Extracellular Matrix Remodeling and Its Role in Myocardial Regeneration Following Infarction
extracellular matrix is no longer considered a static support structure for cells, but a
dynamic signaling network with the power to influence cell, tissue and whole organ
physiology. In the myocardium, the synthesis, deposition and degradation of matrix
proteins are critical for the development and maintenance of functional heart tissue as
well as the stabilization of the organ... read morefollowing injury. However, the extent to which
the extracellular matrix is remodeled during disease progression is often excessive and
greatly impacts heart functionality as well as the efficacy of therapeutic intervention.
Therefore, it is critical to specifically characterize how the biophysical and
biochemical properties of the extracellular matrix are altered as a function of time
following the onset of disease in order to better understand the challenges associated
with repairing the injured myocardium. The application of decellularization to study
alterations in the extracellular matrix of disease tissue as a function of time
following injury was first explored by our research group. This technique enabled us to
specifically characterize how the remodeled ECM impacts the regenerative potential of
mesenchymal stem cells and more specifically, how the chronic infarct ECM promotes
pro-survival paracrine signaling to oxidatively stressed cardiomyocytes in vitro.
Furthermore, the use of non-linear optical microscopy enabled us to identify how the
structure function relationships of the myocardial ECM change following infarction due
to the non-destructive imaging techniques of second harmonic generation and two photon
excited fluorescence. In particular, this work highlighted how the ECM deposited
following infarction is structurally immature relative to its native state, with dense,
but thin collagen fibers that lack cross-links and therefore possesses a reduced elastic
modulus. Incorporation of this remodeled ECM into a complex disease model platform which
describes differences in oxygen tension, immunomodulatory cytokines, matrix composition
and the mechanical properties of the ECM following MI induction, enabled us to predict
cardiac progenitor cell fate following intramyocardial delivery. The results highlighted
how the cytotoxicity of the infarct microenvironment impedes vascular differentiation
and how the variability of progenitor cell isolates and their individual sensitivities
to infarct variables necessitates the selection of an implantation strategy, which is
beneficial for a particular patient's population of cells. Finally, the incorporation of
ECM derived from both fetal and adult developmental stages into a silk scaffold for
cardiac regeneration following myocardial infarction highlighted how the specific
composition of the ECM regulates the therapeutic efficacy of the biomaterial by
impacting host cell migration, infiltration and remodeling. The research described in
this thesis highlights the importance of characterizing the extracellular matrix
throughout development and disease in order to fully understand its impact on organ
function, disease progression and therapeutic
Thesis (Ph.D.)--Tufts University, 2016.
Submitted to the Dept. of Biomedical Engineering.
Advisor: Lauren Black.
Committee: David Kaplan, Gordon Huggins, and Michael Davis.
Keyword: Biomedical engineering.read less