CAR T cell therapy has demonstrated remarkable efficacy in treating haematological malignancies, including B-cell lymphomas, B-cell leukaemias, and multiple myeloma. CAR T cell therapy for acute myeloid leukaemia (AML) is also urgently needed. One of the major challenges is identifying AML-specific antigens, since many potential candidates (e.g. CD33, CD123, CLL-1, CD70, TIM-3 and FLT3) are also expressed on normal haematopoietic progenitors. This can lead to 'on-target/off-tumour' toxicity and bone marrow aplasia. CAR NK cell therapy for AML shows promise as a lower-toxicity, off-the-shelf alternative. NK cells have a lower inherent risk of GVHD and may cause milder CRS/ICANS. In this review, we will describe the current status of CAR T/NK cell development for AML. We will also introduce a new CAR T-cell or NK-cell therapy that targets mismatched HLA-DRB1 in patients with AML who have relapsed following an allogeneic haematopoietic stem cell transplant.

The mechanistic role of trisomy 8 in the development of myelodysplastic syndrome (MDS) remains poorly defined. Here, we generated a trisomy 8 mouse model by transferring a human chromosome 8 into murine embryonic stem cells and prospectively examined the effects on hematopoietic stem cells (HSC) by trisomy 8. The expression of inflammatory genes was enhanced, and hematopoietic programs mediated by transcription factors and polycomb repressive complex 2 (PRC2) were dysregulated in trisomy 8 HSC, which impaired their self-renewal and balanced differentiation. Trisomy 8 HSC altered the chromatin accessibility and conformations and activated Y chromosome genes, such as Uty/Kdm6c epigenetic modifier, which is known to demethylate histone H3K27me3 modification. The Uty gene facilitated the activation of PRC2-target and Runx1-target genes in leukemogenesis and drove the proliferation of human trisomy 8 leukemic cells. Since the RUNX1 gene is frequently mutated in patients with trisomy 8 MDS, its deletion attenuated the enhanced expression of inflammatory genes and mitigated the impaired self-renewal of trisomy 8 HSC in mice. Our findings reveal that trisomy 8 altered the transcriptional programs and chromatin conformations in HSC and drove a pre-malignant state through activating the expression of Uty, suggesting a route for the development of trisomy 8 MDS.

Transendothelial migration (TEM), is a complex, multistep process impacted by diseases like autoimmune disorders and cancer. Deciphering aspects of the process enhances our understanding and possibilities for disease treatments. The extent to which this potential can be leveraged is often limited due to conventional assays neither accurately mimicking specific in vivo conditions like sheer stress nor visualizing the whole transmigration cascade, hence missing distinct mechanisms. Flow-based adhesion assays overcome these limitations and allow the use of various endothelial cells from different tissues with distinct properties. So far, a broader and translational assay application is hampered by potential operator-based bias/lack of standardization, as well as poor scalability due to time-consuming manual analysis. In this study, we successfully combined this assay with AI-based analysis including subsequent classification of cell-transmigration phases by a Keras/TensorFlow-based deep learning model. Trained on healthy-donor and pancreatic cancer patient-derived T cells, the model achieved a high accuracy of 91.6 % in identifying/categorizing cell transmigration, surpassing the currently accepted 80 %-threshold, therefore qualifying as a fast, standardized AI-based live-cell imaging tool. Additionally, its architecture grants highly convenient reconfiguration for various disease-model investigations. Hence, by combining an affordable and simplistic, yet potent live-cell-imaging technique with a comprehensive AI-approach, we have established a powerful tool which allows for integrating TEM-assays into various disease models.

CD34 has long been defined as a canonical marker for endothelial progenitors as well as hematopoietic stem cells, implicating its role in vascular development and hematopoiesis. However, the precise developmental hierarchy and lineage potential of CD34+ cells remain controversial. In this study, we integrated inducible genetic lineage tracing techniques, proteomics and single-cell RNA-seq (scRNA-seq) analyses to elucidate the dynamic developmental trajectory of CD34+ cells during various embryonic periods in both humans and mice. Remarkably, our analyses indicated that the progeny of CD34+ cells marked distinct, spatiotemporally restricted progenitor waves with divergent fates, at which point cells adopted endothelial, hematopoietic and fibroblastic fates, respectively. During gastrulation (E6.5-E8.5), an initial wave of CD34+ progenitors predominantly orchestrates vasculogenesis via a Kdr-dependent mechanism. Subsequently, from E9.5 to E14.5, cell cycle activation serves as a molecular switch, facilitating the endothelial-to-hematopoietic transition (EHT) of CD34+ progenitors. Unexpectedly, we identify a wave of CD34+ progenitors in late embryogenesis that gives rise to fibroblasts, distinct from earlier endothelial or hematopoietic lineages. Furthermore, because umbilical cord blood is a valuable source of different circulating stem/progenitor cells, we distinguish circulating endothelial progenitors from fibroblast progenitors in human cord blood by unique molecular signatures, with GFPT2 specifically marking the fibroblast progenitors. Collectively, our study provides a high-resolution spatiotemporal atlas of CD34+ cells during embryogenesis, redefining the temporal shifts of CD34+ cells in cell states and offering a precise framework for manipulating CD34+ cells in regenerative medicine.

Melanocyte stem cells (McSCs) are a crucial melanocyte reservoir within the hair follicle niche. This review provides an overview of the processes for McSC quiescence and activation. Because McSCs closely interact with hair follicle stem cells, we have focused on this interaction. Given the high prevalence of hair graying, the McSC system serves as a model for cellular aging. Here, we highlight current research on the mechanisms of hair graying.

Iron metabolism is increasingly recognized as a key player in the development and progression of various cancers. Iron is required for vital cellular processes such as energy production; however, it can also interact with reactive oxygen species to cause cellular toxicity. Consequently, a host of proteins coordinate iron homeostasis, and ferritin stands out as a promising therapeutic target due to its pivotal role in buffering cellular iron levels. This review explores the relevance of ferritin in brain cancers, shedding light on how it influences the biology of both tumor cells and cancer stem cells (CSCs), a population of tumor cells that is notable in their resistance to conventional treatment strategies. Ferritin plays a critical role in protecting against oxidative stress and boosting resistance to ferroptosis, a form of cell death often evaded by CSCs. Development of cutting-edge strategies designed to target ferritin, including ferritinophagy-inducing compounds and novel redox-based therapies that can capitalize on the iron dependency of CSCs is discussed in context. We propose that the iron addiction of brain cancer cells provides a specific susceptibility, whereby removing their iron buffering mechanism via targeting of ferritin can result in favorable treatment outcomes, including the induction of iron-dependent cell death. Future studies on the modulation of ferritin offer a ground-breaking therapeutic strategy to undermine CSC-driven tumor growth, overcome resistance to conventional therapies, and ultimately improve treatment outcomes for patients battling brain cancers.

Dental tissues development involves two distinct cell lineages: mesenchymal cells (derived from the cranial neural crest) and epithelial cells (derived from oral ectoderm and pharyngeal epithelium). Emerging evidence highlights the remarkable functional heterogeneity of cranial neural crest-derived dental mesenchymal stem cells (DMSCs), exhibiting pluripotency, self-renewal, and differentiation capacities. This heterogeneity enables a single DMSC population to generate specialized subpopulations with unique roles in teeth and periodontal tissues formation. Significant progress has been made in characterizing six major types of DMSCs and two populations of closely related cells: Tooth germ progenitor cells (TGPCs) and dental follicle stem cells (DFSCs), critical during early morphogenesis; Stem cells from human exfoliated deciduous teeth (SHEDs) and apical papilla stem cells (SCAPs), pivotal for root development; Dental pulp stem cells (DPSCs), periodontal ligament stem cells (PDLSCs), gingival mesenchymal stem cells (GMSCs) and alveolar bone mesenchymal stem cells (ABMSCs), essential for maintaining and regenerating mature dental tissues. A key breakthrough has unveiled the development and hierarchy of DMSCs by applying new techniques like single-cell RNA sequencing (scRNA-seq). To integrate insights into the development of teeth and periodontal tissues, this review synthesizes current knowledge on both developmental heterogeneity and subpopulation heterogeneity within DMSCs and related cells. These insights not only advance fundamental understanding of the developmental mechanisms of teeth and periodontal tissues, but also establish a promising framework for achieving more efficient tissue regeneration and repair engineering.

Diseases associated with obesity and metabolic dysregulation, such as diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD) promote chronic low-grade inflammation, which in turn, may enhance the risk for cardiovascular disease. Emerging evidence in recent years suggests that chronicity of inflammation involves alterations in bone marrow homeostasis. Obesity-related inflammation and metabolic stress, including hyperglycemia or hyperlipidemia, may trigger rewiring of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow, driving production of myeloid cells with heightened inflammatory capacity that in turn fuel and sustain chronic inflammation. This process is akin to trained immunity and may promote an inflammatory memory that links metabolic disorders to their cardiovascular complications. Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by aging-related emergence of somatic mutations in hematopoietic cells that clonally expand and bear higher inflammatory potential. Importantly, a bidirectional link between CHIP and metabolic disorders as well as their cardiovascular sequelae emerges. Here, we review current concepts regarding the links between bone marrow biology and metabolic diseases and associated chronic inflammation.

Post-traumatic stress disorder (PTSD) is a debilitating neuropsychiatric condition triggered by severe trauma, characterised by dysregulated fear circuitry, hippocampal atrophy with impaired neurogenesis, chronic neuroinflammation, neuroendocrine dysregulation, and disrupted prefrontal-limbic connectivity. Existing treatments are largely symptomatic, failing to address underlying neurobiological deficits. Emerging regenerative approaches using human stem cells; particularly induced pluripotent stem cell-derived neural progenitor cells (iPSC-NPCs), human embryonic stem cells (hESCs), mesenchymal stem cells (MSCs), and their extracellular vesicles (EVs), offer mechanistic plausibility for repair through direct neuronal replacement, paracrine neurotrophic support (e.g., BDNF, GDNF, VEGF), immunomodulation (e.g., shifting microglia to anti-inflammatory phenotypes), and promotion of synaptic plasticity and epigenetic reprogramming. Preclinical evidence remains limited and largely indirect, with sparse PTSD-specific studies (e.g., one report of iPSC-NPC transplantation reducing fear behaviour and enhancing hippocampal BDNF/neuronal density in a rat model) supplemented by convergent data from adjacent CNS injury paradigms. MSC- and iPSC-derived EVs, enriched with regulatory miRNAs (e.g., miR-124, miR-21, miR-146a), emerge as a safer, cell-free alternative with strong immunomodulatory potential and greater translational feasibility. However, reproducibility is constrained by model variability, lack of independent replication, and absence of PTSD-focused clinical trials. Major challenges include tumorigenicity risks (especially for pluripotent-derived cells), immune rejection, epigenetic/genomic instability, manufacturing scalability, stringent regulatory requirements, and elevated ethical thresholds for invasive therapies in a non-lethal psychiatric disorder. This review examines how stem cell actions align with PTSD brain changes, critically assesses the limited evidence, and suggests a careful translational plan.

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.