HMGA1 Expression Promotes Heart Regeneration in Mammals
Numerous research groups are investigating the cellular biochemistry of highly regenerative species such as salamanders and zebrafish. The goal is to find the differences that ensure regrowth of lost tissue rather than the scarring that occurs in mammals. So far, many of these differences appear to involve the continued operation of processes of regulated growth that take place during embryonic development. It is hoped that some of these differences can form a practical basis for regenerative therapies that will allow the safe regrowth of loss limbs and organ tissues. The approach noted here appears promising, as it is just a difference in expression of a gene regulating chromatin structure, rather than a difference in protein structure and function between species. Engineering higher or lower expression of specific native genes is practical, but introducing novel proteins with different sequences into an adult organism is more challenging to achieve safely, as the immune system can react poorly.
In contrast to adult mammalian hearts, the adult zebrafish heart efficiently replaces cardiomyocytes lost after injury. Here we reveal shared and species-specific injury response pathways and a correlation between Hmga1, an architectural non-histone protein, and regenerative capacity, as Hmga1 is required and sufficient to induce cardiomyocyte proliferation and required for heart regeneration. In addition, Hmga1 was shown to reactivate developmentally silenced genes, likely through modulation of H3K27me3 levels, poising them for a pro-regenerative gene program.
Furthermore, AAV-mediated Hmga1 expression in injured adult mouse hearts led to controlled cardiomyocyte proliferation in the border zone and enhanced heart function, without cardiomegaly and adverse remodeling. Histone modification mapping in mouse border zone cardiomyocytes revealed a similar modulation of H3K27me3 marks, consistent with findings in zebrafish. Our study demonstrates that Hmga1 mediates chromatin remodeling and drives a regenerative program, positioning it as a promising therapeutic target to enhance cardiac regeneration after injury.