Advisory Committee Chair
Gangjian Qin
Advisory Committee Members
Prasanna Krishnamurthy
Jake Chen
Rajasekaran Soorappan
Lufang Zhou
Document Type
Dissertation
Date of Award
2021
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Mammalian cardiomyocytes exit the cell-cycle shortly after birth. Consequently, the adult heart is unable to properly compensate for cardiac muscle lost to injury. As such, heart failure has remained the leading cause of death in the developed world for more than three decades. In this work, we illustrate our findings in using novel in-vivo animal models to examine two regenerative phenomena observed following myocardial injury:i.) neonate cardiomyocyte proliferation in large mammals ii.) the ‘paracrine effect’ as mediated by mesenchymal stromal cells In i.) we use a large animal model of myocardial injury during the early postnatal develop-mental stage to establish the following novel paradigms of the endogenous cardiac regener-ative response in mammals: 1.) existence of a cardiomyocyte proliferative window in early-stage neonate large mammals after induction of cardiac injury at postnatal day 1, 2.) identi-fication of the cell-cycle regulatory pathways activated during this proliferative window, 3.) extension of the proliferative window past a neonate stage using a double-injury model, with induction of apical resection at post-natal day 1 and a second myocardial infarction at day 28. In ii.), we examine the previously observed ‘paracrine effect’, as reported by a number of clinical studies and trials using various progenitor cell populations to treat heart failure, outlining the development of an in-vivo platform which uses in-vitro biorthogonal-labeling and click-chemistry-based enrichment and immunohistochemistry to identify and visualize in-vivo candidate mesenchymal exosomal surface proteins that dictate exosome trafficking from general circulation to cardiac tissue. We identify an enrichment of desmo-some-associated proteins carried by mesenchymal stromal cell exosomes in infarcted hearts, thus providing a possible mechanism behind reports of lowered arrhythmogenic risk in heart failure patients treated with mesenchymal stromal cells.
Recommended Citation
Zhang, Eric Yang, "Biological Pathways And Processes Underlying The Cardiac Regenerative Response Post-Injury In Small And Large Mammals" (2021). All ETDs from UAB. 723.
https://digitalcommons.library.uab.edu/etd-collection/723
