The mechanics of host cell repopulation of engineered tissues

Project Summary/Abstract
We propose to determine how the hemodynamic environment regulates the attachment,
invasion, and differentiation of host cells into “off-the-shelf” decellularized tissue engineered
heart valves (TEHVs). We hypothesize that dynamic mechanical stretch and fluid shear stress
regulate repopulation of the TEHV matrix by enhancing and aligning 3D matrix adhesions and
activating latent TGF-beta from the matrix. To test our hypothesis, biopolymer scaffolds seeded
with fibroblasts will be cast in stretchable wells and microfluidic chambers until remodeled into
isotropic or aligned neo-tissues and then decellularized in situ. We will then quantify the extent
to which vascular and circulating cells adhere to and invade the matrix under cyclic stretch (Aim
1) and dynamic flow conditions (Aim 2) relevant to in vivo implantation. Cell attachment,
infiltration, proliferation, apoptosis, phenotype, and endothelial-to-mesenchymal transition
markers will be quantitatively monitored over time. TGF-beta activation and 3D matrix adhesion
protein content and alignment will be examined, and associated signal transduction pathways
will be interrogated to determine the mechanisms governing the cell responses. The results
from this systematic study will have a direct impact on TEHV development by determining the
signals that aid (or hinder) host cell repopulation of the valve matrix with the goal of optimizing
valve design for adaptive remodeling under complex in vivo conditions.

Grant Number: 1R15HL167235-01
NIH Institute/Center: NIH
Principal Investigator: Kristen Billiar