Fellowship for Peng: Cardiomyocyte phenotype drives enhanced AMI recovery in spiny mice

Approximately every 40 seconds, there is an incident of heart attack (myocardial infarction, MI). This injury cause necrosis of heart leading to cardia arrhythmia and reduced cardiac contractility, rendering progression of heart failure (HF) in many patients within five years of initial MI. Unfortunately, human heart does not regenerate after injury, and there is no approved clinical treatment that facilitate cardiac repair. Moreover, no regenerative mammalian models is established to identify molecular targets for bona fide cardiac repair. This proposal will address these limitations by studying regenerate mammal with non-regenerator simultaneously. Acomys (African Spiny mice) is a mammal closely related to Mus (laboratory mouse) and human. Recently, independent groups have reported that Acomys are capable of regenerating injured tissue in multiple organs, including nerves, muscle, cartilage, glands, follicles, skin, and kidney. Unlike other vertebrates or mice, Acomys is developmentally and hormonally (have menstruation cycle) similarity to human. Most importantly, after MI, Acomys demonstrated significant cardiac protection, with higher survival rate than mice. Our preliminary study revealed that Acomys exhibited pro-regenerative immune response and is capable of rescuing cardiac function after MI. This proposed study will further dissect the effect of these alternative injury response seem in Acomys and how it contributes to better survival after MI. Based on our preliminary results, I proposed to further investigate how alternative injury response seem in Acomys contributes to increased survival after MI. I hypothesized that Acomys are protected from MI because immediately after injury, they response with more pro-regenerative inflammation that reduce apoptosis and signal cellular proliferation that facilitate tissue regeneration. I will test this hypothesis by implementing the following two aims. Aim 1 will investigate the type and duration of immune activation that immediately after MI. Specifically, I will investigate macrophage and neutrophil profile, activation and cytokine production after MI in both Acomys and Mus to determine how their immune system reacts differently to cardiac injury. The effect of these immune cells on primary cardiac fibroblast and cardiomyocytes will be further tested in vitro by co-culture. Aim 2 will focused on examine the contribution of proliferative cardiomyocyte that drives cardiac repair. Both in vivo and in vitro assays will be employed in this aim to assays the contribution of proliferative cardiomyocytes in Acomys in forming new heart tissue, and if this mechanism is sufficient to rescue cardiac function. While regeneration in has been reported in Acomys attributing to their pro-regenerative immune response, this proposal will be the first to directly test if this feature is responsible to their augmented post-MI survival. This proposal will establish Acomys as a novel mammalian model for studying regenerative cardiac therapy. I anticipate the outcome of this study to provide a blue print for the development of novel cardiac therapy for human patients.