In mammals, spermatogonial cells (SPGs) are undifferentiated male germ cells in testis that are quiescent until birth and then self-renew and differentiate to produce spermatogenic cells and functional sperm from early postnatal life throughout adulthood. The transcriptome of SPGs is highly dynamic and timely regulated during postnatal development. We examined if such dynamics involves changes in chromatin organization by profiling the transcriptome and chromatin accessibility of SPGs from early postnatal stages to adulthood in mice using deep RNA-seq, ATAC-seq and computational deconvolution analyses. By integrating transcriptomic and epigenomic features, we show that SPGs undergo massive chromatin remodeling during postnatal development that partially correlates with distinct gene expression profiles and transcription factors (TF) motif enrichment. We identify genomic regions with significantly different chromatin accessibility in adult SPGs that are marked by histone modifications associated with enhancers and promoters. Some of the regions with increased accessibility correspond to transposable element subtypes enriched in multiple TFs motifs and close to differentially expressed genes. Our results underscore the dynamics of chromatin organization in developing germ cells and complement existing datasets on SPGs by providing maps of the regulatory genome at high resolution from the same cell populations at early postnatal, late postnatal and adult stages collected from single individuals.
© 2023, Lazar-Contes, Arzate-Mejia, Tanwar et al.

Oral squamous cell carcinomas (OSCC) remain a major healthcare burden in Asian countries. In Pakistan alone, it is the most common cancer in males and second only to breast cancer in females. Alarmingly, treatment options for OSCC remain limited. With this context, investigations made to explore the inflammatory milieu of OSCC become highly relevant, with the hope of practicing immunotherapeutic approaches to address this highly prevalent tumor. We investigated the newly identified innate lymphoid cells (ILCs) and associated cytokines in well-defined human oral squamous cell carcinoma (OSCC) as well as in a 7,12-dimethylbenz[a]anthracene (DMBA)-induced murine model of OSCC using flow cytometry and quantitative real-time polymerase chain reaction (qPCR). We further went on to explore molecular circuitry involved in OSCC by developing a murine model of OSCC and using an α-Thy1 antibody to inhibit ILCs. Amongst the ILCs that we found in human OSCC, ILC3 (23%) was the most abundant, followed by ILC2 (17%) and ILC1 (1%). Mice were divided into four groups: DMBA (n = 33), DMBA+antibody (Ab) (n = 30), acetone (n = 5), and control (n = 5). In murine OSCC tissues, ILC1 and ILC3 were down-infiltrated, while ILC2 remained unchanged compared to controls. Interestingly, compared to the controls (DMBA group), mice treated with the α-Thy1 antibody showed fewer numbers of large tumors, and a larger percentage of these mice were tumor-free at this study's end point. We present novel data on the differential expansion/downsizing of ILCs in OSCC, which provides a pivotal basis to dive deeper into molecular circuitry and the OSCC tumor niche to devise novel diagnostic, therapeutic, and prognostic strategies to prevent/treat oral cancers.

Intercellular communication is crucial for collective regulation of cellular behaviors. While clustering T cells have been shown to mutually control the production of key communication signals, it is unclear whether they also jointly regulate their availability and degradation. Here we use newly developed reporter systems, bioinformatic analyses, protein structure modeling and genetic perturbations to assess this. We find that T cells utilize trogocytosis by competing antagonistic receptors to differentially control the abundance of immunoregulatory ligands. Specifically, ligands trogocytosed via CD28 are shuttled to the T cell surface, enabling them to co-stimulate neighboring T cells. In contrast, CTLA4-mediated trogocytosis targets ligands for degradation. Mechanistically, this fate separation is controlled by different acid-sensitivities of receptor-ligand interactions and by the receptor intracellular domains. The ability of CD28 and CTLA4 to confer different fates to trogocytosed ligands reveals an additional layer of collective regulation of cellular behaviors and promotes the robustness of population dynamics.
© 2022. The Author(s).

Hepatic veno-occlusive disease (VOD) is a life-threatening complication of hematopoietic stem cell transplantation, which urgently requires effective prevention and treatment. Endothelial damage is recognized as the first event in patients with hepatic VOD. However, the mechanism by which endothelial injury induces thrombosis in hepatic VOD is still not clear. In the present study, monocrotaline (MCT) was used to induce endothelial cell injury in EA.hy926 cells to imitate in vitro hepatic VOD. MCT significantly increased apoptosis in EA.hy926 endothelial cells and the secretion of endothelial microparticles (EMPs) which can be used to reflect the level of endothelial injury. Additionally, MCT significantly enhanced the expression of soluble tissue factor (TF) and EMP-bound TF protein, suggesting that EMPs may participate in the development of hepatic VOD by regulating coagulation. Ginsenoside Rb1, a major constituent and effective ingredient of Panax ginseng, was found to significantly decrease MCT-induced endothelial injury and release of EMPs. Moreover, Ginsenoside Rb1 decreased soluble TF released by EA.hy926 cells and EMP-bound TF protein induced by MCT. These data suggest that ginsenoside Rb1 may serve as a potent prophylactic and/or as a treatment of hepatic VOD by protecting endothelial cells and preventing microthrombosis induced by endothelial injury.
Copyright: © Zhao et al.

Neurons, especially axons, are metabolically demanding and energetically vulnerable during injury. However, the exact energy budget alterations that occur early after axon injury and the effects of these changes on neuronal survival remain unknown. Using a classic mouse model of optic nerve-crush injury, we found that traumatized optic nerves and retinas harbor the potential to mobilize two primary energetic machineries, glycolysis and oxidative phosphorylation, to satisfy the robustly increased adenosine triphosphate (ATP) demand. Further exploration of metabolic activation showed that mitochondrial oxidative phosphorylation was amplified over other pathways, which may lead to decreased retinal ganglion cell (RGC) survival despite its supplement to ATP production. Gene set enrichment analysis of a microarray (GSE32309) identified significant activation of oxidative phosphorylation in injured retinas from wild-type mice compared to those from mice with deletion of phosphatase and tensin homolog (PTEN), while PTEN-/- mice had more robust RGC survival. Therefore, we speculated that the oxidation-favoring metabolic pattern after optic nerve-crush injury could be adverse for RGC survival. After redirecting metabolic flux toward glycolysis (magnifying the Warburg effect) using the drug meclizine, we successfully increased RGC survival. Thus, we provide novel insights into a potential bioenergetics-based strategy for neuroprotection.