Adult T-cells impair neonatal cardiac regeneration

Author:

Dolejsi Theresa1ORCID,Delgobo Murilo23ORCID,Schuetz Thomas1ORCID,Tortola Luigi4ORCID,Heinze Katrin G5ORCID,Hofmann Ulrich23,Frantz Stefan23ORCID,Bauer Axel1ORCID,Ruschitzka Frank6ORCID,Penninger Josef M78ORCID,Campos Ramos Gustavo23ORCID,Haubner Bernhard J16ORCID

Affiliation:

1. Department of Internal Medicine III (Cardiology and Angiology), Medical University of Innsrbuck , Anichstraße 35, 6020 Innsbruck , Austria

2. Department of Internal Medicine I, University Hospital Würzburg , Oberdürrbacher Straße 6, 97080 Würzburg , Germany

3. Comprehensive Heart Failure Center, University Hospital Würzburg , Am Schwarzenberg 15, D-97078 Würzburg , Germany

4. Institute of Molecular Health Sciences, ETH Zurich , Otto-Stern-Weg 7, 8093 Zurich , Switzerland

5. Rudolf Virchow Center, University of Würzburg , Josef-Schneider-Straße 2, 97080 Würzburg , Germany

6. Department of Cardiology, University Heart Center, University Hospital Zurich , Rämistrasse 100, CH-8091 Zurich , Switzerland

7. Institute of Molecular Biotechnology of the Austrian Academy of Sciences , Dr-Bohr-Gasse 3, 1030 Vienna , Austria

8. Department of Medical Genetics, Life Sciences Institute, University of British Columbia , 2350 Health Sciences Mall, Vancouver, BC , Canada

Abstract

AbstractAimsNewborn mice and humans display transient cardiac regenerative potential that rapidly declines postnatally. Patients who survive a myocardial infarction (MI) often develop chronic heart failure due to the heart’s poor regeneration capacity. We hypothesized that the cardiac ‘regenerative-to-scarring’ transition might be driven by the perinatal shifts observed in the circulating T-cell compartment.Methods and resultsPost-MI immune responses were characterized in 1- (P1) vs. 7-day-old (P7) mice subjected to left anterior descending artery ligation. Myocardial infarction induced robust early inflammatory responses (36 h post-MI) in both age groups, but neonatal hearts exhibited rapid resolution of inflammation and full functional recovery. The perinatal loss of myocardial regenerative capacity was paralleled by a baseline increase in αβ-T cell (CD4+ and CD8+) numbers. Strikingly, P1-infarcted mice reconstituted with adult T-cells shifted to an adult-like healing phenotype, marked by irreversible cardiac functional impairment and increased fibrosis. Infarcted neonatal mice harbouring adult T-cells also had more monocyte-derived macrophage recruitment, as typically seen in adults. At the transcriptome level, infarcted P1 hearts that received isolated adult T-cells showed enriched gene sets linked to fibrosis, inflammation, and interferon-gamma (IFN-γ) signalling. In contrast, newborn mice that received isolated Ifng  –/– adult T-cells prior to MI displayed a regenerative phenotype that resembled that of its age-matched untreated controls.ConclusionPhysiological T-cell development or adoptive transfer of adult IFN-γ-producing T-cells into neonates contributed to impaired cardiac regeneration and promoted irreversible structural and functional cardiac damage. These findings reveal a trade-off between myocardial regenerative potential and the development of T-cell competence.

Funder

Austrian Science Fund

Medical University Innsbruck for young scientists

Wittgenstein award

T. von Zastrow foundation and the Canada 150 Research Chairs Program

Interdisciplinary Centre for Clinical Research Würzburg

German Research Foundation

European Research Area Network—Cardiovascular Diseases/German Federal Ministry of Education and Research

Publisher

Oxford University Press (OUP)

Subject

Cardiology and Cardiovascular Medicine

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