Author ORCID Identifier
0000-0002-9670-7486
Date of Graduation
5-2024
Document Type
Dissertation (PhD)
Program Affiliation
Genetics and Epigenetics
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Jichao Chen
Committee Member
Harry Karmouty-Quintana
Committee Member
Michael Galko
Committee Member
Keri Schadler
Committee Member
Richard Behringer
Abstract
Once thought to be a homogenous population, capillary endothelial cells (ECs) have embodied organotypic specialization and heterogenous properties, both during homeostasis and tissue injury. In the lung, capillary ECs consist of two distinct populations, CAP1 and CAP2s; how each population responds to diverse tissue injury is incompletely understood. In this thesis, I report the induction and function of a truncated isoform of Ntrk2, Ntrk2-tk (lacking the tyrosine kinase domain) in multiple injury models. Using a combinatorial approach of single-cell multiome, mouse genetics and viral infection models, I found that Ntrk2-tk is broadly induced in CAP1s after the initial interferon response, associated with increased intronic chromatin accessibility, and persists long-term in vivo. To identify the specificity of Ntrk2-tk expressing ECs, I used CAP1 and CAP2 lineage reporter mouse models and found that Ntrk2-tk ECs arose distinctly from CAP1s. Further, lineage tracing of Sendai- infected Ntrk2-tk ECs show that these cells proliferate and give rise to more CAP1s, but not CAP2s. While EC-specific deletion of Ntrk2 showed limited molecular and cellular consequences in response to viral infections, I found that Ntrk2 upregulation is a conserved response in systemic inflammatory models and human COVID-19 infection model. Altogether, my original work shows that Ntrk2-tk ECs contributes to a new layer of capillary diversity and Ntrk2-tk serves as a novel EC biomarker of injury- repair in mice and humans.
Keywords
single-cell multiomics, endothelial heterogeneity and injury-repair, lung regeneration, TrkB isoforms
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