Myocardial Regenerative Biology Research Program

Acute Myocardial Infarction (MI) is a leading cause of death worldwide. Survivors of MI usually develop scar tissue in the infarcted regions of the heart, which leads to inefficient cardiac function and other associated pathology. Such patients could benefit greatly from regenerative medicine, which aims to replace the scar with healthy muscle cells, thus restoring normal function. The Myocardial Regenerative Biology Research Program (MRBRP) at KCVRC is investigating novel ways to repair damaged heart tissue utilizing stem cell or cell-free therapies.

This program, led by molecular biologist Loren J. Field, PhD, has a long-standing track record in developing genetic models and strategies to monitor the intrinsic rates of cardiomyocyte cell cycle renewal in normal and injured adult hearts, as well as developing strategies to induce regenerative growth following myocardial injury.

• Transplant stem cell-derived cardiomyocytes into the damaged myocardium.
• Promote regenerative growth by inducing proliferation in surviving cardiomyocytes following myocardial injury.
  
  

Achievements

This group was the first to show that both fetal (PMID: 8140423) and embryonic stem cell-derived cardiomyocytes (PMID: 8690796) can structurally integrate into the adult myocardium and are able to participate in a functional syncytium with the host heart (PMID: 12730096, PMID: 23434590).

This group has demonstrated that targeted expression of the G1/S regulatory protein cyclin D2 results in a 50 percent reduction in infarct size and a concomitant 90 percent recovery in cardiac function within 180 days following permanent coronary artery occlusion (PMID: 15576649, PMID: 18079102).

Dr. Field and his team are currently focusing on using a novel in-house imaging approach to screen for genetic variants which enhance cardiomyocyte cell cycle entry and progression in injured hearts, and to test the impact of these variants on cardiac structure and function following infarction.

“We found that the ability of cardiomyocytes to enter the cell cycle and replicate their DNA is not particularly limiting in an injured heart; they do that pretty rigorously,” said Field. “Unfortunately, the cardiomyocytes get hung up prior to dividing. We’re trying to understand the reasoning for the hang up—and what prevents those cardiomyocytes from completing the cell cycle.” 

Field would like to identify more genes that are capable of impacting cardiomyocyte cell activity, not just for a genetic intervention, but also to identify pathways that may be open to pharmacological intervention, which could be less complicated to translate to the clinic. Ultimately, he would like to develop a large linkage map that would describe the pathways that enhance cardiomyocyte proliferation.

1R01 HL155218 - Myocardial Ischemia and Metabolism

The first aim of the study will test the hypothesis that a single gene within the region of interest is responsible for elevated cardiomyocyte S-phase activity post-infarction. The second aim will test the hypothesis that the elevated cell cycle activity has a positive impact on the diminished cardiac function and adverse myocardial remodeling which is encountered post-infarction.

Timeframe: 2021-2024

Funding source: NHLBI

PI: Field, L.J.

1R01 HL158597 - Integrative Myocardial Physiology / Pathophysiology

The first aim of this study will test the hypothesis that atrial cardiomyocyte cell cycle induction following myocardial infarction contributes to structural modeling of the left atrium. The second aim will test the hypothesis that atrial cardiomyocyte cell cycle induction following myocardial infarction contributes to functional changes in the left atrium and left ventricle.

Timeframe: 2022-2025

Funding source: NHLBI

PI: MPI, Field, L.J. (contact) & Rubart, M.

1PO1 HL345599 - Growth Regulation and Morphogenesis of the Ventricle

This program project grant, which is led by Anthony B. Firulli, the Carleton Buehl McCulloch Professor of Pediatrics, proposes to elucidate mechanisms that regulate growth and morphogenesis of the ventricle during development.

Timeframe: 2017-2028

Funding source: NHLBI

PI: Firulli, AB (PPG PI)