STEM CELLS最新文献

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.

Background: Diabetic kidney disease (DKD), the leading cause of end-stage renal disease, involves injury across multiple renal compartments. Autophagy dysregulation is a key pathogenic mechanism and may reduce Klotho, a renoprotective protein diminished in DKD. This study evaluated whether bone marrow-derived mesenchymal stem cells (MSCs), combined with empagliflozin and calorie restriction, could modulate autophagy and preserve Klotho expression in DKD.

Methods: Male BTBRob/ob mice, a leptin-deficient model that develops diabetes and DKD in a progressive manner, were assigned to experimental groups and euthanized at 14-15 or 18-20 weeks. Kidney tissues were analyzed by qPCR, Western blot, and immunohistochemistry.

Results: MSCs therapy improved hyperglycemia in a time-dependent manner (P < .0001), decreased albuminuria, and modestly improved eGFR, though weight gain persisted. Treatment modulated LC3 protein expression in cortical and medullary regions (P < .05), suggesting attenuation of early autophagy hyperactivation. It also helped maintain Klotho expression, correlating with reduced oxidative stress (P < .05).

Conclusion: Overall, MSCs combined with empagliflozin and calorie restriction show promise as a translational approach for DKD, warranting further long-term preclinical studies.

Background: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) enable cardiovascular disease modeling and regenerative research but exhibit substantial heterogeneity and incomplete metabolic maturation. Palmitate (PA) and oleate (OA) can promote aerobic maturation, although responses vary. Despite sex differences in adult cardiac metabolism, sex effects in hiPSC-CMs remain poorly defined.

Methods: We assessed sex-dependent metabolic and functional responses in hiPSC-CMs from three male and three female lines treated with PA or OA. Contractile function, aerobic metabolism, and transcriptomic profiles were evaluated.

Results: Sex differences were modest at baseline but pronounced after FA treatment. Male- and female-derived hiPSC-CMs responded differently to PA and OA across contractile, metabolic, and transcriptional measures, indicating that FA identity and sex jointly shape hiPSC-CM phenotypes.

Conclusions: Sex contributes to hiPSC-CM heterogeneity and modulates responses to FA-based maturation. Incorporating sex-specific metabolic and functional regulation may improve the consistency and physiological relevance of hiPSC-CM maturation strategies.

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.

Neural organoids have transformed experimental neuroscience by enabling human-specific models of brain development, function, and disease. Emerging at the intersection of stem cell biology and tissue engineering, these self-organizing systems recapitulate key aspects of neurogenesis, gliogenesis, and circuit formation within a controllable in vitro context. Advances in guided patterning, vascularization, and electrophysiological monitoring have enhanced structural and functional fidelity, enabling the study of dynamic processes previously inaccessible in human models. Beyond developmental biology, neural organoids have broad translational applications, including modeling neurodevelopmental and neurodegenerative disorders, screening pharmacological compounds, and testing regenerative strategies. Integration with microfluidics, bioelectronic interfaces, and computational modeling further expands their analytical capacity, transforming organoids into modular and quantifiable platforms for mechanistic and therapeutic discovery. Despite this progress, key challenges remain, including limited maturation, inter-organoid variability, and incomplete physiological integration. Addressing these limitations requires standardized differentiation protocols, robust functional benchmarks, and cross-disciplinary collaboration. The goal is not to replicate the brain in miniature, but to reconstruct its organizing principles in an experimentally accessible system. From this perspective, neural organoids serve as a bridge between biology and technology, offering new insights into human neural complexity while advancing neuroscience and medicine.

Organoid technology has emerged as a powerful platform for modeling human development, disease, and drug responses. Advances in stem cell biology and bioengineering have enabled the generation of increasingly sophisticated organoid systems that recapitulate key structural and cellular features of native tissues. However, despite substantial progress, the translational impact of organoids in regenerative medicine remains limited. Greater structural complexity and anatomical resemblance have not consistently translated into sustained therapeutic function or clinical applicability. Major barriers include incomplete maturation, inadequate vascular and immune integration, limited long-term functional stability, and challenges in reproducibility and scalability. These limitations reflect a conceptual mismatch between structure-driven organoid development and the functional requirements of regenerative medicine. Here, we propose a function-first framework in which regenerative organoids are engineered and evaluated according to measurable therapeutic outcomes, including tissue-specific function, vascular integration, immune compatibility, reproducibility, scalability, and long-term stability. We further discuss emerging bioengineering strategies, including vascularization, immune incorporation, organ-on-a-chip platforms, advanced biomaterials, and automated manufacturing, that may accelerate clinical translation. Reframing organoids as functionally engineered therapeutic platforms rather than increasingly complex anatomical models provides a conceptual foundation for advancing regenerative organoid therapies.

Vacuolar protein sorting 4B (VPS4B) is part of the endosomal sorting complex required for the transport machinery and is essential for autophagosome completion. Vps4b mutation might reduce the ability of dental follicle cells to differentiate during the mineralization process. However, the role of VPS4B in osteogenic and adipogenic differentiation from mesenchymal stem/progenitor cells remains to be explored. In the present study, we observed a substantial presence of VPS4B in bone, as well as an increase in its expression levels during the osteogenic and adipogenic differentiation of mesenchymal progenitor cells. Functional experiments revealed that VPS4B facilitated the differentiation of both osteoblasts and adipocytes. Further mechanistic investigations revealed that VPS4B was involved in autophagy in mesenchymal progenitor cells and the positive influence of VPS4B on osteogenic and adipogenic differentiation was mitigated in the context of autophagy inhibition, indicating that the pro-osteogenic and pro-adipogenic effects of VPS4B are dependent on the autophagy signaling pathway. Our research suggests that sustaining VPS4B expression at an optimal level may be advantageous for the maintenance of bone and fat homeostasis.

Background: Breast cancer (BC) has a high incidence and mortality rate among women. Doxorubicin (DOX) is one of the standard chemotherapeutic drugs for BC. However, chemoresistance to DOX represents a major therapeutic obstacle, and its underlying mechanisms remain elusive. CircEGFR (hsa_circ_0080222) is significantly upregulated in BC tissues and drives the malignant progression of BC. However, the role of circEGFR in DOX resistance remains unclear.

Methods: MTT and colony formation assays were used to assess cell growth. Quantitative real‑time PCR and western blot were performed to examine gene expression at the mRNA and protein levels, respectively. Spheroid formation and ALDH activity assays were employed to evaluate cell stemness. RNA immunoprecipitation was used to explore the interaction between circEGFR and IGF2BP2.

Results: CircEGFR expression was significantly upregulated in DOX-resistant MCF-7 (MCF-7/DOX) cells. CircEGFR overexpression attenuated DOX sensitivity in MCF-7 cells, as evidenced by increased cell viability and enhanced proliferative capacity. Notably, circEGFR also enhanced cancer stem cell (CSC) properties in BC cells. Conversely, circEGFR knockdown reduced chemoresistance and stem-like properties in both MDA-MB-231 and MCF-7/DOX cells. Mechanistically, circEGFR interacted with IGF2BP2 to enhance the stability of the stem cell marker SOX2 mRNA, resulting in elevated SOX2 expression. Rescue experiments demonstrated that silencing IGF2BP2 or SOX2 abrogated circEGFR-mediated chemoresistance and stemness properties in BC cells.

Conclusion: Our study demonstrates for the first time that circEGFR drives DOX chemoresistance and maintains cancer stemness in BC cells via the IGF2BP2/SOX2 axis. Targeting circEGFR may be considered a promising therapeutic strategy for overcoming chemotherapy resistance in BC.