SummaryThe peripheral nervous system has remarkable regenerative capacities in that it can repair a fully cut nerve. This requires Schwann cells to migrate collectively to guide regrowing axons across a ‘bridge’ of new tissue, which forms to reconnect a severed nerve. Here we show that blood vessels direct the migrating cords of Schwann cells. This multicellular process is initiated by hypoxia, selectively sensed by macrophages within the bridge, which via VEGF-A secretion induce a polarized vasculature that relieves the hypoxia. Schwann cells then use the blood vessels as “tracks” to cross the bridge taking regrowing axons with them. Importantly, disrupting the organization of the newly formed blood vessels in vivo, either by inhibiting the angiogenic signal or by re-orienting them, compromises Schwann cell directionality resulting in defective nerve repair. This study provides important insights into how the choreography of multiple cell-types is required for the regeneration of an adult tissue.
Despite advances in the development of highly effective androgen receptor (AR)-directed therapies for the treatment of men with advanced prostate cancer, acquired resistance to such therapies frequently ensues. A significant subset of patients with resistant disease develop AR-negative tumors that lose their luminal identity and display neuroendocrine features (neuroendocrine prostate cancer (NEPC)). The cellular heterogeneity and the molecular evolution during the progression from AR-positive adenocarcinoma to AR-negative NEPC has yet to be characterized. Utilizing a new genetically engineered mouse model, we have characterized the synergy between Rb1 loss and MYCN (encodes N-Myc) overexpression which results in the formation of AR-negative, poorly differentiated tumors with high metastatic potential. Single-cell-based approaches revealed striking temporal changes to the transcriptome and chromatin accessibility which have identified the emergence of distinct cell populations, marked by differential expression of Ascl1 and Pou2f3, during the transition to NEPC. Moreover, global DNA methylation and the N-Myc cistrome are redirected following Rb1 loss. Altogether, our data provide insight into the progression of prostate adenocarcinoma to NEPC.
Sara Suliman is an assistant professor in the Department of Experimental Medicine at the University of California, San Francisco (UCSF). Her lab uses multiple approaches to identify candidate tuberculosis (TB) risk pathways and to determine their role in TB progression. I caught up with Sara to talk about how she got interested in science, what she’s currently working on, and what she thinks about the future of academic science.
Golnaz Vahedi is an associate professor of genetics at the Perelman School of Medicine, University of Pennsylvania. Golnaz runs a multidisciplinary lab that uses cutting-edge computational and experimental approaches to understand the molecular mechanisms by which genomic information in immune cells is interpreted in normal development and during immune-mediated diseases. We talked about her diverse scientific background, the benefits of integrating molecular biology and immunology, and the importance of staying positive in academia.
Michelle Linterman is a group leader at the Babraham Institute, Cambridge, UK. The research focus of her lab is to understand the fundamental biology of the germinal center response after immunization and infection and how this changes with age. We caught up with Michelle to talk about how her interest in germinal center biology started, the benefits of team science, and her collaboration between the Malaghan Institute of Medical Research, New Zealand, and Churchill College, Cambridge.
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