subjected to in vitro assays, including soft agar colony formation, real-time monitoring of cell proliferation, motility and invasion through a reconstituted basement membrane using the xCELLigence system and western blotting. A triple-negative BC cell line was used as a comparator. Aldehyde dehydrogenase (ALDH) activity was quantified using a biochemical assay. As expected, KAIMRC1 cells exhibited high ALDH activity, a characteristic feature of cancer stem-like cells (CSCs). GA induced dose-dependent increases in KAIMRC1 cell proliferation, motility, invasion and colony formation and was associated with elevated levels of the oncoprotein phosphorylated-ERK1/2, the receptor for advanced glycation end products (RAGE) and the stemness-associated proteins OCT3/4 and vimentin. GA-treated KAIMRC1 cells showed notable invasive capacity despite slow proliferation, consistent with known metastatic potential of quiescent CSCs. Conversely, unglycated albumin had no detectable biological effects except for an anti-mitogenic response at high concentration. Bioinformatics analyses showed that vimentin mRNA was upregulated in patients with BC and DM and was associated with a poor prognosis in patients with BC. RAGE neutralization attenuated GA-induced vimentin upregulation. Altogether, these findings show that GA exerts pro-tumorigenic effects in IDC-derived CSCs and upregulates vimentin protein expression via RAGE, highlighting the GA-RAGE axis as a potential therapeutic target and supporting vimentin as a promising prognostic marker for invasive BC in patients with DM.

Tumor cells frequently develop immune resistance through interferon-γ (IFN-γ)-induced PD-L1 expression, acquisition of cancer stem cell (CSC)-like features, and adaptation to hypoxia within the tumor microenvironment (TME). Although IFN-γ activates both STAT1 and STAT3, how these pathways interact to regulate immune evasion under hypoxia remains unclear.

Cerebral organoids derived from human pluripotent stem cells recapitulate key features of early brain development and provide a physiologically relevant model for neurogenesis. Exosomes secreted by these organoids carry bioactive cargo and offer a noninvasive means to monitor maturation and intercellular communication. We performed comprehensive multiomics profiling of exosomes collected from cerebral organoids at defined developmental stages to evaluate their utility as biomarkers of neuronal differentiation. Metabolomic analysis revealed a progressive decline in amino acids, including glutamic acid, consistent with increased metabolic demand during neurogenesis. Lipidomic and neurosteroid profiling showed dynamic increases in phosphatidylethanolamine and pregnenolone, reflecting synaptic membrane formation and signaling. Transcriptomic and proteomic analyses identified stage-specific neurodevelopmental signatures, with key markers mirroring those of parent organoids. Collectively, cerebral organoid-derived exosomes faithfully reflect organoid maturation and provide a robust platform for tracking in vitro brain development.

One of the main bottlenecks in regenerative therapy is low neuronal differentiation after stem cell transplantation. Several approaches can induce neuronal differentiation, such as transcription factor manipulation, growth factors and cytokines, optogenetics, metabolic reprogramming, and Small Molecules (SMs). Each method has advantages and disadvantages; however, shortening the induction time and the maximum rate of neuronal differentiation is a high priority when selecting a method. Among all approaches, SMs can match these properties. Furthermore, SMs can target the developmental signaling pathways in neuronal maturation and generation. For example, they modulate WNT, Notch, TGF-β/SMAD, Sonic Hedgehog (Shh), FGF, Retinoic Acid, MAPK/ERK, PI3K/AKT/mTOR, cAMP/PKA, BMP, JAK/STAT, and Nrf2 pathways. These pathways are essential for regulating neuronal differentiation, and SMs serve as a powerful tool for manipulating them in both research and therapeutic contexts. Therefore, we examine recent studies on SMs and discuss the pitfalls and challenges encountered during neuronal differentiation in preclinical research. Additionally, we review relevant studies that have advanced to clinical stages. Ultimately, based on our findings, we conclude that SMs hold significant promise for inducing neurons from stem cells; however, comprehensive clinical studies are necessary to demonstrate their efficacy in stem cell therapy for neurological disorders.

Glioblastoma (GBM) is an aggressive and treatment-resistant primary brain tumor with a poor prognosis. Conventional therapies are limited by tumor heterogeneity, therapy resistance, and restricted Blood-Brain Barrier (BBB) penetration, highlighting the need for novel multi-targeted therapeutic strategies. This review assesses the therapeutic potential of curcumin analogs in GBM, with a focus on their molecular mechanisms, in silico predictions, preclinical efficacy, and potential synergistic strategies with standard treatments. A comprehensive search of published in vitro, in vivo, and computational studies on curcumin analogs was conducted. Mechanistic investigations included apoptosis induction, cell-cycle arrest, autophagy, ferroptosis, and inhibition of key oncogenic pathways such as STAT3, NF-κB, PI3K/Akt/mTOR, and EGFR. Pharmacokinetic optimization and BBB permeability were also assessed. Curcumin analogs demonstrate enhanced cytotoxicity in GBM cells, including temozolomide-resistant lines, through multi-target modulation of apoptosis, oxidative stress, oncogenic signaling, and glioma stem cell pathways. in silico docking and network pharmacology reveal strong binding to GBM-relevant targets, corroborating experimental efficacy. Preclinical studies show that analogs such as C-150, ALZ003, and DMC-BH suppress tumor growth, inhibit angiogenesis, and prolong survival in orthotopic and xenograft models. Combination with temozolomide, radiotherapy, or anti-angiogenic agents exhibits synergistic anti-tumor effects. Curcumin analogs are promising multi-targeted agents capable of overcoming GBM heterogeneity, therapy resistance, and invasiveness. Optimization of pharmacokinetics and targeted delivery, along with clinical evaluation, is necessary to translate preclinical findings into effective GBM therapies. Glioblastoma (GBM) is a highly aggressive type of brain cancer characterized by treatment resistance and a poor prognosis. The efficacy of conventional treatment approaches is limited by treatment resistance, heterogeneity, and inability to cross the Blood-Brain Barrier (BBB). Therefore, there is a need to develop new multi-targeting treatment approaches. This review aims to describe the therapeutic potential of curcumin analogs for GBM treatment, focusing on their molecular mechanisms, in silico studies, and their potential to act synergistically with conventional treatment approaches. A comprehensive literature review of published studies on curcumin analogs was conducted. Mechanistic studies of curcumin analogs included induction of apoptosis, cell cycle inhibition, induction of autophagy, and ferroptosis, as well as inhibition of key oncogenic pathways, including STAT3, NF-κB, PI3K/Akt/mTOR, and EGFR. In addition, studies aimed at improving their pharmacokinetics and permeability through the BBB were included. Evidence from various studies indicates that curcumin analogs exhibit superior cytotoxic effects against GBM cells, including temozolomide-resistant GBM cells, through multi-targeting approaches. In addition, in silico studies have demonstrated high binding affinities to key GBM-related targets. Preclinical studies have demonstrated the efficacy of curcumin analogs, including C-150, ALZ003, and DMC-BH, in inhibiting GBM growth, angiogenesis, and improving survival in orthotopic and xenograft mouse models. These compounds have demonstrated synergistic effects with temozolomide, radiotherapy, and anti-angiogenic therapy. Therefore, curcumin analogs have demonstrated significant therapeutic potential as multi-targeting agents to address heterogeneity, treatment resistance, and invasiveness of GBM. However, to realize this potential, there is a need to improve their pharmacokinetics and permeability through the BBB.

Mesenchymal stem/stromal cell (MSC) therapy holds promise as a therapeutic option in diabetes treatment. The anti-inflammatory and immunomodulatory activities are enhanced when MSCs are engineered to overexpress alpha-1 antitrypsin (AAT-MSCs). Because a single infusion of AAT-MSCs reversed new-onset diabetes in over 50% of the female nonobese diabetic (NOD) mice, we used single-cell RNA sequencing, flow cytometry, and functional analyses to characterize how AAT-MSCs modulate CD4+ and CD8+ T cells in pancreatic lymph nodes (PLNs) and islets. AAT-MSC treatment increased T regulatory cells (Tregs) and more effectively suppressed T cell proliferation when stimulated with anti-CD3/CD28 antibodies. Treated mice exhibited reduced T helper 1 (Th1) cells and CD8+ cytotoxic T cells. In vitro studies confirmed the capacity of AAT-MSCs to promote Treg expansion in both mouse and human cells, drive CD8+ T cells toward an exhausted phenotype, and enhance mouse and human islet cell survival. Cellchat analysis showed that AAT-MSC therapy strengthens intercellular communication, especially signals originating from Tregs toward other PLN and islet cell populations. These findings clarify how AAT-MSCs modulate immune response and support their potential clinical application for type 1 diabetes and other autoimmune or inflammatory conditions.

The choroid plexus (CP) in the brain ventricles secretes cerebrospinal fluid (CSF) that bathes the adjacent subventricular zone (SVZ). As the largest adult neurogenic region enriched with neural stem/progenitor cells (NSPCs), the SVZ supplies newborn neurons to the olfactory bulb (OB) for normal olfaction. This report depicts the presence of a CP-SVZ regulatory (CSR) axis, in which the CP regulates SVZ adult neurogenesis and olfaction via secretion of small extracellular vesicles (sEVs). The proposed CSR axis was supported by the evidence of (1) a direct effect of CP epithelial cells on the SVZ by in vivo transplantation and in vitro CP-SVZ co-culture assays, (2) differential OB neurogenesis following intracerebroventricular (ICV) infusion of sEVs derived from the CP of control or manganese (Mn)-poisoned mice, (3) progressively diminished SVZ adult neurogenesis after CP-selective inhibition of sEV secretion via AAV5-mediated SMPD3 knockdown, and (4) compromised olfactory performance following CP-selective SMPD3-knockdown. Collectively, our findings demonstrate the physiological, toxicological, and behavioral importance of this sEV-dependent CSR axis in the adult brain.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that significantly impacts children's physical and mental health, yet effective pharmacological treatments remain limited. The primary objective of this study was to investigate the therapeutic effects of human umbilical cord blood mesenchymal stem cells (hUC-MSCs) on ASD, evaluate the safety profile of hUC-MSCs, and elucidate their underlying mechanisms and functional roles.