Abstract Alzheimer’s disease (AD) exhibits marked sex differences in disease prevalence, progression, and therapeutic responsiveness, with women disproportionately affected by both cognitive decline and neuropathological burden. Although sex hormones such as estrogen, progesterone, and testosterone have demonstrated neuroprotective effects in experimental systems, clinical outcomes of hormone-based interventions remain inconsistent. Emerging evidence further indicates that sex-specific molecular programs extend beyond endocrine signaling alone and include cell type-specific transcriptional architectures established across the lifespan. Recent single-cell transcriptomic studies have suggested that biological sex fundamentally shapes multicellular brain vulnerability. However, prevailing preclinical systems incompletely model human endocrine aging, sex chromosome biology, and patient-specific genetic heterogeneity, thereby limiting translational relevance. Human induced pluripotent stem cell (iPSC)-derived neural systems provide a new platform for mechanistically interrogating sex-specific pathways within human genetic backgrounds. By preserving donor-specific genetic backgrounds and sex chromosome complement, iPSC-derived neurons, astrocytes, microglia, and multicellular systems enable controlled investigation of hormone-responsive phenotypes, APOE-associated mechanisms, and cell type-specific transcriptional programs. However, their developmental immaturity and incomplete representation of systemic aging, vascular, immune, and endocrine physiology limit direct extrapolation to patients. Integration of these cellular systems with human omics datasets, neuropathological observations, and clinical studies may therefore help address specific components of the translational gap in AD.
Abstract Aging is increasingly recognized as a systemic process, yet the mechanisms by which signals from senescent peripheral cells accelerate brain aging remain poorly defined. Here, we used chronic exposure of human cerebral organoids to the secretome of senescent osteocytes to investigate how peripheral aging signals from bone reshape brain tissue architecture. We combined spatially resolved optical fiber-based interferometry nanoindentation with transcriptomic and immunofluorescence profiling, revealing distinct mechanical features across complementary measurements, including lower apparent modulus in intact organoids and spatially localized regions of elevated modulus in cryosectioned specimens. This spatially heterogeneous biomechanical remodeling was accompanied by upregulation of extracellular matrix, inflammatory, and senescence pathways, and suppression of neurodevelopmental and synaptic gene networks. Our results suggest that chronic paracrine exposure to senescent osteocyte-derived secretome is associated with localized extracellular matrix-related remodeling and mechanical vulnerability in human brain tissue, providing insight into how peripheral cellular senescence may contribute to regional brain fragility during aging. These pilot-scale findings were obtained using a single iPSC line and a single conditioned-medium batch, with one to six experimental replicates per condition across assays; the mechanical analyses were exploratory.
BACKGROUND:The management of severe diabetic foot ulcers (DFUs) remains a major clinical challenge. Tibial cortex transverse transport (TTT) has emerged as an effective surgical intervention, but its underlying mechanism, particularly concerning stem cell mobilization and signaling pathways, is largely unknown. METHODS:A diabetic DFU model was established in New Zealand White rabbits using STZ, followed by TTT surgery. Wound healing was evaluated through photography, H&E, and Masson's trichrome staining. Angiogenesis was assessed by High-resolution X-ray angiography and immunofluorescence. Bone marrow-derived mesenchymal stem cell (BMSC) mobilization was analyzed via CFU-F assays and flow cytometry. Serum levels of SDF-1α, CXCR4, VEGF, and Ang2 were measured by ELISA and qRT-PCR. The activity of the Wnt/β-catenin pathway was determined by Western blot. RESULTS:TTT significantly accelerated wound closure and enhanced tissue regeneration, with improved epidermal/dermal restoration and collagen deposition. Consistently, neovascularization in wounds was markedly promoted. Mechanistically, TTT activated the Wnt/β‑catenin signaling pathway in BMSCs, which was associated with enhanced BMSC quantity, mobilization, and migration capacity. Inhibition of this pathway attenuated the TTT‑induced pro‑healing effects. CONCLUSION:TTT promotes healing of DFUs primarily by activating the Wnt/β-catenin pathway in BMSCs, thereby enhancing their mobilization, homing, and pro-angiogenic capacity. This study reveals a key molecular mechanism underlying TTT's efficacy and supports its therapeutic potential for refractory DFU.
Cancer stem cells (CSCs) constitute a rare yet highly adaptable tumor subpopulation that drives tumor initiation, intratumorally heterogeneity, metastasis, recurrence, and therapy resistance. Emerging evidence indicates that mitochondrial dynamics and mitochondrial ion signaling form an interconnected regulatory network that enables CSCs to remodel their metabolic and signaling states in response to environmental and therapeutic stress. Mitochondrial architectural remodeling through fission, fusion, biogenesis, and mitophagy cooperates closely with mitochondrial Ca2+ signaling and ion transport systems, including the mitochondrial calcium uniporter (MCU), voltage-dependent anion channels (VDACs), and mitochondrial K+ channels, to regulate mitochondrial membrane potential, oxidative phosphorylation (OXPHOS), reactive oxygen species (ROS) signaling, and bioenergetic adaptation. Selected plasma membrane and ER-associated ion channels further contribute by modulating mitochondrial signaling pathways. Together, these processes govern CSC plasticity, adaptive stress tolerance, and stemness-associated programs, facilitating survival under hypoxia, nutrient deprivation, and anticancer therapy. In this review, we explore how mitochondrial dynamics and ion signaling converge to shape CSC metabolic flexibility and therapeutic resistance. We further discuss emerging diagnostic and therapeutic opportunities targeting mitochondrial dynamics-ion signaling crosstalk, while highlighting key challenges, including CSC heterogeneity, metabolic adaptability, and the need for selective strategies capable of eliminating CSCs while sparing normal stem-cell populations.
BACKGROUND:Loss-of-function mutations in the ABCA4 gene cause Stargardt disease (STGD1), the most common inherited macular dystrophy leading to progressive central vision loss. METHODS:Here, we generated human induced pluripotent stem cell-derived retinal organoids harboring a premature stop codon in exon-24 of ABCA4 to evaluate the impact of this mutation on mRNA and protein levels in a human model. RESULTS:Immunofluorescence analysis revealed the absence of ABCA4 protein in the mutant photoreceptor outer segment discs, while single-cell RNA sequencing detected no major transcriptional alterations in rods and cones. Unexpectedly, differential gene expression and pathway enrichment analyses of Müller glial cells and astrocytes highlighted disruption of neuronal development, microenvironment of glial cells, intercellular communication, and programmed cell death pathways. CONCLUSIONS:These findings suggest that ABCA4 deficiency in photoreceptor discs may trigger early stress-associated transcriptomic responses in retinal glial cells prior to overt photoreceptor degeneration, potentially contributing to Stargardt disease pathogenesis.
