Adult T-cells impair neonatal cardiac regeneration
| Autor: | Dolejsi, Theresa, Delgobo, Murilo, Schuetz, Thomas, Tortola, Luigi, Heinze, Katrin G., Hofmann, Ulrich, Frantz, Stefan, Bauer, Axel, Ruschitzka, Frank, Penninger, Josef M., Ramos, Gustavo Campos, Haubner, Bernhard J. |
|---|---|
| Přispěvatelé: | University of Zurich, Campos Ramos, Gustavo, Haubner, Bernhard J |
| Rok vydání: | 2022 |
| Předmět: |
Adult
Inflammation Myocardium T-cells Wound healing 610 Medicine & health Fibrosis 2705 Cardiology and Cardiovascular Medicine Disease Models Animal Interferon-gamma Mice Myocardial infarction Immune system Pregnancy 10209 Clinic for Cardiology Animals Humans Regeneration Female Myocytes Cardiac Cardiac regeneration Cardiology and Cardiovascular Medicine |
| Zdroj: | European Heart Journal, 43 (28) |
| ISSN: | 1522-9645 0195-668X |
| DOI: | 10.5167/uzh-231593 |
| Popis: | Aims Newborn 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 results Post-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 alpha beta-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-gamma) 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. Conclusion Physiological T-cell development or adoptive transfer of adult IFN-gamma-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. European Heart Journal, 43 (28) ISSN:1522-9645 ISSN:0195-668X |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|