Nickel (Ni) is a naturally occurring heavy metal whose environmental levels have been steadily rising due to industrial activities and the widespread use of Ni-containing products. Ni exposure poses significant health risks, and studies in vertebrate models and human populations link Ni to developmental toxicity. However, the mechanisms by which Ni perturbs early developmental programs remain poorly understood. Here, we examined the effects of Ni exposure on pluripotency in mouse embryonic stem cells (mESCs) maintained under pluripotency-supporting conditions. Ni exposure led to aberrant upregulation of genes associated with mesodermal and endodermal lineages, while ectodermal gene expression remained largely unaffected. However, the expression of core pluripotency factors was preserved, indicating that Ni does not induce differentiation but instead disrupts normal transcriptional control within the pluripotent state. Mechanistically, Ni exposure caused a selective loss of the repressive histone modification H3K27me3 at bivalent promoters of mesoderm-associated genes without altering global H3K27me3 levels. Pharmacological inhibition of H3K27me3 demethylases attenuated Ni-induced gene activation, suggesting that localized H3K27me3 removal contributes to this aberrant activation of developmental genes. ESCs normally exist as heterogeneous populations that dynamically fluctuate between naïve and lineage-primed pluripotent states. Our findings indicate that Ni exposure perturbs this equilibrium through aberrant activation of lineage-associated genes while core pluripotency remains preserved. Such dysregulation of early transcriptional programs may predispose cells to abnormal fate decisions. These findings suggest a mechanistic link between Ni exposure and developmental abnormalities.

To explore the role of bone marrow mesenchymal stem cell-derived exosomes (BMSCs-Exos) in promoting the motility and functional enhancement of tendon-derived stem cells (TDSCs) and assess their potential in tendon regeneration and repair.

Multiple myeloma (MM) is a hematological malignancy that depends on the bone marrow microenvironment, and obesity, along with intramedullary adipocytes, is associated with an increased risk of developing MM. Adipocytes protect MM cells from chemotherapy by secreting adipokines and activating autophagy, while MM cells reprogram bone marrow adipocytes. Strategies to inhibit adipocyte lipolysis have been proposed as a novel approach for treating MM. MM progression is dependent on glutamine and glucose metabolism. Lipoproteins, particularly cholesterol levels, are becoming prognostic factors in MM. However, studies on lipids lack long-term paired data. Therefore, we analyzed long-term follow-up data from 115 autograft patients at Beijing Jishuitan Hospital over the past 7.5 years to investigate the long-term changes in lipid metabolism during the course of MM and the impact of efficacy. Teaser Abstract: Is blood cholesterol a gauge for myeloma relapse? A landmark study shows that with remission, cholesterol levels promptly rise, only to markedly drop upon the cancer's recurrence-unveiling a straightforward new approach to disease tracking.

With population aging, chemotherapy-induced thrombocytopenia (CIT) is a severe complication in elderly cancer patients, yet effective preventive and therapeutic strategies remain limited. Here, we demonstrate that dietary restriction (DR) significantly mitigates 5-fluorouracil (5-FU)-induced thrombocytopenia and promotes platelet recovery in both young and aged mice. Mechanistically, DR improves mitochondrial homeostasis in hematopoietic stem and progenitor cells and enhances their hematopoietic reconstitution capacity. This preconditioning facilitates mitochondrial activation after chemotherapy, thereby promoting megakaryocytic lineage recovery. Pharmacological mitochondrial activation in ad libitum-fed mice mimics the protective effects of DR, whereas mitochondrial inhibition in DR-treated mice markedly attenuates these benefits. Clinically, cancer patients with lower pre-chemotherapy body mass index ([BMI] 18.5-22.95 kg/m2) showed a lower incidence of CIT following 5-FU treatment than those with higher BMI. Together, we show that short-term DR significantly mitigates CIT and that targeting mitochondria may represent a novel therapeutic strategy for CIT in elderly cancer patients.

Neurons derived from human pluripotent stem cells (hPSCs) are valuable models for studying brain development and developing therapies for brain disorders. Evaluating hPSC-derived neurons requires assessing their electrical activity, which can be achieved using multi-electrode arrays (MEAs) for extracellular recordings. Because each electrode channel generally detects activity from multiple neurons, resolving the activity of single neurons requires a process called spike sorting. However, currently available methods were not developed for analyzing data from hPSC-derived neurons and require complex workflows and time-consuming manual intervention. Here, we introduce a semi-automated MEA spike sorting software (SAMS) designed specifically for low-density MEA recordings of cultured neurons. SAMS outperforms commercially available automated spike sorting algorithms in terms of accuracy and greatly reduces computational and human processing time. By providing an accessible, efficient, and integrated platform for spike sorting, SAMS enhances the resolution and utility of MEA in disease modeling and drug development using hPSC-derived neurons.

The clinical application of human stem cell-derived islet organoids (SC-islets) is hindered by immaturity and ischemia-induced dysfunction post-transplantation. Hypoxia-driven angiogenesis is a common adaptation, but the metabolic fragility of SC-islet β cells leads to early functional damage and suppressed vascular endothelial growth factor A (VEGFA) expression, thereby delaying vascularization and causing graft loss. The key challenge in SC-islet transplantation is how to prevent hypoxia-induced stress and promote rapid angiogenesis. We found that excessive zinc in SC-islet β cells induces oxidative modification that inhibits AMP-activated protein kinase (AMPK) activity. Chemical inhibition of zinc transportation activates AMPK, enhances functional maturation, improves hypoxia resistance, and increases hypoxia-inducible factor 1α (HIF1A)-independent VEGFA expression to facilitate endothelial cell integration. In diabetic animal models, this approach significantly improved hypoxia resistance, accelerated angiogenesis, and enhanced glycemic control. Our findings demonstrate that chemical inhibition of zinc transportation boosts SC-islet functional competence, offering a potential strategy to advance pre-adaptation to stress in regenerative medicine.

Detoxification of endogenous aldehydes is critical for preserving genomic integrity in hematopoietic stem cells. In this issue, Kamimae-Lanning et al.1 show that excess formaldehyde can drive clonal hematopoiesis through attrition of blood-forming progenitors, accelerating neutral drift in the absence of known genetic drivers of positive selection.

Autoimmune hepatitis (AIH) is a progressive, life-threatening liver disease that remains treated largely with broad immunosuppression. In this issue of Cell Stem Cell, Jing and colleagues reprogram follicular helper T (Tfh) cells in vivo into antigen-specific FOXP3⁺ CAR-Tfh cells to restore immune tolerance by rewiring core drivers of autoimmunity.

Zinc is required for insulin packaging into secretory granules, yet reduced zinc transporter activity paradoxically enhances beta cell function. In this issue, Wang et al.1 show that pharmacologic inhibition of zinc transport in stem cell-derived islets activates AMPK signaling and improves maturation, hypoxia resistance, VEGFA expression, and graft performance.

Directing the differentiation of human pluripotent stem cells into atrioventricular node-like cells is a critical strategy for restoring atrioventricular node dysfunction in patients. In this issue, Lohbihler et al. define a BMP2-driven protocol to engineer functional conduction bridges that recapitulate the heart's native "gatekeeper" properties in vivo.

How can the effectiveness of exome sequencing be improved for diagnosing infertility, and what are the key challenges and lessons learned from analysing nine unrelated cases?

The p.Thr369Met variant in the glucosylcerebrosidase Beta I gene (GBA1) is associated with Parkinson disease (PD) but its impact is debated. We generated and characterized human induced pluripotent stem cells from PBMCs of three PD patients: one carrying the p.Thr369Met variant in GBA1, and two carrying no GBA1 variants. These lines exhibited typical pluripotent stem cell morphology, expressed pluripotency markers, and displayed normal karyotypes. All lines were transgene-free and capable of in vitro differentiation into the three germ layers. These iPSC lines provide tools to investigate p.Thr369Met variant-specific PD mechanisms and contribute to the development and refinement of targeted therapeutics.

Legg-Calvé-Perthes disease (LCPD) remains a pediatric condition that causes hip joint deformities, with complicated pathogenesis. This study explored the influence of hypoxia-preconditioned human embryonic stem cells (hESCs)-derived exosomes on LCPD and its related mechanism.

Accumulating evidence shows that excess cholesterol and glucose uptake stimulates the expansion of hematopoietic stem/progenitor cells and myeloid progenitors, resulting in increased production of inflammatory cells and atherosclerotic progression. However, the role of other metabolites in plaque progression remains unclear. Hereby, we observed elevated α-ketoglutarate levels in granulocyte-monocyte progenitors (GMPs) of Ldlr-/- mice on a high-fat diet (HFD), determined by targeted metabolomics. On top of HFD, α-ketoglutarate administration further increased GMP proportion, myeloid cell production, and plaque progression in Ldlr-/- mice. The regulation of α-ketoglutarate in atherosclerosis required the expression of its receptor, oxoglutarate receptor 1 (OXGR1), in bone marrow cells (BMCs), as transplantation of OXGR1-/- BMCs attenuated plaque progression compared to transplantation of OXGR1+/+ BMCs in HFD-fed Ldlr-/- recipients. Using targeted metabolomics, single-cell RNA sequencing and validation experiments, we demonstrated that the α-ketoglutarate/OXGR1 axis upregulated the expression of purine nucleoside phosphorylase (PNP) in GMPs, which promoted de novo purine biosynthesis and reduced the levels of nicotinamide mononucleotide and nicotinamide adenine dinucleotide (NAD), thereby disturbing mitochondrial homeostasis and increasing the production of myeloid cells. Furthermore, proteomics data revealed that PNP treatment regulated the redox status by increasing the expression of NAD kinase (NADK), thereby accelerating NAD consumption. Additionally, PNP promoted the transcriptional activation of NF-κB via ubiquitin, enhancing ROS production and inflammation in lineage-/low cells. Spearman's correlation analysis revealed a positive association between isocitrate and low-density lipoprotein cholesterol levels in human plasma. Overall, HFD potentiated α-ketoglutarate, contributing to atherosclerosis.

Matrine (MAT), a commonly employed Chinese botanical, has a long-standing history of application in the treatment of inflammation and cancer. Nevertheless, the precise molecular mechanism underlying MAT's impact on thymoma remains unresolved. Consequently, the objective of this investigation was to assess the influence of MAT on thymomas and ascertain the potential mechanisms through which it modulates the Wnt3a/β-catenin pathway. Thy0517 cells were treated with different doses of MAT to construct a thymoma cell therapy model in vitro, and given Wnt3a/β-catenin pathway agonist Laduviglusib for follow-up experiments. The effect of different doses of MAT on the proliferation, colony formation ability, apoptosis, migration, invasion, and stemness of Thy0517 cells was determined by MTT, colony formation assay, flow cytometry, wound healing assay, Transwell assay, and spheroid formation assay, respectively. Genes and proteins were evaluated by RT-qPCR and/or Western blot. High-dose MAT significantly inhibited the proliferation, migration, invasion, and stemness of Thy0517 cells, which also proved the anti-tumor effect of MAT. The suppressive impact of MAT on cellular function could potentially be augmented through the blockade of the Wnt3a/β-catenin pathway, thereby providing additional evidence for the pivotal role of MAT as a signaling pathway in governing the migratory and invasive capabilities of thymoma cells. We found that MAT has anti-tumor effects, inhibiting the proliferation, migration, invasion, and stemness of thymoma cells by regulating the Wnt3a/β-catenin pathway.

The effect of bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) on intervertebral disc degeneration (IVDD) repair and healing and its possible mechanism were investigated. Tail IVDD puncture was performed on mice, and BMSC-Exos were injected into the joint cavity. The disc morphology was observed by HE staining, apoptosis rate of nucleus pulposus (NP) tissues was determined by TUNEL, and polarization of macrophages and NP cell damage were detected by Western Blot. An in vitro experimental model was established by co-culture of nucleus pulposus (NP) cells and M1 macrophages in a conditioned medium, and the improvement effect of BMSC-Exos on the proliferation of damaged NP cells was detected by CCK-8 assay. NP cell apoptosis was determined by flow cytometry. Inflammatory factors in NP cell supernatant was measured by ELISA. In results: BMSC-Exos reversed the degenerative changes of IVDD in mice. BMSC-Exos promoted the transformation of THP-1 cells from M1 to M2 and inhibited the release of inflammatory cytokines. BMSC-Exos inhibited matrix metallopeptidase 13 (MMP-13), matrix metallopeptidase 3 (MMP-3), and Cleaved caspase-3 expression in damaged NP tissues. BMSC-Exos significantly increased NP cell proliferation and blocked apoptosis. The concentration of inflammatory factors in the supernatant of NP cells treated with BMSC-Exos was significantly down-regulated. Conclusion: BMSC-Exos have a regenerative effect on IVDD, encourage macrophages to transform from M1 to M2, suppress NP cell apoptosis and inflammatory responses, and improve degenerative alterations in the intervertebral disc.

Dermatoporosis (DP) or chronic cutaneous fragility syndrome has traditionally been linked to extracellular matrix (ECM) dehydration, reduced cellular turnover, epidermal thinning, and vascular fragility. However, recent imaging methods and clinical evidence indicate that the dermoepidermal junction (DEJ) might be the earliest change reflecting DP reversal.

Periodontitis is a common inflammatory disease of the oral cavity that often leads to alveolar bone loss and eventually causes tooth detachment, seriously damaging the physical and mental health of patients. This study developed an osteogenic scaffold (G-nHA/SIS) derived from porcine small-intestinal submucosa (SIS), functionalized with Gly-Arg-Gly-Asp-Ser (GRGDS) peptide and nanohydroxyapatite (nHA) to promote alveolar bone regeneration. The scaffold has a three-dimensional (3D) porous structure, similar to that of the natural extracellular matrix (ECM), providing physical support for cell infiltration and nutrient exchange. The GRGDS peptide and nHA work synergistically to promote the proliferation and adhesion of bone marrow mesenchymal stem cells (BMSCs), enhance alkaline phosphatase (ALP) activity, upregulate the expression of osteogenesis-related genes and proteins, and facilitate osteogenic differentiation of cells. In a periodontitis rat model with an alveolar bone defect, the G-nHA/SIS scaffold exhibited excellent biocompatibility and mechanical properties. Its osteogenic effect was comparable to that of commercially available products but with lower cost and easier availability. Therefore, this scaffold has broad clinical application potential in the field of bone repairs.

NOTCH3 variants cause CADASIL (cerebral autosomal dominant arteriopathy and subcortical infarcts and leukoencephalopathy), the most common monogenetic form of small vessel disease (SVD) and vascular dementia (VaD). The molecular mechanisms driving CADASIL pathogenesis remain poorly understood, and no specific treatments are currently available. NOTCH3 is mainly expressed in vascular smooth muscle cells (VSMCs) that arise from different embryonic origins. Using human induced pluripotent stem cell (iPSC) models, we generated origin-specific VSMCs and found that cerebral, but not peripheral, VSMC mimics are selectively vulnerable to NOTCH3 variants. CADASIL iPSC-derived brain-specific VSMCs acquired a synthetic phenotype, accompanied with extensive extracellular matrix accumulation and impaired cell adhesion leading to anoikis. Furthermore, an endothelial-independent nitric oxide signaling was substantially impaired in CADASIL iPSC-derived VSMCs. Phosphodiesterase-5 inhibition successfully reversed the functional abnormality and survival of mutant VSMCs. Our findings uncovered mechanistic insights and suggest a viable therapeutic strategy for NOTCH3-associated SVD/VaD, reinforcing the value of patient-specific iPSCs for disease modeling and potential drug discovery.

It has been demonstrated that both hUCMSC-exo and Cyasterone exhibit protective effects against steroid-induced osteonecrosis of the femoral head (SIONFH). Additionally, studies have shown that CTSD N-glycosylation influences BMSC apoptosis. Based on these findings, we aim to investigate the mechanism of hUCMSCs-exo@Cyasterone in the Dex-induced BMSCs model of SIONFH, focusing on its regulatory role in CTSD N-glycosylation during apoptosis.