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.

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.

Aspiration pneumonia (AP) is a prevalent and life-threatening pulmonary disease resulting from repeated aspiration of exogenous materials such as food or gastric contents. However, most existing animal models simulate only acute injury and fail to reproduce the chronic pathological features observed in patients. This study aimed to establish a stable and clinically relevant chronic AP mouse model.

Human induced pluripotent stem cells (hiPSCs) may acquire genomic alterations during reprogramming and culture, which poses significant risks for clinical applications. Current detection methods, such as karyotyping analysis, often fail to identify critical submicroscopic variations. This highlights an urgent need for comprehensive genomic surveillance strategies.

Neurodegenerative diseases are characterized by progressive neuron loss and brain atrophy. While conventional studies focused on neuronal death as the primary cause of these diseases, accumulating evidence suggests that impaired neurogenesis, particularly the dysfunction of adult neural stem cells (NSCs), may also contribute significantly to disease pathogenesis. Adult neurogenesis occurs primarily in two adult NSC niches. These specialized niches are enriched with complex cytokine networks, neuronal activity, and non-cellular components such as the extracellular matrix. Understanding the regulation of NSCs in the adult brain and how their dysregulation exacerbates neurodegeneration provides novel insights into therapeutic strategies. This review proposes that dysfunction of the NSC microenvironment, rather than neuronal death alone, may drive neurodegeneration, and that restoring this microenvironment offers a novel research direction of stem cell-based therapies.

The role of inflammation-induced myeloid-biased hematopoiesis in driving resistance to immune checkpoint blockade (ICB) is recognized, yet the intricate mechanisms through which tumors orchestrate it are not fully defined.

Short stature (SS) is a common growth disorder with multiple aetiologies. Variants in the MMP13 gene can result in varying degrees of SS, typically accompanied by pronounced skeletal abnormalities. This study aimed to investigate the genetic basis of SS in a family lacking significant imaging abnormalities and elucidate the underlying pathogenic mechanism.

Steroid-refractory acute graft-versus-host disease (SR-aGVHD) is the predominant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT), with gastrointestinal involvement (SR-GI-aGVHD) remaining a key obstacle. We conducted a multicenter, single-arm, pivotal trial to assess the efficacy and safety of hUC-MSC PLEB001, a human umbilical cord-derived mesenchymal stromal cells (MSCs) product, plus anti-CD25 monoclonal antibody as second-line therapy for SR-GI-aGVHD.

Clinical responses to mesenchymal stromal cell (MSC) therapies remain variable because MSCs are often treated as uniform biologics despite donor-programmed differences. Evidence indicates that developmental maturity (fetal vs. adult) and biological sex (female vs. male) bias the MSC secretome and downstream signalling (NF-κB, PI3K/AKT-ERK, TGF-β/Smad, Wnt/β-catenin), potentially shaping anti-inflammatory, angiogenic, anti-fibrotic, and regenerative functions.