Metabolic dysfunction-associated steatotic liver (MASLD) is a prevalent cause of chronic liver disease, affecting roughly 38% of adults in the USA. Growing evidence suggests that metabolic conditions such as MASLD and obesity may influence the epidemiology, biology, and clinical outcomes of patients with leukemia. Limited studies indicate that MASLD's pro-inflammatory milieu may contribute to clonal hematopoiesis and leukemogenesis by promoting DNA damage, clonal expansion of mutated hematopoietic stem cells, and providing pro-survival signals. Here we review the current evidence linking MASLD with acute leukemias. We discuss epidemiological trends, mechanistic insights from preclinical and clinical studies, and prognostic implications of MASLD in acute myeloid leukemia and acute lymphoblastic leukemia. We highlight that while metabolic dysfunction appears to adversely impact leukemia outcomes, the interactions are complex and occasionally paradoxical. Finally, we identify key gaps in the literature, underscoring the need for dedicated studies on MASLD in leukemia patients and whether modifying MASLD can improve leukemia outcomes.

WNT, BMP, FGF, and Nodal signalling gradients drive naive to primed epiblast transitions and primitive endoderm specification, as well as subsequent gastrulation of the implanted embryo. Recently, these pathways were shown to control a signalling rheostat that modulates chromosome replication and segregation fidelity in human pluripotent stem cells. In particular, WNT and BMP antagonists associated with embryo anteriorization during gastrulation (DKK1, Cerberus, LEFTY2, Noggin, and Chordin) induce DNA replication stress and damage in S-phase leading to ultra-fine-bridges and whole-chromosome mis segregation in the subsequent mitosis. Of note, aneuploidy in pre- and early post-implantation embryos is the first cause of miscarriage in humans, and has also been associated with neurodevelopmental disorders. Here, we hypothesize that the antero-posterior (A-P) signalling gradient generates overlapping patterns of genome and chromosomal mosaicism in human embryos, with potential links to human infertility and lineage-specific developmental disorders.

Heart failure (HF) remains a major clinical and healthcare challenge with high morbidity, mortality, and impaired quality of life (QOL). Approximately 30-40% of HF cases in the western world are of nonischemic heart failure (NIHF) origin; yet, regenerative therapies are lacking. Evidence suggests that systemic inflammation contributes to disease progression in NIHF, highlighting immunomodulation as a potential therapeutic target. Mesenchymal stromal cells (MSCs) possess regenerative and immunomodulatory properties, with adipose tissue derived stromal cells (ASCs) emerging as particularly promising. ARIISE is a Danish, multicenter, randomized, double-blinded, placebo-controlled study evaluating the efficacy and safety of intravenous allogeneic ASC therapy (C2C_ASC110) in patients with NIHF and reduced left ventricular ejection fraction (LVEF ≤ 45%). Ninety patients will be randomized to receive either C2C_ASC110 or placebo dimethyl sulfoxide (DMSO) (Cryostor®) intravenously twice 1 month apart, in addition to optimal guideline-directed medical therapy. The primary endpoint is a change in LVEF at 6-month follow-up after second ASC/placebo infusion. Secondary endpoints include other echocardiographic measurements, functional capacity, biomarkers, quality of life (QOL), and safety outcomes. If successful, ARIISE may establish clinical evidence for intravenous ASC therapy as a safe, feasible, and effective regenerative treatment for patients with NIHF.Clinical trial registration: EU CT number: 2025-520837-22-00, UTN number: U1111-1315-7011, Clinicaltrials.gov number: NCT06840275.

The interactions between human viruses and human stem cells may differ from those with differentiated cells. These differences may arise through heterogeneous intercellular mechanisms and responses to specific infectious agents, resulting in different phenotypes that affect human pathophysiology. Understanding and exploiting such differences could have clinical and translational potential. Here, we discuss the various mechanistic interactions between stem cells and viruses related to entry mechanisms, replication dynamics, and immunomodulation. In doing so, we critically assess proposed models and hypotheses about how viruses manipulate stem cell biology, while also providing new paradigms for stem cell biology and therapeutic interventions. We highlight recent discoveries on the dual role of viruses in oncogenesis and oncolysis. In parallel, we explore similarities between stem cells and complex viruses-such as giant viruses and jumbo phages-to propose novel perspectives on viral adaptability and pathogenesis. We examine both established mechanisms and emerging viral phenomena to encourage further research and debate on the clinical implications of viral interactions with stem cells.

Bone tissue engineering (BTE) represents an innovative strategy for repairing bone defects by integrating biomaterials, cells, and bioactive factors, aiming to mimic the structural and functional properties of natural bone tissue to facilitate regeneration. Bone healing is a multi-stage process involving inflammation, soft callus formation, hard callus development, and bone remodeling, which are regulated by the synergistic action of various cells and molecular signaling pathways. Gelatin methacryloyl (GelMA) hydrogel scaffolds, with their excellent biocompatibility, tunable mechanical properties, and photocrosslinking ability, provide a three-dimensional (3D) microenvironment similar to the natural extracellular matrix for cells. In recent years, combining mesenchymal stem cells (MSCs) with GelMA hydrogels has become a cutting-edge strategy for bone regeneration. GelMA not only supports the survival and proliferation of MSCs but also promotes osteogenic differentiation and accelerates bone defect repair through its adjustable physicochemical properties. This review, based on current literature, explores the unique properties of MSCs and the latest advancements in the synergistic effects of MSCs and GelMA hydrogels in promoting bone regeneration.

Iron is an essential element for most cellular processes and recent evidence highlighted its role in regulating the function of hematopoietic stem cells (HSCs). Abnormal iron levels impact HSC quiescence and self-renewal, however, the mechanism by which iron overload (IO) influences HSC function is still unknown. Here, we show that intracellular IO impairs mitochondrial fitness and bioenergetics, inducing metabolic rewiring. In thalassemic mice, as a model of chronic IO, HSCs accumulate mitochondria with elevated reactive oxygen species (mtROS), low membrane potential and reduced oxidative phosphorylation (OXPHOS). Mitochondrial defects are confirmed in other two models of IO, sickle cell disease and iron-loaded wild-type mice, and in vivo iron reduction rescues HSC mitochondria. IO HSCs are highly proliferating and in presence of damaged mitochondria rely on glycolysis for energy production. Notably, restoration of mitochondrial function by targeting in vivo mtROS improved the quiescence and self-renewal of IO HSCs. Our results unravel the critical interplay between iron, ROS and mitochondrial activity in HSCs, revealing that IO shapes HSC metabolic programs.

Facial nerve injury poses a major challenge in otolaryngology, where functional restoration remains critical. As autologous nerve grafts present limitations, biomaterial-based nerve guidance conduits (NGCs) offer a viable alternative for bridging nerve defects.

Steroid-induced osteonecrosis of the femoral head (SONFH) is a rapidly progressing and disabling complication of long-term glucocorticoid therapy, lacking effective early-stage intervention mechanisms. Its early manifestation involves a fate shift in bone marrow mesenchymal stem cells (BMSCs) characterized by decreased osteogenic differentiation (OGD) and increased adipogenic differentiation (AGD), yet the upstream regulatory mechanisms remain unclear. Herein, we integrated AGD-related microRNA (miRNA) microarray data with exosomal miRNA sequencing data and identified miR-199a-3p as a crucial candidate driver of this lineage imbalance. Our results revealed the up-regulation of miR-199a-3p in SONFH tissues and in glucocorticoid-treated cellular models, and indicated that its overexpression suppresses the OGD of BMSCs while markedly promoting the AGD. Further integrating mRNA-sequencing profiling during AGD with target prediction, protein-protein interaction network analysis, and dual-luciferase reporter assays, we confirmed integrin β8 (ITGB8) as a direct target of miR-199a-3p, which is consistently decreased in SONFH tissues and during adipogenic induction. We further revealed that miR-199a-3p suppressed the OGD of BMSCs by repressing ITGB8 expression, thereby inactivating the focal adhesion kinase (FAK)-extracellular signal-regulated kinase (ERK)-runt-related transcription factor 2 (RUNX2) signaling cascade. Conversely, silencing miR-199a-3p restores ITGB8 levels, reactivates this pathway, and corrects the OGD/AGD bias. In vivo, local administration of antagomiR-199a-3p in a SONFH rat model markedly improved trabecular bone architecture, increased bone mass, and up-regulated RUNX2 expression. These findings reveal for the first time that the miR-199a-3p/ITGB8-FAK-ERK-RUNX2 axis represents an unrecognized pathogenic pathway in SONFH, and support the local suppression of miR-199a-3p as a translatable early intervention strategy.

Mitochondrial permeability transition-driven necrosis (MPTDN) has been implicated in a variety of diseases, but its relationship with colorectal cancer (CRC) prognosis is unclear.

The bone marrow microenvironment comprises a complex network of hematopoietic stem cells, immune cells, stromal cells, and non-cellular components such as the extracellular matrix and soluble factors, collectively maintaining the homeostasis of hematopoietic stem and progenitor cells. It is highly vulnerable to pathological perturbations induced by hematologic malignancies, solid tumors, inflammatory stress, and therapeutic exposure, which collectively destabilize microenvironmental homeostasis and promote hematopoietic failure, malignant progression, and immune dysregulation. Natural products exhibit unique advantages in modulating the blood microenvironment due to their structural diversity, multitarget effects, and low toxicity. Their biological activities span multiple mechanistic dimensions, including redox regulation, metal ion homeostasis, signaling inhibition, and microenvironment remodeling. However, the intrinsic relationships between their chemical structures and biological functions have not yet been systematically elucidated. Therefore, from a translational medicine perspective, this review focuses on elucidating the pharmacological mechanisms by which natural products regulate the hematopoietic microenvironment. We systematically summarize their chemical basis and structure-activity relationships, together with recent advances in extraction techniques, chemical modification, and targeted delivery strategies. The aim is to bridge the gap between chemical research on natural products and their clinical therapeutic applications, providing a framework and innovative directions for drug development targeting hematological diseases.

The aim of this study was to develop a novel biocompatible composite for the regeneration of damaged dental pulp tissue.

Growth differentiation factor 11 (GDF11) has emerged as a potential regulator of bone regeneration; however, the molecular mechanisms through which it influences osteogenic differentiation, particularly in relation to mitochondrial quality control, remain unclear. This study aimed to elucidate the role of adenosine monophosphate-activated protein kinase (AMPK)-dependent mitophagy in GDF11-mediated osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMMSCs).

Vascularized composite allotransplantation (VCA) enables functional reconstruction for patients with extensive tissue defects, but has obstacles such as immune rejection, lifelong immunosuppression, and systems-level barriers that limit widespread adoption. VCA has rapidly evolved through novel surgical, immunologic, and bioengineering technologies. This systematic review synthesizes the current landscape of emerging VCA technologies, identifies literature gaps, and emphasizes opportunities for future research. We conducted a systematic literature review of PubMed and Embase with supplemental manual reference review. English-language experimental studies reporting novel VCA technologies and innovations published after 2004 were included. Case reports, reviews, studies without technological innovation, and non-English publications were excluded. Seventy-two studies fit the inclusion criteria. Novel immunomodulation strategies including belatacept, phototherapy, siRNA therapeutics, and tolerance induction via regulatory T-cells show potential to reduce systemic immunosuppression, while mesenchymal stem cell approaches may increase graft tolerance. On another front, advanced surgical techniques with real-time monitoring and nerve regeneration protocols are looking to promote functional recovery. Digital innovations like 3D modeling and virtual surgical planning allow for patient-specific preoperative planning and intra-operative assistance. In parallel, machine perfusion and cryopreservation extend tolerable ischemia times and may also enable early rejection detection. Similarly, biomarkers and imaging provide early and noninvasive rejection prediction. On a bigger scale, patient selection incorporating evidence-backed psychosocial factors and communication training work to address systems-level barriers to expand access. Ongoing research to translate these innovations into clinical practice will be important in realizing the potential of VCA.

Preeclampsia (PE) is a pregnancy-specific disease with limited treatment options. Although human placental mesenchymal stem cells (hPMSCs) hold therapeutic potential, their clinical use faces safety and practical challenges. Placental mesenchymal stem cell exosomes (PMSC-Exos) offer a promising cell-free alternative. We hypothesized that PMSC-Exos may effectively alleviate PE and investigated the underlying molecular mechanisms.

Oral health is vital to human well-being. As a result, various conditions in the oral cavity, including exposure to dentin and edentulous states, lead to diverse oral issues and tissue loss. Although conventional treatments are available, they often have limitations in drug delivery and tissue regeneration. For example, delivered drugs may fail to disrupt bacterial biofilms, thereby increasing resistance within the oral microbiome and weakening immune responses. Additionally, the limited regenerative capacity of dental pulp cells can lead to serious dental emergencies. To address these challenges, innovative nanoarchitectures have been developed to improve their antimicrobial effects and enhance the regenerative potential of oral tissues for oro-dental tissue engineering. This review discusses different nanotechnological strategies for delivery and subsequent tissue engineering in the oral cavity. We first explore concepts to boost regenerative capacity, emphasizing the roles of various nanomaterials that act as antibacterial agents, activate the differentiation of human dental pulp stem cells, and support their integration with soft oral tissues. Beyond nano-therapeutic strategies involving dental implants, we also discuss nanotoxicity issues and remaining challenges in oral health. Finally, we offer perspectives on translating these developments into clinical practice.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disorder marked by excessive extracellular matrix deposition and limited treatment options. Ferroptosis has emerged as a critical driver of epithelial injury and fibrogenesis, while fibroblast activation further accelerates pathological remodeling. The transferrin receptor (TFRC), aberrantly upregulated in both alveolar epithelial cells and fibroblasts during fibrosis, represents a promising target for precision therapy.

Bone in adult mammals plays critical structural and endocrine functions, both largely rely on osteocytes-the most abundant bone cells and principal source of bone-derived hormones, such as fibroblast growth factor 23 and sclerostin. The widely used 10-kb promoter-driven transgenic Tg(Dmp1-Cre) and Tg(Dmp1-CreERT2) lines, while widely used and helpful, utilize transgenic approaches with transgene expression driven by the Dmp1 promoter. The transgene expression suffers from positional effects with off-target expression in muscle, brain, and other tissues, limiting their applications, causing a major technical gap in the investigation of osteocyte-specific functions. Here, we generated 2 novel mouse lines-Dmp1em1(CreERT2) and Dmp1em2(ZsGreen) -via CRISPR-Cas9 mediated "knock-in" approaches to insert an internal ribosome entry site (IRES)-CreERT2 or IRES-ZsGreen cassette into the Dmp1 locus, allowing CreERT2 or ZsGreen expression under the genetic control of the endogenous Dmp1 locus while preserving Dmp1 gene expression. We show that the Dmp1em1(CreERT2) enabled highly efficient tamoxifen-inducible recombination (>90% in cortical and trabecular osteocytes) with minimal off-target expression in non-bone tissues. The Dmp1em2(ZsGreen) line showed robust, fixation-, and decalcification-resistant green fluorescence in osteocytes from birth through adulthood, faithfully reflecting endogenous Dmp1 expression. Lineage tracing using the Dmp1em1(CreERT2) line further revealed that the cortical osteocytes are long-lived, whereas trabecular osteocytes undergo continuous renewal, uncovering compartment-specific differences in osteocyte lifespan. By eliminating off-target recombination or gene expression in skeletal muscle, brain, gastrointestinal tract, and marrow compartments, the 2 mouse lines offer powerful tools for rigorous studies in osteocyte biology, mechanotransduction, and bone regulation of systemic physiology that impact health, aging, and diseases, while minimizing complications due to off-target transgene expression.

Trained immunity refers to the long-term functional adaptation of innate immune responses following an initial stimulus, representing a conceptual expansion of immune memory beyond adaptive immunity. Given the rapid expansion of this field, this study aimed to systematically map the research landscape of trained immunity and to identify major research hotspots and emerging frontiers using bibliometric approaches.

Midkine (MK) protein plays a critical regulatory role in tooth development and odontogenic differentiation, and has been shown to significantly promote reparative dentine formation. However, the direct application of recombinant MK protein as a pulp capping material presents clinical challenges and may increase medical costs. In contrast, peptides offer a cost-effective and feasible alternative by overcoming many of the limitations associated with full-length proteins. This study aimed to develop a novel MK-derived peptide for use in vital pulp therapy (VPT).