Lindsey Mehl

All Publications

• Precise timing of audiovisual stimulation conquers chemobrain. Trends in cancer Mehl, L. C., Gibson, E. M. 2024

  Abstract

  In a recent study, Kim et al. utilized gamma entrainment using sensory stimuli (GENUS) to rescue cognitive impairment and glial dysregulation associated with cisplatin and methotrexate chemotherapy, specifically when applied both throughout and after chemotherapy administration. GENUS provides a time-dependent, non-invasive method for treating chemobrain, with broader implications for resolving neurodegenerative neuroinflammation.

  View details for DOI 10.1016/j.trecan.2024.04.002

  View details for PubMedID 38644103

• CIRCADIAN REGULATION OF NEUROINFLAMMATION DRIVING CANCER THERAPY-RELATED COGNITIVE IMPAIRMENT Mehl, L., Gibson, E. OXFORD UNIV PRESS INC. 2023

  View details for Web of Science ID 001115245401023

• BMAL1 loss in oligodendroglia contributes to abnormal myelination and sleep. Neuron Rojo, D., Dal Cengio, L., Badner, A., Kim, S., Sakai, N., Greene, J., Dierckx, T., Mehl, L. C., Eisinger, E., Ransom, J., Arellano-Garcia, C., Gumma, M. E., Soyk, R. L., Lewis, C. M., Lam, M., Weigel, M. K., Damonte, V. M., Yalçın, B., Jones, S. E., Ollila, H. M., Nishino, S., Gibson, E. M. 2023

  Abstract

  Myelination depends on the maintenance of oligodendrocytes that arise from oligodendrocyte precursor cells (OPCs). We show that OPC-specific proliferation, morphology, and BMAL1 are time-of-day dependent. Knockout of Bmal1 in mouse OPCs during development disrupts the expression of genes associated with circadian rhythms, proliferation, density, morphology, and migration, leading to changes in OPC dynamics in a spatiotemporal manner. Furthermore, these deficits translate into thinner myelin, dysregulated cognitive and motor functions, and sleep fragmentation. OPC-specific Bmal1 loss in adulthood does not alter OPC density at baseline but impairs the remyelination of a demyelinated lesion driven by changes in OPC morphology and migration. Lastly, we show that sleep fragmentation is associated with increased prevalence of the demyelinating disorder multiple sclerosis (MS), suggesting a link between MS and sleep that requires further investigation. These findings have broad mechanistic and therapeutic implications for brain disorders that include both myelin and sleep phenotypes.

  View details for DOI 10.1016/j.neuron.2023.08.002

  View details for PubMedID 37657440

• Microglia in brain development and regeneration. Development (Cambridge, England) Mehl, L. C., Manjally, A. V., Bouadi, O., Gibson, E. M., Leng Tay, T. 2022; 149 (8)

  Abstract

  It has recently emerged that microglia, the tissue-resident macrophages of the central nervous system, play significant non-innate immune roles to support the development, maintenance, homeostasis and repair of the brain. Apart from being highly specialized brain phagocytes, microglia modulate the development and functions of neurons and glial cells through both direct and indirect interactions. Thus, recognizing the elements that influence the homeostasis and heterogeneity of microglia in normal brain development is crucial to understanding the mechanisms that lead to early disease pathogenesis of neurodevelopmental disorders. In this Review, we discuss recent studies that have elucidated the physiological development of microglia and summarize our knowledge of their non-innate immune functions in brain development and tissue repair.

  View details for DOI 10.1242/dev.200425

  View details for PubMedID 35502782

• Multi-omics analysis of spatially distinct stromal cells reveals tumor-induced O-glycosylation of the CDK4-pRB axis in fibroblasts at the invasive tumor edge. Cancer research Bouchard, G., Garcia-Marques, F. J., Karacosta, L. G., Zhang, W., Bermudez, A., Riley, N. M., Varma, S., Mehl, L. C., Benson, J. A., Shrager, J. B., Bertozzi, C. R., Pitteri, S. J., Giaccia, A. J., Plevritis, S. K. 2021

  Abstract

  The invasive leading edge represents a potential gateway for tumor metastasis. The role of fibroblasts from the tumor edge in promoting cancer invasion and metastasis has not been comprehensively elucidated. We hypothesize that crosstalk between tumor and stromal cells within the tumor microenvironment (TME) results in activation of key biological pathways depending on their position in the tumor (edge vs core). Here we highlight phenotypic differences between tumor-adjacent-fibroblasts (TAF) from the invasive edge and tumor core fibroblasts (TCF) from the tumor core, established from human lung adenocarcinomas. A multi-omics approach that includes genomics, proteomics, and O-glycoproteomics was used to characterize crosstalk between TAFs and cancer cells. These analyses showed that O-glycosylation, an essential post-translational modification resulting from sugar metabolism, alters key biological pathways including the cyclin-dependent kinase 4 and phosphorylated retinoblastoma protein (CDK4-pRB) axis in the stroma and indirectly modulates pro-invasive features of cancer cells. In summary, the O-glycoproteome represents a new consideration for important biological processes involved in tumor-stroma crosstalk and a potential avenue to improve the anti-cancer efficacy of CDK4 inhibitors.

  View details for DOI 10.1158/0008-5472.CAN-21-1705

  View details for PubMedID 34853070