Using Engineered Bioactive 3D Cell Culture Hydrogels to
Manipulate Valvular Interstitial Cells (VICs) Behavior:
Understanding Heart Valve Biology for Regeneration and
Treatment
I am studying the phenotypic changes
seen in VICs, isolated from swine aortic heart valves,
to better understand how this cell type contributes to
heart valve hardening (fibrosis). This understanding
will aid in the development of tissue engineered heart
valve replacements through manipulation of the VICs
phenotype. Stenosis and heart valve defects result in
hundreds of thousands of aortic valve replacement
surgeries per year in the United States. These
replacements are usually made of synthetic material, and
some even require head-up orientation to function
properly, which makes childhood cartwheels dangerous.
This restriction of movement and the need for
multiple surgeries in child patients with valve defects
makes regenerated heart valve tissue implants an
attractive alternative.
When VICs are subjected to different
biological stimuli, such as the signaling molecule
transforming growth factor-beta1 (TGF-b1),
they become activated from a quiescent fibroblast state
to a myofibroblast state that produces elevated amounts
of extracellular matrix (ECM) proteins; leading to valve
hardening. This effect has been well characterized in 2
dimensional hydrogel cultures by Julie Benton, a senior
member of our group. I am transitioning into a 3
dimensional cell culture platform using a newly
developed hydrogel polymer, PEG-Norbornene. Initially, I
will be running comparison studies to ensure that 2D
results are still valid in 3D cultures; mainly VIC
activation in response to ECM and TGF-b1 concentrations.
Activated VICs are such an important
aspect of heart valve regeneration because in this
state, they remodel tissue architecture and produce
excessive amounts of ECM molecules like collagen. This
naturally produced matrix can replace the synthetic
scaffold used initially as a template to support VIC
growth and differentiation throughout the hydrogel. Once
the completely cellularized natural ECM scaffold is of
desired valve dimensions and mechanical properties, the
VICs then need to be deactivated back to the healthy,
quiescent state before the regenerated valve can be
implanted without complications. This myofibroblast
deactivation of VICs has yet to be accomplished and is a
mechanism that my work will help to understand.
Combining knowledge of the activation and
deactivation pathways of VICs will be a firm platform to
begin regenerating live heart valve tissue; putting this
tissue engineered treatment even closer to clinical
trials.
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