Development of a structurally and mechanically-tunable cardiac patch for the controlled delivery of cardiovascular progenitors in heart failure. – CardiacPatch

Cardiac cell therapy holds a real promise for improving function of the chronically failing myocardium. However, so far, clinical outcomes of patients included in cell therapy trials have not met the expectations raised by the preceding experimental studies. Analysis of the causes for these suboptimal results leads to three major conclusions : (1) repair of scarred myocardium should be best achieved by cells endowed with a cardiomyogenic differentiation potential as cell types used so far clinically (skeletal myoblasts, bone marrow-derived cells, adipose tissue-derived cells) lack the ability to convert into cardiomyocytes; (2) injection-based cell delivery is not satisfactory, primarily because it involves a proteolytic dissociation of the cells which sets the stage for their apoptotic death; and (3) the efficacy of the cell transplant is largely dependent on the engraftment rate which, in turn, requires cells to receive an adequate blood supply to survive. To address these issues, we propose to switch from mere cell therapy to a more composite tissue engineering construct entailing the use of human embryonic stem cell (hESC)-derived cardiac progenitors seeded onto a biocompatible scaffold along with endothelial cells from the same hESC source to provide the necessary trophic support. Although the concept of such a co-seeded patch is not new, a remaining issue is that of the migration of the cells away from the scaffold to colonize the underlying myocardium. The basic objective of this project is to design a patch allowing such a migration with the premise that the patch-derived cells will then improve angiogenesis and heart function, possibly through their coupling with host cardiomyocytes.

To achieve this objective, we plan to develop an electrospun nanofibrous collagen-based patch co-seeded with two synergistically cross-talking cell populations originating from the same hESC cell line and differentially pre-committed to yield both cardiac progenitors and endothelial cells. By controlling the porous size and the mechanical and chemical properties of the scaffolds, we will first optimize their suitability for cell loading, cell survival and proliferation before assessing their permissivity with regard to cell migration. We will then optimize the permissivity of this patch with regard to cell migration by physical (pore size), chemical (surface chemistry) and eventually biological (active molecule adjuncts) adjustments. To mimic the future environment of the patch, we will then develop an ex vivo model whereby the patch is put in contact with an epicardial layer obtained during cardiac surgical operations, with the assumption that epicardium-secreted factors may play a key role in driving the patch-bound cells towards the inner layers of the myocardium, keeping the additional intramyocardial delivery of chemoattractants as a back-up solution. The development of this ex vivo model which mimics the cardiac in vivo environment, should allow us to limit unnecessary use of animals and to screen rapidly different parameters to obtain more appropriate cellularized biomaterial for cardiac cell therapy. Following this step, the capacity of the cells to migrate away from this patch and subsequently to enhance function of the chronically infarcted myocardium will ultimately be tested in an in vivo model of permanent coronary artery ligation.

To achieve these objectives, we have built a multidisciplinary consortium which involve three laboratories and a company which have expertise in 1) nanotechnology and biomaterial architecture, 2) development of collagen-based biomaterials for clinical use, 3) cardiovascular development and differentiation of hESC towards the cardiac and endothelial lineages, and 4) small and large animal models of myocardial infarction and clinical cell-based trials for cardiovascular repair.