Project Background

The main objective of this project is to understand how peptides derived from the cardiac extracellular matrix (ECM) influence the wound-healing capabilities of cardiac cells.

It has been shown that the fetal/neonatal cardiac extracellular matrix can promote neonatal rat cardiomyocyte proliferation in vitro more effectively than neonatal or adult ECM. Understanding the interactions that inhibit proliferation as the organism ages could be used to induce proliferation post-injury. The peptide F1R1, a specific region of matrix component fibrillin-1, has been shown to improve the wound-healing capabilities of iPSC-derived cardiomyocytes. Alongside F1R1, other regions of interest in the N-terminus of fibrillin-1 were also found to be associated with cardiomyocyte regeneration in past experiments.

However, the underlying biological mechanism behind the effects of F1R1 and these other fibrillin-derived peptides is a black box. In discovering the effects of F1R1, it was also observed that it has sequential homology with TGF-B, a growth factor that inhibits hematopoiesis and induces cardiac fibroblasts to produce scar tissue.

So, the first steps are to observe the interactions between F1R1 and TGF-B in neonatal cardiac fibroblasts to see if inhibiting TGF-B-induced scar tissue formation is how F1R1 achieves cardiomyocyte proliferation. Using quantitative sequence homology, this procedure can be applied to the other fibrillin-1-derived peptides to determine their respective growth factor interactions. Further testing with the fibrillin-1 regions and their corresponding cellular factors will identify their relationships and their mechanism of action. By determining the targeted pathways of the cECM peptides of interest, a combinatory treatment of fibrillin-1 peptides could be hypothesized. This could then be tested in mature rat cardiac cell cultures to see if the F1R1-4 can carry out their proliferation-promoting mechanism in postnatal tissue. If time allows, 3D cultures of mature rat cardiac cells could be treated with these fibrillin-1 peptide regions for a better representation of in vivo therapeutic potential.

Overall, the project seeks to characterize how fibrillin-1 liberated peptides can elicit neonatal regeneration and determine if these mechanisms can be translated to mature tissue to lay the groundwork for an in vivo, protein-based therapeutic for cardiac injury and congenital heart defects.