Small-diameter vascular grafts (≤ 6 mm) remain a critical unmet need in cardiovascular surgery, as autologous vessels are unavailable in up to 30% of patients requiring coronary or peripheral bypass. Induced pluripotent stem cells (iPSCs) have emerged as a transformative cell source for tissue-engineered vascular grafts (TEVGs), offering unlimited self-renewal, patient-specific or universal donor potential, and the capacity to generate all vascular cell lineages. Recent breakthroughs-including iPSC-derived grafts achieving 100% patency in allogeneic primate models and the first United States Food and Drug Administration (FDA) approval of an acellular tissue-engineered vessel (SYMVESS, December 2024)-signal that clinical translation is accelerating. This review provides a comprehensive synthesis of the iPSC-to-graft pipeline, encompassing vascular cell differentiation protocols, biomaterial scaffold design, immune engineering strategies for universal grafts, bioreactor maturation, preclinical evaluation, and the evolving clinical-regulatory landscape. We critically evaluate how the convergence of clustered regularly interspaced short palindromic repeats (CRISPR)-based immune editing, advanced biomaterials, and scalable manufacturing is reshaping the field toward off-the-shelf vascular grafts. Finally, we identify remaining challenges in long-term patency, thrombogenicity, and manufacturing scalability, and propose a translational roadmap for the next decade.
Intervertebral disc degeneration (IDD) serves as a critical structural basis for chronic low back pain, severely impairing patients' quality of life and imposing a significant socioeconomic burden. Current interventions remain largely limited to symptomatic treatments including pharmacological analgesia and surgical intervention. The recently proposed "gut-disc axis" suggests that the gut microbiome can reshape the endplate-disc microenvironment by influencing intestinal barrier integrity, microbial metabolite profiles, and host immune-metabolic status. Existing evidence indicates that dysbiosis-related increases in endotoxin load, dysregulated metabolism of short-chain fatty acids, tryptophan, and bile acids, systemic low-grade inflammation, and shifts in immune cell lineages may collectively promote nucleus pulposus cell senescence and apoptosis, matrix degradation, and endplate pathology. Mendelian randomization studies have also suggested potential causal links between certain gut microbiota and disc diseases. However, the determination of whether "microbial signals" detected within the intervertebral disc represent true colonization is currently hindered by methodological limitations, particularly low-biomass contamination. This review focuses on mechanisms through which gut microbiota influence the endplate-disc microenvironment via immune-metabolic pathways, including the LPS/TLR4/NF-κB axis, SCFAs-AhR axis, and lipid/iron metabolism, while only briefly addressing studies related to mechanical injury and surgery. Building on these insights, we integrate advances from clinical cohorts, animal models, and multiomics studies, summarize key actionable intervention nodes, and propose a preliminary patient stratification framework and validation pathway based on gut-immune-metabolic typing, providing a theoretical foundation for developing microbiome-guided disease-modifying interventions.
The adenylyl cyclase (ADCY) family comprises key signal transduction enzymes that catalyze the conversion of ATP to the second messenger cyclic adenosine monophosphate (cAMP). Through the downstream cAMP-protein kinase A (PKA) signaling pathway, this family exerts central regulatory effects on glucose and lipid homeostasis. In mammals, the ADCY family consists of nine transmembrane isoforms (ADCY1-9) and one soluble isoform (ADCY10), all of which exhibit tissue‑specific distribution, distinct regulatory mechanisms, and non‑redundant functions in core metabolic organs. Compelling evidence from gene‑edited animal models, functional validation studies, and multi‑ethnic genetic association analyses has demonstrated that dysfunction of specific ADCY isoforms is closely linked to the pathogenesis of obesity, type 2 diabetes mellitus (T2DM), metabolic dysfunction‑associated steatotic liver disease (MASLD), and other metabolic disorders. This review systematically summarizes the classification, structural characteristics, and multilayered regulatory mechanisms of the ADCY family, with a particular focus on the physiological and pathological roles of its isoforms in glucose metabolism, lipid metabolism, and feeding regulation. It also discusses recent advances in ADCY‑targeted agents and highlights unresolved challenges and future directions. Particular emphasis is given to recent structural biology breakthroughs, genetic evidence from diverse populations, and isoform‑specific therapeutic strategies, with the aim of providing a theoretical basis for mechanistic research and the development of targeted therapeutics for metabolic diseases.
Microgravity brings various pathological changes to astronauts, which may be related to the senescence of adult stem cells. However, how microgravity affects the senescence of stem cells remains barely known. In this study, it was found that microgravity simulated by Rotating Flat Chamber induced MSC senescence and promoted the expression of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING), and C176, a STING inhibitor, alleviated the rotating culture-induced MSC senescence. Rotating culture also promoted the cytosolic leakage of mitochondrial DNA (mtDNA), while the depletion of mtDNA inhibited cGAS-STING activation and reversed MSC senescence. Knockdown of either BAK or BAX, proteins forming pores on the mitochondrial outer membrane, suppressed mtDNA leakage, cGAS-STING activation, and MSC senescence, suggesting that BAK/BAX mediates the activation of mtDNA-cGAS-STING axis and the associated MSC senescence. Recovering mitochondrial function by Mito TEMPO inhibited the activation of mtDNA-cGAS-STING axis and reversed MSC senescence. In vivo, using rat hindlimb unloading (HU) model to simulate microgravity, it was found that inhibition of STING ameliorated MSC senescence induced by HU. Together, our study demonstrated that simulated microgravity induces MSC senescence by the activation of cytosolic mtDNA-cGAS-STING axis and indicated cGAS-STING pathway as a therapeutic target of MSC senescence under microgravity.
