Few diseases represent the optimal potential target for regenerative cellular therapy more than the abdominal aortic aneurysm (AAA). A disease that affects a large number of elderly in the United States with a natural history that results in structural failure of the aortic wall and death, AAA continues to represent a critical need for biologic therapy. Regenerative therapy consisting of the delivery of stem cells to the damaged aorta presents a conceptually strong opportunity for the reconstitution of the aortic mural matrix and therefore aortic strength - any test of such a therapy must be done on an established aneurysm to most accurately represent what occurs in the clinic. In this proposal, we have combined the strengths of two laboratories with complementary scientific capability, and with a common interest in the development of effective biologic therapies for AAA disease. The early product of this collaborative pairing is published proof of concept evidence that mesenchymal stem cell (MSC) delivery to the wall of a murine AAA can slow progression. The purpose of this R21 Exploratory/Developmental Research Proposal is to develop a clinically- translatable MSC delivery system that would result in aortic matrix repair and regeneration. Our hypothesis is that local stem cell delivery to a murine AAA via an adventitially-applied hydrogel and magnetic assistance will result in intramural cell engraftment, matrix repair, and mechanical stabilization of the aortic wall. To address our hypothesis, we will execute the following specific aims:
Specific Aim 1 is to develop and validate a technique to deliver MSCs into the aortic wall periadventitially using a hydrogel vehicle and magnetic guidance. The technique will be optimized by testing a cadre of iron nanoparticle types, fibrin hydrogel formulations, and stem cell concentrations both in vitro and in vitro.
Specific Aim 2 is to demonstrate that local MSC delivery halts and reverses the functional and structural degeneration of an AAA in an established rodent model. MSC hydrogels developed in Specific Aim 1 will be applied to the adventitia of an elastase-induced model AAA after allowing for varying degrees of matrix degeneration. Metrics for success of the various therapies versus cell-free hydrogel controls on aortic tissue will involve: i) functional assessment (including aortic diameter and biomechanical parameters) and ii) detailed microstructural and cellular composition assessment. The expected outcome of this work is the development and proof-of-concept of a new technology for stem cell delivery to AAA.
Abdominal aortic aneurysm leads to 10,000 American deaths annually - at the root of this disease is the loss of a critical protein for blood vessel function, elastin. This proposal presents a strategy for delivering therapeutic cells to the diseased aorta which will restore elastin levels and regenerate the aorta.
