Stem Cell Reviews and Reports最新文献

All cells within an organism share identical genetic material, yet epigenetic mechanisms determine stem cell fate by precisely regulating transcriptional programs. Histone acetylation is a key epigenetic modification that establishes an open chromatin structure, which is recognized by proteins involved in modulating chromatin dynamics essential for stem cell functions. Bromodomain (BrD)-containing proteins specifically recognize acetylated lysines on histones and act as critical epigenetic regulators within larger protein complexes. This review comprehensively describes the BrD protein family, highlighting their structural classifications and diverse functions, and explores their critical roles in regulating stem cell pluripotency and differentiation, and their implications in cancer development. Dysregulated BrD proteins can drive cancer by increasing stem cell-like features and tumor heterogeneity, making them a potential target for cancer treatment. Furthermore, this review emphasizes BrD inhibitors as promising therapeutic targets capable of targeting cancer stem cells and potentially mitigating cancer progression. Understanding the detailed functions and regulatory pathways of BrD proteins may open new avenues for improved cancer stem cell-targeted therapies.

Objective: The global shortage of platelets presents a significant challenge in healthcare. Although human induced pluripotent stem cells (hiPSCs) offer a renewable source for ex vivo platelet production, the current approach remains constrained by heterogeneity, low yield, and high costs. This study introduces an optimized differentiation scheme (ODS) to improve ex vivo platelet differentiation from hiPSCs.

Methods: A systematically optimized culture protocol was developed, incorporating: (1) a higher initial dose of embryoid body (EB) cells, (2) refining culture medium, (3) substitution of cytokines with small molecules, and (4) enhancement of megakaryocyte (MK) polyploidization via small-molecule supplementation. Feasibility and effectiveness were evaluated using microscopy, cell counting, flow cytometry, Wright-Giemsa staining, immunofluorescence (IF), and transmission electron microscopy (TEM).

Results: Increasing the initial EB cell count significantly promoted megakaryocyte production and accelerated the process. A serum-free medium supplemented with human platelet lysate (HPL) was favorable for megakaryocyte generation. Small molecules 740Y-P and butyzamide effectively substituted SCF and TPO for differentiation, while the combination of blebbistatin and 616452 enhanced megakaryocyte maturation. Mature megakaryocytes continuously generated functional platelets that, upon thrombin activation, facilitated fibrin clot formation and contraction in vitro. This method shortened differentiation to 19 days, enhanced output to 1.42 CD41⁺ megakaryocytes and 14.9 platelets per iPSC, and reduced costs by 58.3%.

Conclusion: We have established a cost-effective strategy for platelet production via hiPSC differentiation, with potential applications in cell therapy and gene editing.

Demyelinating diseases, such as multiple sclerosis, damage the protective myelin sheaths of the central nervous system. The development of effective therapies has been hampered by the lack of models that accurately replicate human myelin biology. Here we present a novel method to generate human myelin spheres (MyS) by coculturing of hPSC-derived neuronal and oligodendrocyte precursor cells, to create myelinated neurons. Using multimodal analyses including confocal and (electron)microscopy, single-nuclei transcriptomics, lipidomics, and electrophysiology, we demonstrate myelination in MyS as early as six weeks into coculture. These myelinated structures mature over time into multilamellar and compacted myelin sheaths with lipid compositions and transcriptomic profiles mirror the temporal dynamics of in vivo human oligodendrocyte development and neuronal myelination, resembling those of late fetal oligodendrocytes. By employing lysolecithin-induced demyelination and Rabies virus infection experiments, we demonstrate the potential of MyS as an innovative, physiologically relevant platform for studying myelin-related neurodegeneration and neuroinfection.

Despite recent novel drug approvals and numerous treatment options, the steroid-refractory chronic graft-versus-host disease (SR-cGvHD) remains a significant clinical problem. We aimed to evaluate the efficacy and safety of available therapies in adult patients, based on a systematic review and meta-analysis. The analyzed treatment options included: axatilimab, belumosudil, extracorporeal photopheresis (ECP), ibrutinib, imatinib, rovadicitinib, and ruxolitinib. The endpoints included: best overall response rate (ORR), 12-month failure-free survival (FFS), the ratio of patients who discontinued therapy due to unacceptable toxicity, and the ratio of patients who experienced grade 3-5 adverse events. Rovadicitinib was the most effective treatment option, with manageable safety profile. Axatilimab produced a high response rate, yet worse 12-month FFS. It was a very safe option in SR-cGvHD. Despite promising efficacy, belumosudil produced the highest incidence of adverse events of all drugs. Ruxolitinib was proven to be an efficient and safe drug. Ibrutinib produced poor results in terms of both efficacy and safety. ECP was proven to be a very safe therapy, without spectacular efficacy. The analysis of imatinib yielded inconsistent results. As cGvHD is a disease with a heterogeneous clinical image, clinical experience remains an important factor that affects treatment choice for patients with certain disease manifestations.