Biochemical and Biophysical Properties of the Cellular Microenvironment Influence the Fibrotic Response of Cardiac Fibroblasts
and biophysical properties of the cellular microenvironment can influence gene
expression, however, there needs to be further investigation into how these parameters
affect the pro-fibrotic response of cardiac fibroblasts (CF) and myofibroblasts (MF)
following myocardial infarction (MI). Following MI, an inflammatory response occurs to
stabilize the tissue, but ultimately ... read moreleads to scar formation. In response to
inflammatory stimuli, CF in the injured tissue differentiate towards an activated MF and
gain characteristics such as increased proliferation, mobility, and ECM secretion. This
leads to a pro-fibrotic response in which secretion and accumulation of ECM proteins
increases within the ischemic tissue leading to eventual scar formation. The
accumulation of collagen I is most prominent and its abundance and further crosslinking
by lysyl oxidase (LOX) can impart increases in tissue stiffness. The changes to the
biochemical and biophysical properties of the EC are caused by fibroblast activity,
however, the fibroblasts are also responsive to changes to their local environment.
Therefore, it is important to understand how these parameters affect gene expression of
pro-fibrotic genes in CF and MF in order to develop therapeutic strategies to attenuate
deleterious fibrosis which occurs following MI. To investigate how substrate composition
and mechanics alter gene expression in fibroblasts, a polyacrylamide model
recapitulating healthy and infarcted tissue was used. Further, investigation into
integrin interactions with collagen I identified a regulatory role of the
α2β1 integrin on LOX expression. Lastly, the potential for LOX to be used as
a therapeutic is explored and a CF cell line overexpressing LOX is created for future
applications. Overall, the results determine that the biochemical and biophysical
factors present in the cellular microenvironment influence the expression of ECM
proteins and LOX. This leads to potential development of therapeutics to target CF and
MF via these interactions to limit the development and progression of fibrosis following
Thesis (M.S.)--Tufts University, 2016.
Submitted to the Dept. of Biomedical Engineering.
Advisor: Lauren Black III.
Committee: David Kaplan, Irene Georgakoudi, and Jonathan Garlick.
Keywords: Biomedical engineering, and Biology.read less