Adult T-cells impair neonatal cardiac regeneration

Eur Heart J. 2022 Jul 21;43(28):2698-2709. doi: 10.1093/eurheartj/ehac153.

Abstract

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 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.

Conclusion: Physiological 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.

Keywords: Cardiac regeneration; Immune system; Myocardial infarction; T-cells; Wound healing.

MeSH terms

  • Adult
  • Animals
  • Disease Models, Animal
  • Female
  • Fibrosis
  • Humans
  • Inflammation / pathology
  • Interferon-gamma
  • Mice
  • Myocardial Infarction*
  • Myocardium / pathology
  • Myocytes, Cardiac* / physiology
  • Pregnancy
  • Regeneration / physiology

Substances

  • Interferon-gamma