Heart failure (HF), the terminal stage of most cardiovascular diseases, remains a major global health burden with limited therapeutic options that do not fully achieve myocardial repair or functional recovery. Extracellular vesicles (EVs), nanoscale membrane-bound particles released by cells, have been increasingly recognized as important mediators in the pathophysiology of HF and as potential therapeutic targets. As intercellular messengers carrying bioactive molecules, including proteins, lipids, and non-coding RNAs, EVs regulate gene expression and functional states in recipient cells. This review summarizes current evidence on the roles of EVs in key pathological processes of HF, including inflammation, mitochondrial dysfunction, myocardial hypertrophy, fibrosis, apoptosis, and angiogenesis. We also discuss their potential as circulating biomarkers for the diagnosis and prognosis of HF. In addition, we describe emerging therapeutic strategies, including stem cell-derived EVs and engineered EVs as delivery platforms for therapeutic molecules. Furthermore, we discuss the pharmacological implications of EVs in current heart failure treatment paradigms, highlighting their potential role in bridging mechanistic insights with clinical therapeutic strategies. Collectively, these findings highlight the relevance of EVs in HF research and suggest directions for future investigation.

Osteogenesis imperfecta (OI), characterised by low bone mass and bone fragility, is a heritable disorder with a heterogeneous genetic cause. Type I collagen is the most predominant type of collagen in the bone. Hence, the vast majority of patients with OI carry genetic variants in the genes that encode for type I collagen. However, a fraction of patients have defects in genes that either participate in collagen synthesis and maturation, in osteoblast maturation and functions including bone mineralisation, or with yet fully-understood mechanisms. An intriguing example is MBTPS2, a gene in which missense variants cause two non-overlapping clinical spectrums - either OI or a dermatological spectrum condition (IFAP/KFSD). Our work in the past decade aimed at molecular profiling of MBTPS2-OI using patient-derived fibroblasts. Here, we expand on this by generating induced pluripotent stem cells (iPSCs) from patient-derived fibroblasts and subsequently differentiated step-wise through the sclerotome and into osteoblasts. We also developed a Fiji-based image analysis pipeline to examine extracellular collagen misfolding and fibril organization in 2-dimensional (2D) fibroblast cultures in vitro, which will complement existing methods to qualitatively assess collagen. Together, qualitative assessment of type I collagen and iPSC-based in vitro bone modelling revealed differences in pathomechanisms underlying MBTPS2-OI and classical COL1-OI This showcases diverging pathologies underlying different genetic forms of OI and highlights the need for better molecular characterization of each genetic form to optimise approaches for patient management and treatment.

Sporadic Parkinson's disease (PD) is typically a late-onset disorder caused by a combination of genetics, environment, and aging, manifesting when the loss of midbrain dopaminergic neurons exceeds a critical threshold, usually after the age of 50. Conversely, early-onset PD, as observed in cases linked to parkin (PRKN) gene mutations, suggests mechanisms involving either accelerated postnatal neuron loss or an insufficient number of neurons at birth. Patients with the 22q11.2 deletion syndrome (DS) have a significantly higher prevalence of early-onset PD. The absence of known genes associated with hereditary PD in the deleted region suggests the involvement of novel, non-traditional risk factors. This could potentially implicate the neurodevelopmental origin of dopaminergic neurons arising from the floor plate. To investigate this hypothesis, we generated midbrain organoids from induced pluripotent stem cells derived from a patient with 22q11.2 DS. The organoids recapitulated key aspects of in vivo neurogenesis, revealing enhanced differentiation of dopaminergic neurons in 22q11.2DS- and PRKN-derived organoids compared to controls on days 28 and 56 of culture. These findings suggest that, in early-onset PD patients with 22q11.2 DS or PRKN mutation, enhanced neurogenesis could result in reduced number of dopaminergic neurons during early development. The organoids of early-onset PD demonstrated that progenitors undergo enhanced differentiation at an early stage. This suggests that the atypical developmental process could reduce progenitors before there are enough mature dopaminergic neurons. This in turn indicates that the onset of PD may occur as early as the embryonic stage.

Myotonic dystrophy type 1 (DM1) is a progressive muscular disorder caused by the expansion of CTG repeats in the 3' UTR of the DMPK gene. Although the pathogenic mechanisms remain unclear, recent evidence suggests that activation of innate immune responses may contribute to disease progression. In this study, we examined the ultrastructure and proteomic data of myoblasts from young adult DM1 patients carrying approximately 800 and 1300 CTG repeats in order to investigate a link between cellular stress and immune activation. We observed activation of the type I interferon (IFN-I) pathway associated with rough endoplasmic reticulum stress (sRER). The sRER response is likely triggered by the accumulation of toxic RNA species generated from the expanded DMPK allele. Our data suggest that this inappropriate activation of the IFN-I pathway contributes to muscle pathology, not by blocking differentiation directly, but through chronic stress signalling. These findings support a model in which innate immune dysregulation plays a central role in DM1 muscle degeneration and highlight the IFN1 pathway as a potential therapeutic target for restoring normal muscle function.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are now widely applied in treatment plans for heart failure with reduced ejection fraction (HFrEF) patients, regardless of the presence of diabetes. SGLT2i, such as empagliflozin (EMP), reduce the risk of cardiovascular death and heart failure hospitalizations in HFrEF patients. However, the underlying molecular mechanisms of action, by which SGLT2i benefit cardiomyocytes (CMs) in HFrEF hearts, are not well understood.

Mesenchymal stem cells (MSCs) are multipotent stromal cells with dual regenerative and immunomodulatory properties that have attracted growing attention in cancer therapy. Their inherent tumor-homing ability enables localized delivery of therapeutic agents, while their capacity to regulate both innate and adaptive immunity positions MSCs at the interface of stromal biology and cancer immunotherapy. However, MSC functions are highly context-dependent and vary across tumor types.

Osteoarthritis (OA) is a chronic degenerative joint disorder characterized by articular cartilage deterioration, synovial inflammation, and progressive loss of joint function. Current treatments predominantly address symptoms without modifying structural disease progression, highlighting the need for disease-modifying strategies. Mesenchymal stem cells (MSCs), particularly umbilical cord-derived MSCs (UC-MSCs), exert therapeutic effects primarily through paracrine mechanisms rather than direct engraftment. The UC-MSCs secretome, comprising soluble bioactive factors and extracellular vesicles, modulates pro-inflammatory signaling, inhibits chondrocyte apoptosis, and promotes cartilage matrix biosynthesis. In vitro studies demonstrate restoration of anabolic chondrocyte phenotype, suppression of catabolic enzymes (MMP-13, ADAMTS-5), and attenuation of NF-κB and MAPK pathway activation. Preclinical models show preservation of cartilage architecture, reduced synovial inflammation, and improved joint function following intra-articular administration. Early clinical investigations report reductions in pain scores and functional improvements with favorable short-term safety profiles, though evidence remains largely derived from MSCs-based rather than secretome-specific interventions. Current findings support the biological plausibility and translational potential of UC-MSCs secretome therapy; however, clinical evidence remains limited and heterogeneous. Adequately powered randomized controlled trials with standardized protocols and extended follow-up are required to establish long-term efficacy and safety.

Malignant gliomas are common primary brain tumors. Glioblastoma carries a poor prognosis, with median survival of less than 2 years. Given the urgent need for novel therapies, oncolytic virus (OV) therapy has developed rapidly. However, challenges remain with effective OV delivery to tumor sites and efficient infection of tumor cells. This study investigated the use of stem cells from human exfoliated deciduous teeth (SHED) as a potential vehicle for oncolytic herpes simplex virus-1 therapy (SHED-OV) to enhance treatment efficacy. SHED-OV showed a greater reduction in tumor cell viability in vitro than direct OV infection. Migration assays revealed that SHED-OV actively migrated toward glioma cell-conditioned medium, demonstrating their tumor-homing ability. In vivo experiments demonstrated significantly prolonged survival in both the glioma cell/SHED-OV co-implantation group and the OV-infected glioma cell group compared with controls. In a glioma stem cell model, both SHED-OV and OV alone significantly improved survival compared with controls, with SHED-OV achieving anti-tumor effects comparable to those of direct OV administration and complete tumor regression in a subset of mice. SHED-OV also exhibited tumor-homing ability. These results suggest that SHED could serve as an effective vehicle for OV delivery, potentially improving tumor infection and therapeutic efficacy.

Unconventional T cells (UTCs), including γδ T cells, mucosal-associated invariant T cells, and natural killer T cells, recognize conserved nonpeptide antigens through semi-invariant T cell receptors in an human leukocyte antigen-independent manner, making them attractive candidates for broadly applicable immunotherapies. However, their clinical translation remains limited by poor spatiotemporal control of activation, functional exhaustion, and insufficient tissue homing in vivo, particularly in solid tumors. Biomaterial-based delivery systems provide a promising strategy to overcome these barriers by enabling localized and sustained delivery of UTC ligands, cytokines, and nucleic acids within diseased tissues. Through precise in situ programming of UTC responses, these platforms may enhance therapeutic efficacy and safety. This review summarizes current biomaterial-based strategies and discusses emerging opportunities for in situ UTC programming in human cancers.

Hematopoietic stem and progenitor cells (HSPCs) gene therapy may transform the therapeutic landscape for inherited hematological disorders and already offers potentially curative options for some diseases, including inborn errors of immunity and β-hemoglobinopathies. Its continued success relies on further refinement of gene transfer technologies, gene editing tools such as CRISPR-Cas, and optimized ex vivo HSPC manipulation protocols that ensure robust, long-term engraftment and clonal diversity with reduced-toxicity, non-genotoxic conditioning strategies. Here, we review recent developments and refinements in gene transfer and editing technologies for HSPCs, while also discussing the critical limitations and hurdles to clinical translation, as recently presented at the New Investigator Committee Gene Therapy webinar. Future directions must prioritize integrating technological innovation with the development of equitable and simplified models to reduce costs and ensure that these life-saving cellular therapies reach patients worldwide. Teaser abstract Hematopoietic stem and progenitor cells (HSPCs) gene therapy is advancing rapidly, with lentiviral gene transfer, genome editing, and emerging in vivo delivery approaches expanding the therapeutic landscape for inherited hematologic disorders. Recent clinical successes have demonstrated the potential for durable correction, while ongoing refinements continue to improve safety, efficacy, and feasibility. Key challenges remain in genotoxicity, conditioning toxicity, manufacturing scalability, and equitable global access.

Leukemia stem cells (LSC) are thought to be responsible for relapse in patient with acute myeloid leukemia (AML). LSC can be quantified at diagnosis to improve risk stratification, and during follow-up to monitor residual disease. To systematically evaluate the prognostic relevance of measuring LSC at diagnosis and in remission in patients with AML, we conducted a systematic and reconstructed individual patient data meta-analysis. We performed a comprehensive search for studies that reported overall survival (OS) and/or event-free survival (EFS) in relation to LSC measurements at diagnosis or in remission. We reconstructed individual patient data based on Kaplan Meier curves. Fifty-six studies were included, including a total of 44 cohorts (n=7781) for OS and 37 cohorts (n=5032) for EFS at diagnosis, and 19 cohorts (n=2006) for OS and 22 cohorts (n=1342) for EFS in remission. Positive LSC status was significantly associated with inferior OS and EFS at diagnosis (OS: hazard ratio [HR] 1.96 (1.85-2.08); EFS: HR 2.32 (2.15-2.49)) and in remission (OS: HR 2.59 (2.23-3.03); EFS: HR 2.53 (2.18-2.94)). To conclude, we found that measuring LSC has prognostic relevance both at diagnosis and in remission. This supports LSC frequency as a key prognostic factor that warrants implementation into clinical practice.

SIGLEC6, a human-specific transmembrane receptor, is highly expressed in placenta. SIGLEC6 is elevated in maternal circulation preceding preeclampsia and in women with preeclampsia, correlating with disease severity. This study aimed to investigate the regulatory mechanisms of placental SIGLEC6 and its involvement in processes associated with preeclampsia pathogenesis.

Endocardial cushions, derived from the atrioventricular canal (AVC) and outflow tract (OFT), serve as the primordia for the formation of the septum and valves. Improper morphogenesis of the endocardial cushion leads to septal and valvular abnormalities, which contribute to the largest proportion of congenital heart diseases (CHDs). The development and maturation of the endocardial cushion rely on endothelial-to-mesenchymal transition (EndMT), a process by which endocardial cells undergo morphological remodeling and develop into the endocardial cushion mesenchyme. This biological event is strictly governed by regional signals originating from the myocardium, endocardium, and mesenchyme. Various signaling pathways, including TGFβ/BMP, Wnt, Notch, Hippo/YAP, PI3K/AKT, VEGF, and mechanical stress, are involved in the modulation of endocardial cell proliferation, migration, and mesenchymal transition. Transcription factors, such as SMAD, SNAIL, TWIST, TBX2, SOX9, KLF2/4, and NFATc1, exert distinct effects on endocardial EndMT. Maternal environmental exposures can disrupt signaling pathways and transcriptional network during endocardial cushion development, thereby enhancing susceptibility to CHDs. This review summarizes the mechanistic pathways and transcriptional regulation in AVC endocardial cushion development and EndMT, highlighting their association with CHDs.

Myeloid cells orchestrate vascular inflammation through transcriptional programs that control their maturation, effector function, and survival. While lineage-determining transcription factors establish myeloid identity, our understanding of the transcriptional regulation of myeloid cell behavior in chronic inflammatory contexts remains limited. Nuclear factor-Y (NF-Y) is a trimeric CCAAT-binding transcription factor that regulates cell proliferation and differentiation and is essential for maintaining stem and progenitor cell fitness. Here, we investigate NF-Y activity in myeloid cell function and survival using integrated single-cell transcriptomics and myeloid-specific deletion of the NF-YA subunit. At RNA level, NF-Y subunit transcripts were detected across myeloid compartments, with NF-YA enriched in proliferative macrophages and immature neutrophils. In mouse atherosclerotic lesions, low NF-YA levels were associated with macrophages exhibiting lipid-handling and phagocytic signatures and with neutrophils displaying a proinflammatory phenotype. NF-Y deficiency impaired neutrophil adhesion and rolling, increased their susceptibility to apoptosis, and promoted activation and lipid accumulation in macrophages. In vivo, myeloid NF-YA deficiency reduced circulating neutrophil counts, increased macrophage and neutrophil apoptosis during acute inflammation, expanded necrotic cores, leading to larger and more unstable atherosclerotic lesions, and aggravated both atherosclerosis and injury-induced neointimal thickening. These findings identify NF-Y as a transcriptional safeguard of myeloid cell survival during inflammatory stress, thereby shaping disease progression and outcomes in vascular disease.

The life cycle of most medusozoan cnidarians is marked by the metagenesis from the asexually reproducing sessile polyp and the sexually reproducing motile medusa. At present, it is unknown to what extent this drastic morphological transformation is accompanied by molecular changes in the cell type composition. Here, we provide a single-cell transcriptome atlas of the cosmopolitan scyphozoan Aurelia coerulea focusing on changes in individual cell states during the transition from polyp to medusa. Notably, this transition is marked by an increase in cell type diversity, including an expansion of neural subtypes and the appearance of striated muscles. We find that two families of neuronal lineages are specified by homologous transcription factors in the sea anemone Nematostella vectensis and A. coerulea, suggesting an origin in the common ancestor of medusozoans and anthozoans about 500 Myr ago. Our analysis suggests that gene duplications might be drivers for the increase of cellular complexity during the evolution of cnidarian neuroglandular lineages and highlights the close relationship of neurons and muscles. One key medusozoan-specific cell type is the striated muscle in the subumbrella. Evaluating muscle types by fiber anatomy and gene expression validation of their individual molecular profiles made it possible for the first time to investigate transcriptome differences between smooth and striated muscles. Although smooth and striated muscles are phenotypically different, both have a similar regulation of the contractile complex, reminiscent to the regulation of smooth muscles in bilaterians. This contrasts with bilaterian striated muscles, where the regulation of muscle contraction involves Ca2+ binding troponins and their interaction with Tropomyosin. These data suggest that smooth muscle contraction regulation is ancestral and the use of troponins in striated muscles only evolved in bilaterians.

Human stem cell (SC)-generated beta cell implants represent a potential cure for type 1 diabetes. Studies in rodents and patients showed that they can establish a glucose-regulated source of insulin in recipients with depleted pancreatic beta cell mass. Their therapeutic significance is, however, determined by their capacity to restore glycemic control by the human glucostat. It is so far unknown which implant characteristics are needed for this key endpoint. The present study addresses this question in mice. SC-derived preparations with a defined beta cell dose and alpha cell proportion were implanted in the epididymal fat pad of normoglycemic SCID/beige mice (mouse glucostat basal glycemia 166 mg/dL). At post-transplant week 20, 12/25 recipients reached glycemic control at the human glucostat (glycemia ≤ 90 mg/dL) following a time-dependent increase of basal and glucose-induced plasma human C-peptide and decrease of mouse C-peptide towards under detection limit. Formation of their functional human beta cell mass was preceded by formation of a human alpha cell mass that became the source for circulating glucagon and a contributor to glycemic control. The insulin content of the implants reached the values in the pancreas of control mice and were thus identified as in situ markers for implants that established the glycemic endpoint. Co-existence with a functional alpha cell mass places alpha cell formation as a potential additional component for achieving the goal. Our study also demonstrates the relevance of using normoglycemic mice to assess stem cell therapy protocols for beta cell replacement.

Objective Pediatric obesity is associated with early metabolic complications and increased risk of persistent obesity in adulthood. Beyond fat accumulation, obesity may induce long-lasting molecular alterations in adipose tissue, described as "obesogenic memory." However, whether such intrinsic alterations are already present in pediatric adipose progenitor cells remains poorly understood. This study aimed to develop an in vitro model of adipogenesis using pediatric adipose-derived mesenchymal stem cells (hMSCs) and to investigate whether obesity is associated with intrinsic metabolic reprogramming of adipose progenitors. Methods hMSCs were isolated from periumbilical subcutaneous adipose tissue obtained from pediatric subjects with normal weight (NW), overweight (OW) and obesity (OB). Cells were expanded and induced to undergo adipogenic differentiation for up to 14 days using defined adipogenic media. Differentiation was evaluated through morphological analysis, lipid accumulation (BODIPY staining), gene expression profiling by RT-qPCR, and protein analysis by Western blot. Results Two differentiation protocols efficiently induced adipocyte maturation without cytotoxicity. hMSCs derived from NW and OB subjects showed comparable adipogenic differentiation capacity, with similar lipid droplet accumulation and expression of canonical adipogenic markers including C/EBPα, PPARγ, and FABP4. Despite this comparable differentiation efficiency, OB-derived adipocytes exhibited altered transcriptional regulation of genes involved in lipid metabolism, including pathways associated with lipogenesis, lipolysis, and fatty acid β-oxidation. Protein analyses further revealed dysregulated expression of key metabolic regulators such as SCD1, SREBP1, PNPLA2, and FADS1, suggesting altered lipid metabolic programming. Conclusions Pediatric obesity does not impair adipogenic differentiation but is associated with intrinsic metabolic alterations in adipose progenitor cells. These findings support the presence of an early obesogenic memory in adipose tissue that may contribute to long-term metabolic dysfunction.

The metabolic importance of brown adipose tissue (BAT) has been recognized, but its origins, particularly supraclavicular BAT (scBAT), remain unclear. Here, we traced scBAT to Mef2c-anterior heart field (AHF)-marked cells. Mef2c-AHF-marked cells isolated from scBAT can spontaneously differentiate into brown adipocytes, express mesenchymal stem cell markers, and can be isolated from the stromal-vascular fraction (SVF) of wild-type scBAT as [CD31-CD45-Sca-1+CD29+CD34-CD24-] (CD34-) cells. Mef2c-AHF-marked cells substantially overlap with Prrx1-marked cells in scBAT, which also contribute to beige adipocytes in inguinal white adipose tissue (iWAT). Similarly, CD34- cells isolated from the SVF of iWAT can spontaneously differentiate into beige adipocytes in vitro. Intersectional lineage tracing shows that common progenitors of Mef2c-AHF- and Prrx1-marked cells in scBAT emerge from the developing heart. Thus, these studies reveal a common origin for scBAT and cardiac tissue and suggest that scBAT and iWAT beige adipocytes arise from progenitor populations with overlapping lineage origins and molecular characteristics.

Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive loss of dopaminergic neurons. Studies have shown that mesenchymal stem cells (MSCs) have prominent neuroprotective potential to improve PD. Previous study found that dental pulp‑derived MSCs, including stem cells from human exfoliated deciduous teeth (SHED), significantly ameliorated PD-related pathology, but the underlying molecular mechanism remains unclear. In this study, HSPB1 and PARK7 were initially identified through transcriptomic analyses of mouse and clinical samples, immunoprecipitation‑mass spectrometry (IP‑pulldown), and protein‑protein interaction (PPI) network analysis. Using an MPTP-induced SH-SY5Y cell model of PD, we found that SHED treatment alleviated oxidative stress, restored mitochondrial membrane potential, and inhibited apoptosis, accompanied by significant upregulation of HSPB1 and PARK7. Using siRNA interference, we confirmed that both HSPB1 and PARK7 are involved in the improvement of PD by SHED. Rescue experiments showed that HSPB1 overexpression partially restored the neuroprotective effects impaired by PARK7 knockdown, whereas PARK7 overexpression failed to compensate for HSPB1 deficiency, suggesting a functional dependence between PARK7 and HSPB1 in SHED-mediated neuroprotection. This study demonstrates that SHED improves PD pathological progression through the PARK7/HSPB1-related mechanism and indicates that HSPB1 may serve as a potential therapeutic target for PD.

Macrophages play key roles in innate immunity, inflammation, and homeostasis. However, conventional macrophage models, particularly primary macrophages derived from donor monocytes (MDMs), are limited by donor-to-donor variability, limited proliferative capacity and non-renewable nature, low scalability, and poor genetic tractability. Induced pluripotent stem cell-derived macrophages (iMacs) have emerged as an alternative that offers a renewable source of engineered human macrophages. This review summarizes the approaches used to generate and characterize iMacs, highlighting their functional properties such as phagocytosis, efferocytosis, cytokine secretion, lipid metabolism, and macrophage polarization. We then focus on translational applications of iMacs in three important areas: (i) disease modeling, where iMacs enable large-scale production, precise genetic modification, and accurately mimic host-pathogen interactions, autoimmune phenotypes, metabolic inflammation, and tissue-specific macrophage functions; (ii) drug discovery, where the combination of large-scale production and assay miniaturization allows high-content and high-throughput screening with increased physiological accuracy over immortalized cell lines; and (iii) therapeutics, which comprise engineered iMac-based therapies and novel cell therapy approaches for various infectious, genetic, and inflammatory diseases. Finally, we discuss current challenges and opportunities in developing iMacs toward clinical applications. Overall, iMacs are a versatile bridge between mechanistic immunology and next-generation translational medicine.