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Transcriptomic Analysis of Skeletal Muscle Regeneration Across Mouse Lifespan Identifies Altered Stem Cell States
Walter et al., Nature Aging. 2024.
https://pubmed.ncbi.nlm.nih.gov/39578558
Age-related skeletal muscle regeneration dysfunction is poorly understood. Using single-cell transcriptomics and high-resolution spatial transcriptomics, researchers evaluated factors contributing to age-related decline in skeletal muscle regeneration after injury in young, old, and geriatric male and female mice (5, 20, and 26 months old). Eight immune cell types were identified and associated with age-related dynamics and distinct muscle stem cell states specific to old and geriatric tissue. The findings emphasize the role of extrinsic and intrinsic factors, including cellular senescence, in disrupting muscle repair. This study provides a spatial and molecular framework for understanding regenerative decline and cellular heterogeneity in aging skeletal muscle. Supported by ORIP (F30OD032097), NIA, NIAID, NIAMS, NICHD, and NIDA.
Systematic Multi-trait AAV Capsid Engineering for Efficient Gene Delivery
Eid et al., Nature Communications. 2024.
https://doi.org/10.1038/s41467-024-50555-y
Engineering novel functions into proteins while retaining desired traits is a key challenge for developers of viral vectors, antibodies, and inhibitors of medical and industrial value. In this study, investigators developed Fit4Function, a generalizable machine learning (ML) approach for systematically engineering multi-trait adeno-associated virus (AAV) capsids. Fit4Function was used to generate reproducible screening data from a capsid library that samples the entire manufacturable sequence space. The Fit4Function data were used to train accurate sequence-to-function models, which were combined to develop a library of capsid candidates. Compared to AAV9, top candidates from the Fit4Function capsid library exhibited comparable production yields; more efficient murine liver transduction; up to 1,000-fold greater human hepatocyte transduction; and increased enrichment in a screen for liver transduction in macaques. The Fit4Function strategy enables prediction of peptide-modified AAV capsid traits across species and is a critical step toward assembling an ML atlas that predicts AAV capsid performance across dozens of traits. Supported by ORIP (P51OD011107, U42OD027094), NIDDK, NIMH, and NINDS.
Murine MHC-Deficient Nonobese Diabetic Mice Carrying Human HLA-DQ8 Develop Severe Myocarditis and Myositis in Response to Anti-PD-1 Immune Checkpoint Inhibitor Cancer Therapy
Racine et al., Journal of Immunology. 2024.
Myocarditis has emerged as a relatively rare but often lethal autoimmune complication of checkpoint inhibitor (ICI) cancer therapy, and significant mortality is associated with this phenomenon. Investigators developed a new mouse model system that spontaneously develops myocarditis. These mice are highly susceptible to myocarditis and acute heart failure following anti-PD-1 ICI-induced treatment. Additionally, the treatment accelerates skeletal muscle myositis. The team performed characterization of cardiac and skeletal muscle T cells using histology, flow cytometry, adoptive transfers, and RNA sequencing analyses. This study sheds light on underlying immunological mechanisms in ICI myocarditis and provides the basis for further detailed analyses of diagnostic and therapeutic strategies. Supported by ORIP (U54OD020351, U54OD030187), NCI, NIA, NIDDK, and NIGMS.
Molecular Basis of Human Trace Amine-Associated Receptor 1 Activation
Zilberg et al., Nature Communications. 2024.
https://www.nature.com/articles/s41467-023-44601-4
The authors reported the cryogenic electron microscopy structure of human trace amine-associated receptor 1 (hTAAR1, hTA1) signaling complex, a key modulator in monoaminergic neurotransmission, as well as its similarities and differences with other TAAR members and rodent TA1 receptors. This discovery has elucidated hTA1’s molecular mechanisms underlining the strongly divergent pharmacological properties of human and rodent TA1 and therefore will boost the translation of preclinical studies to clinical applications in treating disorders of dopaminergic dysfunction, metabolic disorders, cognitive impairment, and sleep-related dysfunction. Supported by ORIP (S10OD019994, S10OD026880, and S10OD030463), NIDA, NIGMS, NIMH, and NCATS.
Intestinal Microbiota Controls Graft-Versus-Host Disease Independent of Donor–Host Genetic Disparity
Koyama et al., Immunity. 2023.
https://pubmed.ncbi.nlm.nih.gov/37480848/
Allogeneic hematopoietic stem cell transplantation is a curative therapy for hematopoietic malignancies and non-malignant diseases, but acute graft-versus-host disease (GVHD) remains a serious complication. Specifically, severe gut GVHD is the major cause of transplant-related mortality. Here, the authors show that genetically identical mice, sourced from different vendors, had distinct commensal bacterial compositions, which resulted in significantly discordant severity in GVHD. These studies highlight the importance of pre-transplant microbiota composition for the initiation and suppression of immune-mediated pathology in the gastrointestinal tract, demonstrating the impact of non-genetic environmental determinants to transplant outcome. Supported by ORIP (S10OD028685), NIA, NCI, and NHLBI.
SALL1 Enforces Microglia-Specific DNA Binding and Function of SMADs to Establish Microglia Identity
Fixsen et al., Nature Immunology. 2023.
https://doi.org/10.1038/s41590-023-01528-8
Microglia function is thought to play a role in neurodevelopmental, psychiatric, and neurodegenerative diseases. Using knockout mice, investigators explored functional interactions between spalt-like transcription factor 1 (SALL1) and SMAD4, which demonstrated that interactions are mediated by a conserved microglia-specific SALL1 super-enhancer and result in direct activation of regulatory elements. The concerted interactions induce a microglia lineage determining program of gene expression. These findings indicate that expression of SALL1 and associated genes could contribute to phenotypes of aging and neurodegenerative diseases. Supported by ORIP (S10OD026929), NIA, NIMH, and NINDS.
Osteopontin Is an Integral Mediator of Cardiac Interstitial Fibrosis in Models of Human Immunodeficiency Virus Infection
Robinson et al., The Journal of Infectious Diseases. 2023.
https://www.doi.org/10.1093/infdis/jiad149
HIV infection is associated with increased risk of cardiovascular disease. Plasma osteopontin (Opn) is correlated with cardiac pathology, but more work is needed to understand the underlying mechanisms driving cardiac fibrosis. Researchers explored this topic using mouse embryonic fibroblasts, male macaques, and humanized mice of both sexes. They reported the accumulation of Opn in the heart with simian immunodeficiency virus infection. Systemic inhibition of Opn can prevent HIV-associated interstitial fibrosis in the left ventricle. These findings suggest that Opn could be a potential target for adjunctive therapies to reduce cardiac fibrosis in people with HIV. Supported by ORIP (P51OD011104), NIAID, NHLBI, NIMH, and NINDS.
Phytochemical Compound PB125 Attenuates Skeletal Muscle Mitochondrial Dysfunction and Impaired Proteostasis in a Model of Musculoskeletal Decline
Musci et al., Journal of Physiology. 2023.
https://physoc.onlinelibrary.wiley.com/doi/10.1113/JP282273
Age-related musculoskeletal decline contributes to disability and cardiometabolic diseases and is linked to impaired mitochondrial function and disrupted proteostasis. Using male and female Hartley guinea pigs, investigators tested a purported phytochemical activator of nuclear factor erythroid 2-related factor 2, which helps promote redox homeostasis, proteome maintenance, and mitochondrial energetics. They reported that the activator, PB125, improved mitochondrial respiration and attenuated disease- and age-related declines in skeletal muscle protein synthesis. This study provides insights for the development of interventions in humans. Supported by ORIP (T32OD010437) and NIA.
p38MAPKα Stromal Reprogramming Sensitizes Metastatic Breast Cancer to Immunotherapy
Faget et al., Cancer Discovery. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10238649/
This study emphasizes the importance of the metastatic tumor microenvironment in metastatic breast cancer growth and the identification of effective antimetastatic therapies. Using a stromal labeling approach and single-cell RNA sequencing, the authors showed that a combination of p38MAPK inhibition (p38i) and anti-OX40 synergistically reduced metastatic tumor growth and increased overall survival. Further engagement of cytotoxic T cells cured all metastatic disease in mice and produced durable immunologic memory. The Cancer Genome Atlas data analysis revealed that patients with p38i metastatic stromal signature and a high tumor mutational burden (TMB) had increased overall survival. These findings suggest that patients with high TMB would benefit the most from the p38i plus anti-OX40 approach. Supported by ORIP (S10OD028483), NIA, NCI, and NIGMS.
A Class of Anti-Inflammatory Lipids Decrease with Aging in the Central Nervous System
Tan et al., Nature Chemical Biology. 2023.
https://doi.org/10.1038/s41589-022-01165-6
Impaired lipid metabolism in the brain has been implicated in neurological disorders of aging, yet analyses of lipid pathway changes with age have been lacking. The researchers examined the brain lipidome of mice of both sexes across the lifespan using untargeted lipidomics. They found that 3-sulfogalactosyl diacylglycerols (SGDGs) are structural components of myelin and decline with age in the central nervous system. The researchers discovered that SGDGs also are present in male human and rhesus macaque brains, demonstrating their evolutionary conservation in mammals. The investigators showed that SGDGs possess anti-inflammatory activity, suggesting a potential role for this lipid class in age-related neurodegenerative diseases. Supported by ORIP (P51OD011092), NIA, NCI, NIDDK, and NINDS.