Dissecting the interplay of cardiomyocytes and cardiac fibroblasts using human stem cell models of disease

Hall, Caitlin ORCID: 0000-0002-5713-5980 (2024). Dissecting the interplay of cardiomyocytes and cardiac fibroblasts using human stem cell models of disease. University of Birmingham. Ph.D.

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Abstract

The cardiac fibroblast is an important cardiac cell type whose main role is to maintain the extracellular matrix of the heart and provide structural support for cardiomyocytes. During disease, cardiac fibroblasts become activated to myofibroblasts. This process is a key hallmark of the pathological remodelling known as cardiac fibrosis - resulting from persistent myofibroblasts and excessive deposition of matrix proteins. Cardiac fibrosis is associated with a majority of cardiovascular diseases as well as increased mortality and morbidity. Reversing the myofibroblast phenotype provides an avenue to reduce cardiac fibrosis and restore normal cardiac function. This has been explored to a certain degree using
rodent models but has yet to be fully explored using human cells.
The primary activator of myofibroblasts is TGF-β, however, mechanical stress has also been linked to this process. In this work, we investigated whether inhibition of TGF-β receptor 1 or decreasing tensile strength in vitro could reverse activated myofibroblasts back to a quiescent cardiac fibroblast phenotype. This was explored using both primary human cells and human induced pluripotent stem cells (iPSC).
Cardiac fibroblasts and myofibroblasts have also been investigated for both their direct and indirect effects on cardiomyocytes. Again, this has been explored predominantly using animal models. Optical mapping is a method often utilised in the study of arrhythmogenesis to interrogate the disruption of electrical wave propagation in the heart. Recently, it has been advanced to map human iPSC derived cardiomyocyte (hiPSC-CM) monolayers enabling study of disease phenotypes and drug testing in vitro using human models. The work presented here aimed to investigate the effects of quiescent cardiac fibroblasts and activated myofibroblasts on cardiomyocyte electrophysiology and contraction using human iPSC-derived cells and optical mapping.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):