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.

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.

Two-cell-like cells (2CLCs), a rare totipotent-like population within mouse embryonic stem cells (mESCs) cultures, serve as a valuable model for studying early embryonic events like zygotic genome activation. However, the molecular mechanisms restraining their spontaneous emergence remain elusive. Here, we identify Msl3, an essential component of the MSL complex that is required for H4K16ac deposition, as a key suppressor of 2C-like reprogramming. Msl3 mediated H4K16ac promotes the expression of LINE1 retrotransposons, which act as upstream repressors of the 2C-lineage master regulator Dux. Consequently, Msl3 depletion reduces LINE1 expression, de-represses Dux, and robustly activates 2C-specific genes. Furthermore, LINE1 inhibition leads to heterochromatin dispersal and fragmented nucleoli. Our findings unveil a novel MSL3-H4K16ac-LINE1-Dux axis that actively safeguards mESCs pluripotency by suppressing a latent 2C-like program.

Organoid technologies offer promising new ways to study human biology and develop innovative therapies. While their scientific potential is clear, public awareness and acceptability remain largely unexplored - critical factors for ethical and equitable implementation. We conducted the first national survey of Australians (N = 502) to assess awareness, knowledge, attitudes, and acceptability of organoid technology. Awareness of stem cells was high, but organoids were largely unfamiliar. After a brief explanatory video, participants appeared to have more accurate conceptual framing (e.g., organoids as "research tools" and "mini-organs"), though objective knowledge remained limited. There was strong support for organoids, and more people expressed willingness to donate cells for stem cell or organoid research than have previously done so. Acceptability was correlated with attitudes toward animal research, knowledge, and some sociodemographic factors. Overall, public endorsement of organoid technology appears high but conditional, underscoring the need for transparent governance, clear consent, and inclusive communication.

Ischemic stroke remains a major cause of long-term disability worldwide. Despite advances in acute reperfusion therapies, many survivors experience persistent neurological deficits due to irreversible neuronal loss and limited endogenous repair, highlighting the need for effective regenerative strategies. Mesenchymal stem cells (MSCs) have emerged as promising candidates for cell-based therapy because of their multimodal paracrine effects, including immunomodulation, promotion of angiogenesis and neurogenesis, attenuation of neuroinflammation, and enhancement of endogenous neuroplasticity. This Concise Review synthesizes the current clinical evidence supporting MSC therapy for ischemic stroke, critically examines the biological and translational determinants of therapeutic efficacy, and discusses emerging strategies, including engineered MSCs, extracellular vesicle (EV)-based therapies, and integration with neurorehabilitation. A structured literature search of PubMed/MEDLINE, Embase, Web of Science, and the Cochrane Library through June 2026 prioritized randomized controlled trials, systematic reviews, and meta-analyses. The largest contemporary meta-analysis, encompassing 30 clinical studies and 1217 participants, confirmed the favorable safety profile of MSC therapy while emphasizing the need for larger, standardized randomized trials to establish definitive clinical efficacy. Available evidence indicates that MSC therapy is generally safe, with serious treatment-related adverse events being uncommon, and may improve neurological impairment and functional recovery. However, heterogeneity in cell source, manufacturing protocols, administration route, treatment timing, dosing strategies, and patient selection continues to limit definitive conclusions regarding efficacy. Future progress will depend on standardized Good Manufacturing Practice-compliant manufacturing, validated potency assays, optimized patient selection, identification of the optimal therapeutic window, and integration of engineered MSCs, EV-based therapies, and combination approaches with neuromodulation.

The landmark derivation of induced pluripotent stem cells (iPSCs) sparked an enormous range of research on development of diverse cell populations. Perhaps no aspect of this work has been as productive as studies on blood and immune cell production. Indeed, essentially all human blood cell populations can be derived from human iPSCs. While derivation of transplantable hematopoietic stem cells (HSCs) from iPSCs has been relatively challenging, clinical translation of iPSC-derived immune cells has been particularly productive. Notably, more patients have been treated with iPSC-derived natural killer (NK) cells than any other iPSC-derived cell type. Use of iPSCs provides a key platform to incorporate multiplexed gene edits before differentiation, enabling NK cells to be engineered with tumor-targeting CARs, cytokine support for improved persistence, enhanced tumor trafficking, and resistance to host immune rejection, modifications uniformly expressed across the entire cellular product. While T cells, macrophages and other immune cells can be produced from human iPSCs, iPSC-derived NK cells have been the most widely used in clinical trials for treatment of refractory malignancies, as well as autoimmune disease. This review summarizes research with a focus on clinical translation of iPSC-derived immune cells, as well as highlights continued challenges and prospects of this field.

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.