The roles played by acetylcholine in cardiac regeneration : insights from 3D modeling of the heart : exploring acetylcholine and cardiovascular disease scenarios

Liu Chung Ming, Clara

The roles played by acetylcholine in cardiac regeneration : insights from 3D modeling of the heart : exploring acetylcholine and cardiovascular disease scenarios

Liu Chung Ming, Clara

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Publication Type:: Thesis
Issue Date:: 2024

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Field	Value	Language
dc.contributor.author	Liu Chung Ming, Clara
dc.date.accessioned	2025-10-03T03:45:09Z
dc.date.available	2025-10-03T03:45:09Z
dc.date.issued	2024
dc.identifier.uri	http://hdl.handle.net/10453/190298
dc.description	University of Technology Sydney. Faculty of Engineering and Information Technology.	en_US.UTF-8
dc.description.abstract	Cardiovascular disease (CVD) is the leading cause of death worldwide. However, existing therapeutic interventions are limited, as they only delay the progression to chronic heart failure (HF) and do not regenerate the damaged heart tissue. Acetylcholine (ACh) is a well-known neurotransmitter that controls cardiac function, and its production is significantly reduced following myocardial damage. Increasing ACh in the infarcted heart reduces infarct size in in vivo models, activates anti-inflammatory pathways, and promotes cell survival. Nonetheless, the protective role of ACh against myocardial damge remains underexplored as current approaches to increasing ACh levels are invasive and unsafe for patients. Furthermore, current in vitro and in vivo models fail to fully recapitulate the complex scenario of human pathophysiology, leading to poor translation of findings from the bench to the bedside. We developed 3D in vitro cardiac spheroid (CS) models, comprising of stem cells-derived cardiomyocytes, fibroblast and endothelial cells that better mimic the molecular, cellular, and extracellular features typical of the human cardiac microenvironment compared to existing models. In this project, we first develop 𝘪𝘯 𝘷𝘪𝘵𝘳𝘰 models using bioengineered CSs for 1) myocardial injury following ischemic-reperfusion (I/R) and doxorubicin (DOX) treatment and for 2) hypertensive disorder pregnancy (HDP)-induced CVD. We then investigate the protective role of ACh against I/R- and DOX-induced injury using our models mentioned above. Three different methods to deliver ACh are explored: 𝘪) freely-dissolved 100μM ACh, 𝘪𝘪) Ach-producing cholinergic nerves (CNs), and 𝘪𝘪𝘪) ACh-loaded nanoparticles (ACh-NPs). Our results show that ACh significantly attenuates cell death and restores contractile activity against I/R and DOX-induced myocardial damage. Our qPCR analyses show that ACh also protects against the I/R- and DOX-induced decrease of genes regulating contractile function, ATPase activity, cell cycle and survival. To translate our findings from 𝘪𝘯 𝘷𝘪𝘵𝘳𝘰 to 𝘪𝘯 𝘷𝘪𝘷𝘰 studies, we also investigate the protective effects of ACh-NPs in a myocardial infarction (MI) mouse model. Our results show that ACh-NPs attenuate MI-induced left ventricle dysfunction and remodeling and increase cell cycle and cell proliferation. Overall, our findings underscore the potential use of ACh-NPs to target deliver ACh and protect against myocardial injury.	en_US.UTF-8
dc.format	Thesis (PhD)
dc.language.iso	en_US	en_US.UTF-8
dc.relation	https://opus.lib.uts.edu.au/bitstream/10453/190298/1/thesis.pdf
dc.rights	info:eu-repo/semantics/openAccess
dc.rights	The author owns the copyright in this thesis including all reproduction and reuse rights for the work. The work may not be altered without the permission of the copyright owner. Attribution is essential when quoting or paraphrasing from this thesis.
dc.rights	© 2024 Clara Liu Chung Ming
dc.rights	au.edu.uts.lib/cph
dc.title	The roles played by acetylcholine in cardiac regeneration : insights from 3D modeling of the heart : exploring acetylcholine and cardiovascular disease scenarios	en_US.UTF-8
dc.type	Thesis
utslib.copyright.status	open_access	*

Abstract:

Cardiovascular disease (CVD) is the leading cause of death worldwide. However, existing therapeutic interventions are limited, as they only delay the progression to chronic heart failure (HF) and do not regenerate the damaged heart tissue. Acetylcholine (ACh) is a well-known neurotransmitter that controls cardiac function, and its production is significantly reduced following myocardial damage. Increasing ACh in the infarcted heart reduces infarct size in in vivo models, activates anti-inflammatory pathways, and promotes cell survival. Nonetheless, the protective role of ACh against myocardial damge remains underexplored as current approaches to increasing ACh levels are invasive and unsafe for patients. Furthermore, current in vitro and in vivo models fail to fully recapitulate the complex scenario of human pathophysiology, leading to poor translation of findings from the bench to the bedside. We developed 3D in vitro cardiac spheroid (CS) models, comprising of stem cells-derived cardiomyocytes, fibroblast and endothelial cells that better mimic the molecular, cellular, and extracellular features typical of the human cardiac microenvironment compared to existing models. In this project, we first develop 𝘪𝘯 𝘷𝘪𝘵𝘳𝘰 models using bioengineered CSs for 1) myocardial injury following ischemic-reperfusion (I/R) and doxorubicin (DOX) treatment and for 2) hypertensive disorder pregnancy (HDP)-induced CVD. We then investigate the protective role of ACh against I/R- and DOX-induced injury using our models mentioned above. Three different methods to deliver ACh are explored: 𝘪) freely-dissolved 100μM ACh, 𝘪𝘪) Ach-producing cholinergic nerves (CNs), and 𝘪𝘪𝘪) ACh-loaded nanoparticles (ACh-NPs). Our results show that ACh significantly attenuates cell death and restores contractile activity against I/R and DOX-induced myocardial damage. Our qPCR analyses show that ACh also protects against the I/R- and DOX-induced decrease of genes regulating contractile function, ATPase activity, cell cycle and survival. To translate our findings from 𝘪𝘯 𝘷𝘪𝘵𝘳𝘰 to 𝘪𝘯 𝘷𝘪𝘷𝘰 studies, we also investigate the protective effects of ACh-NPs in a myocardial infarction (MI) mouse model. Our results show that ACh-NPs attenuate MI-induced left ventricle dysfunction and remodeling and increase cell cycle and cell proliferation. Overall, our findings underscore the potential use of ACh-NPs to target deliver ACh and protect against myocardial injury.

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http://hdl.handle.net/10453/190298