Abstract Body: Background:
Chronic ischemic heart disease leads to cellular inflammation which can lead to death. Few therapies promote regeneration in chronic ischemia. Cytokine-based therapies can alter post-infarction inflammation, however, its role in chronic settings is unknown. Here, we use our cellular platform (VitaGraft) for local cytokine delivery in chronic ischemia.
Research Question:
Does combinatorial immunomodulatory cytokine delivery promote repair better than monotherapy after chronic myocardial ischemia?
Methods:
VitaGrafts were made by 3D printing a lattice with engineered retinal pigment epithelium cells expressing rat IL10 and IL1ra, embedded in an alginate hydrogel. VitaGrafts were implanted in chronic post-MI rats. VitaGrafts cytokine production was assessed by ELISA. Heart function was assessed with echocardiography. Cells were assessed by single-cell RNA sequencing (scRNAseq).
Results:
We engineered VitaGrafts to produce IL10 and IL1ra ~1ug/day. Echocardiography showed ~72% improvement in combination therapy compared to ~32.8% in monotherapy. scRNAseq revealed nine cell clusters in chronic ischemia, with M1 macrophages and monocytes reduced in combination therapy compared to monotherapy. We found a pro-resolution T cell and activating effector T cell only present in the combination therapy. Interferon gamma and inflammatory response pathways were only reduced in combination therapy.
Conclusions:
The VitaGraft offers a bioengineering tool that promotes heart regeneration and can allow multiplexed therapies.