Investigating the role of SPRR1A in border zone cardiomyocytes during neonatal cardiac repair

PROJECT SUMMARY/ABSTRACT Myocardial infarction (MI) causes localized cardiomyocyte (CM) death which predisposes the adult mammalian heart to persistent fibrosis and subsequent complications such as heart failure. Border zone (BZ) CMs are a phenotypically distinct population of cells adjacent to the ischemic region, and their response may impact the

course of heart recovery. Adult BZ CMs become hypocontractile and may be susceptible to continued cell death, which can lead to scar expansion and exacerbate pathologic remodeling. In contrast, neonatal BZ CMs may activate programs promoting cell survival, dedifferentiation, and proliferation that can contribute to scarless heart

repair via cardiac regeneration. Therefore, it is imperative to study how BZ CMs respond under different conditions, as this will improve our understanding of regenerative versus non-regenerative cardiac repair. Neonatal mouse CMs retain some proliferative capacity through the first week of life, making the neonatal heart

an excellent model to study the differences between BZ CM phenotypes. Using RNA-Sequencing and spatial transcriptomics, we identified that small proline-rich protein 1A (Sprr1a) is transiently upregulated following cardiac insult and is predominantly expressed in BZ CMs. To investigate BZ CM function, we made a knock-

in/knockout mouse by replacing the Sprr1a locus with a GFP expression cassette (Sprr1aGFP). Importantly, we verified that GFP recapitulates endogenous SPRR1A expression after cardiac insult. The aims of this proposal are to determine the role of Sprr1a during cardiac injury and characterize the BZ CM response to cardiac insult

in regenerative versus non-regenerative cardiac repair. Aim 1 will investigate how Sprr1a deletion impacts neonatal heart regeneration in response to cryoinjury and/or apical resection. Aim 2 will explore how SPRR1A may regulate BZ CM survival via predicted interactions with cIAP1/2. Aim 3 will characterize the transcriptomic

profile of GFP+ BZ CMs isolated from hearts injured within the proliferative window (P1) versus post-mitotic stage (P7) in control and SPRR1A KO hearts. These findings will characterize the phenotypic response of BZ CMs in regenerative versus non-regenerative cardiac repair and define the role of Sprr1a in this process. The

discovery of additional markers within this sub-population will be beneficial for translational research as this may facilitate the design of targeted therapies to enhance CM cell survival or proliferation post-MI.