1Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, California, USA. 2Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. 3Neuroscience Graduate Program, University of Southern California, Los Angeles, CA, 90089, USA. 4USC Davis School - Buck Institute Graduate Program in the Biology of Aging, University of Southern California, Los Angeles, CA 90033, USA. 5Davis School of Gerontology, University of Southern California, Los Angeles, CA 90033, USA. 6Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA. 7Department of Anatomy, University of California, San Francisco, CA, USA. 8Bakar Aging Research Institute, University of California San Francisco, San Francisco, California, USA.

Rejuvenation of neural stem cell function and cognition through single-cell pharmacotranscriptomics with ROOT

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Lei Peng1,2,3,#, Maxwell Bay1,2,3,#, Adam B. Schroer7,8, Albina Ibrayeva1,2,4,5, Naibo Zhang1,2, Lily Sumrow1,2, Jonathan Levi1,2,4,5, Wang Xiang1,2,4,5, Saul A. Villeda7,8, and Michael A. Bonaguidi1-6,*. Rejuvenation of neural stem cell function and cognition through single-cell pharmacotranscriptomics with ROOT. Uploaded to https://www.posterpresentations.com/research/groups/UCLA/UCLA-53/. Submitted on May 10, 2022.

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Poster - #UCLA-53 - Keywords: Neural stem cell, Neurogenesis, Cognition, Aging, Pharmacotranscriptomics, Drug discovery

Rejuvenation of neural stem cell function and cognition through single-cell pharmacotranscriptomics with ROOT

Lei Peng1,2,3,#, Maxwell Bay1,2,3,#, Adam B. Schroer7,8, Albina Ibrayeva1,2,4,5, Naibo Zhang1,2, Lily Sumrow1,2, Jonathan Levi1,2,4,5, Wang Xiang1,2,4,5, Saul A. Villeda7,8, and Michael A. Bonaguidi1-6,*
1Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, California, USA. 2Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. 3Neuroscience Graduate Program, University of Southern California, Los Angeles, CA, 90089, USA. 4USC Davis School - Buck Institute Graduate Program in the Biology of Aging, University of Southern California, Los Angeles, CA 90033, USA. 5Davis School of Gerontology, University of Southern California, Los Angeles, CA 90033, USA. 6Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA. 7Department of Anatomy, University of California, San Francisco, CA, USA. 8Bakar Aging Research Institute, University of California San Francisco, San Francisco, California, USA.

ABSTRACT:
Regenerative medicine offers the unrealized potential to reverse brain aging. However, endogenous neural stem cell (NSC) function declines with age of unclear mechanisms. Here, we developed a single cell computational drug screening technology to reinstate NSC activity, neurogenesis, and cognition in older mice through mimicking younger NSC programs. “Revealing Origins and Ontological Targets (ROOT)” first reconstructed single cell transcriptomes in cell-lineage pseudotime and identified transcriptomic signatures (TS) that define age-related NSC activity loss. ROOT then screened 1309 clinically relevant small molecules for their ability to recapitulate the TS gene networks mediating NSC activity. Three of the top 5 prioritized compounds reactivated NSCs from quiescence within middle-aged mice. Among them, SS further proved to sustain NSC proliferation, expand the NSC pool, increase neurogenesis, and improve cognitive function. We thus demonstrate the utility of a new single cell pharmacogenomics platform by revealing unexpected neural stem cell capacity for regenerative medicine.