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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.

Illustration of infarcted heart and regenerated heart, showing the process of the delivery of stem cell-derived cardiomyocytes and induction of cardiomyocyte cell cycle activity.

Approaches to promote regenerative growth

Illustration of stem cells used to grow new heart tissue.
  • 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.

Active Funded Research

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)

Highlighted Publications

Cardiac Troponin I-Interacting Kinase Affects Cardiomyocyte S-Phase Activity but Not Cardiomyocyte Proliferation

Reuter SP, Soonpaa MH, Field D, Simpson E, Rubart-von der Lohe M, Lee HK, Sridhar A, Ware SM, Green N, Li X, Ofner S, Marchuk DA, Wollert KC, Field LJ. Circulation. 2023 Jan 10;147(2):142-153. doi: 10.1161/CIRCULATIONAHA.122.061130. Epub 2022 Nov 16. PMID: 36382596

This figure illustrates relative levels of cardiomyocyte S-phase activity indicated by small white circles and shows a comparison between mice with a DBA/2J genetic background (left panel) as compared to mice with a C57BI/6N genetic background (right panel)

Musings on intrinsic cardiomyocyte cell cycle activity and myocardial regeneration

Soonpaa MH, Reuter SP, Castelluccio PF, Field LJJ Mol Cell Cardiol. 2023 Jul 28;182:86-91. doi: 10.1016/j.yjmcc.2023.07.007. Online ahead of print. PMID: 37517369



Targeted expression of cyclin D2 ameliorates late stage anthracycline cardiotoxicity

Zhu W, Reuter S, Field LJ. Cardiovasc Res. 2019 Apr 15;115(5):960-965. doi: 10.1093/cvr/cvy273.PMID: 30423020

This figure shows improvement in cardiac function over time in doxorubicin-treated mice which exhibit cardiomyocyte cell cycle activity (blue line, diamond symbols), as compared to mice without cardiomyocyte cell cycle activity (red line, square symbols). The figure also shows points from acute stage to late stage.

Absence of Cardiomyocyte Differentiation Following Transplantation of Adult Cardiac-Resident Sca-1+ Cells Into Infarcted Mouse Hearts

Soonpaa MH, Lafontant PJ, Reuter S, Scherschel JA, Srour EF, Zaruba MM, Rubart-von der Lohe M, Field LJ. Circulation. 2018 Dec 18;138(25):2963-2966. doi: 10.1161/CIRCULATIONAHA.118.035391. PMID: 30566013




Principal Investigator
4906-Field, Loren

Loren J. Field, PhD

Distinguished Professor

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Dorothy Field, MS

Lab Manager

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Sean P. Reuter, BS

Senior Technician

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Mark H. Soonpaa, PhD

Assistant Scientist in Medicine

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IU School of Medicine Collaborators

Anthony B. Firulli, PhD

Carleton Buehl McCulloch Professor of Pediatrics

Weinian Shou, PhD

Professor of Pediatrics

Early Investigator Opportunities

This group is accepting student researchers.