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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.
Establishing the Hybrid Rat Diversity Program: A Resource for Dissecting Complex Traits
Dwinell et al., Mammalian Genome. 2025.
https://pubmed.ncbi.nlm.nih.gov/39907792
Rat models have been extensively used for studying human complex disease mechanisms, behavioral phenotypes, and environmental factors and for discovering and developing drugs. Systems genetics approaches have been used to study the effects of both genetic variation and environmental factors. This approach recognizes the complexity of common disorders and uses intermediate phenotypes to find relationships between genetic variation and clinical traits. This article describes the Hybrid Rat Diversity Program (HDRP) at the Medical College of Wisconsin, which involves 96 inbred rat strains and aims to provide a renewable and reusable resource in terms of the HRDP panel of inbred rat strains, the genomic data derived from the HRDP strains, and banked resources available for additional studies. Supported by ORIP (R24OD024617) and NHLBI.
Stat3 Mediates Fyn Kinase-Driven Dopaminergic Neurodegeneration and Microglia Activation
Siddiqui et al., Disease Models & Mechanisms. 2024.
https://pubmed.ncbi.nlm.nih.gov/39641161
The FYN gene is a risk locus for Alzheimer’s disease and several other neurodegenerative disorders. FYN encodes Fyn kinase, and previous studies have shown that Fyn signaling in dopaminergic neurons and microglia plays a role during neurodegeneration. This study investigated Fyn signaling using zebrafish that express a constitutively active Fyn Y531F mutant in neural cells. Activated neural Fyn signaling in the mutant animals resulted in dopaminergic neuron loss and induced inflammatory cytokine expression when compared with controls. Transcriptomic and chemical inhibition analyses revealed that Fyn-driven changes were dependent on the Stat3 and NF-κB signaling pathways, which work synergistically to activate neuronal inflammation and degeneration. This study provides insight into the mechanisms underlying neurodegeneration, identifying Stat3 as a novel effector of Fyn signaling and a potential translational target. Supported by ORIP (R24OD020166).
Proof-of-Concept Studies With a Computationally Designed Mpro Inhibitor as a Synergistic Combination Regimen Alternative to Paxlovid
Papini et al., PNAS. 2024.
As the spread and evolution of SARS-CoV-2 continues, it is important to continue to not only work to prevent transmission but to develop improved antiviral treatments as well. The SARS-CoV-2 main protease (Mpro) has been established as a prominent druggable target. In the current study, investigators evaluate Mpro61 as a lead compound, utilizing structural studies, in vitro pharmacological profiling to examine possible off-target effects and toxicity, cellular studies, and testing in a male and female mouse model for SARS-CoV-2 infection. Results indicate favorable pharmacological properties, efficacy, and drug synergy, as well as complete recovery from subsequent challenge by SARS-CoV-2, establishing Mpro61 as a promising potential preclinical candidate. Supported by ORIP (R24OD026440, S10OD021527), NIAID, and NIGMS.
Epigenetic MLH1 Silencing Concurs With Mismatch Repair Deficiency in Sporadic, Naturally Occurring Colorectal Cancer in Rhesus Macaques
Deycmar et al., Journal of Translational Medicine. 2024.
https://pubmed.ncbi.nlm.nih.gov/38504345
Rhesus macaques serve as a useful model for colorectal cancer (CRC) in humans, but more data are needed to understand the molecular pathogenesis of these cancers. Using male and female rhesus macaques, researchers investigated mismatch repair status, microsatellite instability, genetic mutations, transcriptional differences, and epigenetic alterations associated with CRC. Their data indicate that epigenetic silencing suppresses MLH1 transcription, induces the loss of MLH1 protein, abrogates mismatch repair, and drives genomic instability in naturally occurring CRC in rhesus macaques. This work provides a uniquely informative model for human CRC. Supported by ORIP (P51OD011092, R24OD010947, R24OD021324, P40OD012217, U42OD010426, T35OD010946, T32OD010957), NCATS, and NCI.
Establishment of a Practical Sperm Cryopreservation Pathway for the Axolotl (Ambystoma mexicanum): A Community-Level Approach to Germplasm Repository Development
Coxe et al., Animals (Basel). 2024.
https://pubmed.ncbi.nlm.nih.gov/38254376/
The axolotl (Ambystoma mexicanum) is an important biomedical research model for organ regeneration, but housing and maintaining live animals is expensive and risky as new transgenic lines are developed. The authors report an initial practical pathway for sperm cryopreservation to support germplasm repository development. They assembled a pathway through the investigation of axolotl sperm collection by stripping, refrigerated storage in various osmotic pressures, cryopreservation in various cryoprotectants, and in vitro fertilization using thawed sperm. This work is the first report of successful production of axolotl offspring with cryopreserved sperm and provides a general framework for pathway development to establish Ambystoma germplasm repositories for future research and applications. Supported by ORIP (R24OD010441, R24OD028443, P40OD019794).
Conduction-Dominated Cryomesh for Organism Vitrification
Guo et al., Advanced Science. 2024.
https://pubmed.ncbi.nlm.nih.gov/38018294/
Vitrification-based cryopreservation via cryomesh is a promising approach for maintaining biodiversity, health care, and sustainable food production via long-term preservation of biological systems. Here, researchers conducted a series of experiments aimed at optimizing the cooling and rewarming rates of cryomesh to increase the viability of various cryopreserved biosystems. They found that vitrification was significantly improved by increasing thermal conductivity, reducing mesh wire diameter and pore size, and minimizing the nitrogen vapor barrier of the conduction-dominated cryomesh. Cooling rates increased twofold to tenfold in a variety of biosystems. The conduction-dominated cryomesh improved the cryopreservation outcomes of coral larvae, Drosophila embryos, and zebrafish embryos by vitrification. These findings suggest that the conduction-dominated cryomesh can improve vitrification in such biosystems for biorepositories, agriculture and aquaculture, and research. Supported by ORIP (R24OD028444, R21OD028758, R24OD034063, R21OD028214), NIDDK, and NIGMS.