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Senescent-like Microglia Limit Remyelination Through the Senescence Associated Secretory Phenotype

Gross et al., Nature Communications. 2025.

https://www.nature.com/articles/s41467-025-57632-w

Multiple sclerosis (MS) is a chronic, immune-mediated demyelinating disease in which immune cells infiltrate the central nervous system and promote deterioration of myelin and neurodegeneration. The capacity to regenerate myelin in the central nervous system diminishes with age. In this study, researchers used 2- to 3-month-old (young), 12-month-old (middle-aged), and 18- to 22-month-old (aged) C57BL/6 male and female mice. Results showed an upregulation of the senescence marker P16ink4a (P16) in microglial and macrophage cells within demyelinated lesions. Notably, treatment of senescent cells using genetic and pharmacological senolytic methods leads to enhanced remyelination in young and middle-aged mice but fails to improve remyelination in aged mice. These results suggest that therapeutic targeting of senescence-associated secretory phenotype components may improve remyelination in aging and MS. Supported by ORIP (R24OD036199), NIA, NINDS, and NIMH.

Differentiation Success of Reprogrammed Cells Is Heterogeneous In Vivo and Modulated by Somatic Cell Identity Memory

Zikmund et al., Stem Cell Reports. 2025.

https://pubmed.ncbi.nlm.nih.gov/40086446

Nuclear reprogramming can change cellular fates, yet reprogramming efficiency is low, and the resulting cell types are often not functional. Researchers used nuclear transfer to Xenopus eggs to follow single cells during reprogramming in vivo. Results showed that the differentiation success of reprogrammed cells varies across cell types and depends on the expression of genes specific to the previous cellular identity. Subsets of reprogramming-resistant cells fail to form functional cell types and undergo cell death or disrupt normal body patterning. Reducing expression levels of genes specific to the cell type of origin leads to better reprogramming and improved differentiation trajectories. This study demonstrates that failing to reprogram in vivo is cell type specific and emphasizes the necessity of minimizing aberrant transcripts of the previous somatic identity for improving reprogramming. Supported by ORIP (R24OD031956).

Suppressing APOE4-Induced Neural Pathologies by Targeting the VHL-HIF Axis

Jiang et al., PNAS. 2025.

https://pubmed.ncbi.nlm.nih.gov/39874294

The ε4 variant of human apolipoprotein E (APOE4) is a major genetic risk factor for Alzheimer’s disease and increases mortality and neurodegeneration. Using Caenorhabditis elegans and male APOE-expressing mice, researchers determined that the Von Hippel-Lindau 1 (VHL-1) protein is a key modulator of APOE4-induced neural pathologies. This study demonstrated protective effects of the VHL-1 protein; the loss of this protein reduced APOE4-associated neuronal and behavioral damage by stabilizing hypoxia-inducible factor 1 (HIF-1), a transcription factor that protects against cellular stress and injury. Genetic VHL-1 inhibition also mitigated cerebral vascular injury and synaptic damage in APOE4-expressing mice. These findings suggest that targeting the VHL–HIF axis in nonproliferative tissues could reduce APOE4-driven mortality and neurodegeneration. Supported by ORIP (R24OD010943, R21OD032463, P40OD010440), NHGRI, NIA, and NIGMS.

A Collection of Split-Gal4 Drivers Targeting Conserved Signaling Ligands in Drosophila

Ewen-Campen et al., G3 (Bethesda). 2025.

https://pubmed.ncbi.nlm.nih.gov/39569452

A modest number of highly conserved signaling pathways are known to generate a broad range of responses in multicellular animals, including mammals. How this remarkable feat is achieved is not well understood. Investigators developed and characterized a collection of genetic resources, called knock-in split-Gal4 lines, that target ligands from highly conserved signaling pathways in development and biological processes, including Notch, Hedgehog, fibroblast growth factor, epidermal growth factor, and transforming growth factor β. These Drosophila lines are useful in identifying tissues that co-express ligands of interest, genetically manipulating specific cell populations, and elucidating potential crosstalk among different conserved pathways. These resources are highly valuable for studying conserved intercellular signaling pathways relevant to human health and disease. Supported by ORIP (R24OD026435, R24OD031952, P40OD018537) and NIGMS.