Article Text

PDF

10 Macrophage-derived wnts are required for scar-free regeneration of the neonatal mouse myocardium
  1. Castellan RFP1,
  2. Thompson M2,
  3. Soong DYH3,
  4. Mylonas KJ1,
  5. Thomson A1,
  6. Moran CM1,
  7. Kitsis RN2,
  8. Pollard JW3,
  9. Gray GA1
  1. 1Centre for Cardiovascular Science, QMRI, The University of Edinburgh, Edinburgh, UK
  2. 2Albert Einstein College of Medicine, Bronx, UK
  3. 3MRC Centre for Reproductive Health, QMRI, The University of Edinburgh, Edinburgh, UK

Abstract

Objective In contrast to the adult, neonatal mice regenerate their myocardium following injury, at least during the first week after birth.1 Macrophages (M&x0424;) contribute to vessel formation and scar removal following neonatal myocardial infarction (MI)2. In the kidney3 liver4,7 and gut5 M&x0424;-derived WNTs are required for scar free regeneration following injury. Secretion of WNTs is dependent on acylation by Porcupine (PORCN). In the present study it was hypothesised that neonatal cardiac regeneration would be impaired in mice with Csf1r-Cre driven M&x0424; specific Porcn deletion.5

Methods Csf1r-EGFP(MacGreen), Porcnfl/Csf1rCre-ve and Porcnfl/Csf1rCre+ve mice underwent coronary artery ligation at post-natal day 1 (P1). Functional loss 1 day after MI, and recovery by P21 were assessed by high-resolution ultrasound. Heart sections were stained with isolectin B4 (vessel density) and picrosirius res (fibrosis). Myocardial gene expression was determined by PCR array in wild-type (WT) mice after injury.

Results At day 1 and day 7 post-MI, Csf1r-expressing cells accumulated within the injured myocardium, consistent with a role in regeneration.2 At day 1 post-MI, fractional area change (FAC) decreased from 40.9% ± 1.6 to 18.0% ± 2.4% (p<0.0001) and from 41.0% ± 1.3 to 16.5% ± 2.7% (p<0.0001) in Porcnfl/Csf1rCre-ve and Porcnfl/Csf1rCre-ve mice respectively. By 21 days after MI, FAC had recovered to 47.4% ± 2.5% (p<0.0001) in Porcnfl/Csf1rCre-ve and 45.8% ± 1.9% (p<0.0001) in Porcnfl/Csf1rCre-ve littermates. Coronary vascularisation was restored in the infarct area by 21 days in both lines, but interstitial fibrosis was significantly higher in Porcnfl/Csf1rCre-ve (6.0 ± 0.9% LV) compared to Porcnfl/Csf1rCre-ve (3.8 ± 0.5% LV, p<0.05). In WT neonatal hearts, MI increased the expression of Wnt5b and Fzd2, genes associated with regulation of fibrosis.8

Conclusion M&x0424;-derived WNTs are not required for re-vascularisation or restoration of myocardial function after neonatal myocardial injury, but are necessary for scar removal during regeneration.

References

  1. Porrello et al. PNAS 2013;110:p187–92.

  2. Aurora et al. JCI 2014;124:p1382–92.

  3. Lin et al. PNAS 2010;107:p4194–99.

  4. Boulter et al. Nat Med 2012;18:572–9.

  5. Saha et al. Nat Com 2016;7:1–16.

  6. Derlindati et al. PLoS ONE 2015;10:1–17.

  7. Irvine et al. Fibrogenesis Tissue Repair 2015;8:19–32.

  8. Laeremans et al. Cardiovascular Research 2010;87:514–523.

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.