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Cerebral organoids co-cultured with patient derived glioma stem cells (GLICOs) are an experimentally tractable research tool useful for investigating the role of the human brain tumor microenvironment in glioblastoma. Here we describe long-term GLICOs,a novel model in which COs are grown from embryonic stem cell cultures containing low levels of GSCs and tumor development is monitored over extended durations (ltGLICOs). Single-cell profiling of ltGLICOs revealed an unexpectedly long latency period prior to GSC expansion,and that normal organoid development was unimpaired by the presence of low numbers of GSCs. However,as organoids age they experience chronic hypoxia and oxidative stress which remodels the tumor microenvironment to promote GSC expansion. Receptor-ligand modelling identified astrocytes,which secreted various pro-tumorigenic ligands including FGF1,as the primary cell type for GSC crosstalk and single-cell multi-omic analysis revealed these astrocytes were under the control of ischemic regulatory networks. Functional validation confirmed hypoxia as a driver of pro-tumorigenic astrocytic ligand secretion and that GSC expansion was accelerated by pharmacological induction of oxidative stress. When controlled for genotype,the close association between glioma aggressiveness and patient age has very few proposed biological explanations. Our findings indicate that age-associated increases in cerebral vascular insufficiency and associated regional chronic cerebral hypoxia may contribute to this phenomenon.Supplementary InformationThe online version contains supplementary material available at 10.1186/s40478-024-01755-6. View Publication

Accumulating evidence suggests that mitogenic signaling during cell cycle arrest can lead to severe cytotoxic outcomes,such as senescence,though the underlying mechanisms remain poorly understood. Here,we explored the link between cell cycle dynamics and the formation of PML-nuclear bodies (PML-NBs),intranuclear structures known to mediate cellular stress responses. Our findings demonstrate that PML-NBs increase their number during interphase arrest. Moreover,the activation of mitogenic ERK signaling by all-trans retinoic acid (ATRA) during CDK4/6 inhibitor-induced cell cycle arrest synergistically enhances the formation of larger PML-NBs by associating with SUMO. This enlargement,triggered by the simultaneous engagement of opposing cell cycle signals,leads to potent cytotoxicity accompanied by either terminal differentiation or apoptosis,depending on the cell type,across multiple acute myeloid leukemia (AML) cell lines. Importantly,in an AML mouse model,this combination treatment significantly improved therapeutic efficacy with minimal effects on normal hematopoiesis. Our results introduce conflicting cell cycle signal-induced cytotoxicity as a promising therapeutic strategy for AML. Subject terms: PML bodies,Apoptosis View Publication

If iPS cells can be established easily and efficiently using freshly collected blood cells,it will enhance regenerative and personalized medicine. While reports of iPS derivation from blood-derived endothelial progenitor cells using RNA have been documented,none have been reported from peripheral blood-derived mononuclear cells (PBMCs). In this study,we established a method to generate iPS cells from PBMCs using synthetic RNAs and found that MDM4,which suppresses p53,improved reprogramming efficiency. Subject terms: Reprogramming,Induced pluripotent stem cells View Publication

Cancer is believed to arise from stem cells,but mechanisms that limit the acquisition of mutations and tumor development have not been well defined. We show that a +4 stem cell (SC) in the gastric antrum,marked by expression of Cck2r (a GPCR) and Delta-like ligand 1 (DLL1),is a label-retaining cell that undergoes predominant asymmetric cell division. This +4 antral SC is Notch1low/ Numb+ and repressed by signaling from gastrin-expressing endocrine (G) cells. Chemical carcinogenesis of the stomach is associated with loss of G cells,increased symmetric stem cell division,glandular fission,and more rapid stem cell lineage tracing,a process that can be suppressed by exogenous gastrin treatment. This hormonal suppression is associated with a marked reduction in gastric cancer mutational load,as revealed by exomic sequencing. Taken together,our results show that gastric tumorigenesis is associated with increased symmetric cell division that facilitates mutation and is suppressed by GPCR signaling. View Publication

Blood oxygen saturation (SaO2) is one of the most important environmental factors in clinical heart protection. This study used human heart samples and human induced pluripotent stem cell-cardiomyocytes (iPSC-CMs) to assess how SaO2 affects human CM cell cycle activities. The results showed that there were significantly more cell cycle markers in the moderate hypoxia group (SaO2: 75{\%} to 85{\%}) than in the other 2 groups (SaO2 {\textless}75{\%} or {\textgreater}85{\%}). In iPSC-CMs 15{\%} and 10{\%} oxygen (O2) treatment increased cell cycle markers,whereas 5{\%} and rapid change of O2 decreased the markers. Moderate hypoxia is beneficial to the cell cycle activities of post-natal human CMs. View Publication

In humans,the stages and dynamics of B cell development after antigen encounter remain unclear. Identifying early B cell differentiation stages could reveal biomarkers for humoral immunity and potential targets to prevent unwanted antibody responses. We characterized antigen‐specific B cell responses longitudinally after SARS‐CoV‐2 mRNA vaccination using multiparameter spectral flow cytometry. Spike‐specific IgG+ CD27+ CD71+ activated B cells (ActBCs),presumed to be germinal center‐derived and IgG+ DN2 extrafollicular B cells,dominated the early antigen‐specific B cell response,while memory B cells were the main population 6 months after vaccination. Within the IgG+ ActBC compartment,we delineated six novel clusters with specific contraction dynamics. Following the second vaccination,certain ActBC clusters displayed sustained expansion over time,being phenotypically similar to memory B cells,while others strongly expanded and subsequently contracted. Several of the rapidly contracting ActBC clusters expressed CD11c,a defining marker for atypical B cells,suggesting a possible extrafollicular origin of these clusters. The transient presence of heterogeneous ActBC clusters was also observed for total B cells when gated in an antigen‐independent manner. Characterization of novel ActBC clusters early after antigen encounter helps delineate and dissect the complexity of B cell differentiation,which is vital for understanding unwanted B cell responses. Characterization of the early antigen‐specific B cell response post‐SARS‐CoV‐2 vaccination reveals novel activated B cell clusters,showing different phenotypes and contraction dynamics. Some short‐lived activated B cells expressed both CD71 and the extrafollicular marker CD11c. These results advance our understanding of B‐cell differentiation regulation and biomarker potential. View Publication