XB-ART-55694Proc Natl Acad Sci U S A January 1, 2019; 116 (9): 3614-3623.
Stage-dependent cardiac regeneration in Xenopus is regulated by thyroid hormone availability.
Despite therapeutic advances, heart failure is the major cause of morbidity and mortality worldwide, but why cardiac regenerative capacity is lost in adult humans remains an enigma. Cardiac regenerative capacity widely varies across vertebrates. Zebrafish and newt hearts regenerate throughout life. In mice, this ability is lost in the first postnatal week, a period physiologically similar to thyroid hormone (TH)-regulated metamorphosis in anuran amphibians. We thus assessed heart regeneration in Xenopus laevis before, during, and after TH-dependent metamorphosis. We found that tadpoles display efficient cardiac regeneration, but this capacity is abrogated during the metamorphic larval-to-adult switch. Therefore, we examined the consequence of TH excess and deprivation on the efficiently regenerating tadpole heart. We found that either acute TH treatment or blocking TH production before resection significantly but differentially altered gene expression and kinetics of extracellular matrix components deposition, and negatively impacted myocardial wall closure, both resulting in an impeded regenerative process. However, neither treatment significantly influenced DNA synthesis or mitosis in cardiac tissue after amputation. Overall, our data highlight an unexplored role of TH availability in modulating the cardiac regenerative outcome, and present X. laevis as an alternative model to decipher the developmental switches underlying stage-dependent constraint on cardiac regeneration.
PubMed ID: 30755533
PMC ID: PMC6397552
Article link: Proc Natl Acad Sci U S A
Genes referenced: col1a1 ctrl fn1 jmjd6 mmp1 mmp11 mmp13 mmp14 mmp2 pdlim7 thibz tnc
Article Images: [+] show captions
|Fig. 1. Transient fibrotic response followed by complete ventricle rebuilding after cardiac resection in tadpole heart. (Top) Cardiac resection was performed on prometamorphic NF57 X. laevis tadpoles by dissecting the abdominal skin and opening the pericardium, then removing ∼10–15% of the ventricle toward the apex. Hearts were collected at 1, 3, 14, 30, 50, 90, and 180 dpa. (A–G) PSR histological labeling reveals an intensification of fibrotic connective tissue up to 14 dpa at the site of amputation (labeled in dark red). From 30 dpa up to 90 dpa, the fibrotic zone regressed and progressively disappeared as the ventricle apex regained a normal morphology, and was strongly reduced or undetectable after 90 (F2 and F1, respectively) or 180 dpa (G). (A′–G′) Higher magnifications, with dotted lines indicating amputated area and arrows indicating the amputation site. (Scale bars, 100 μm.)|
|Fig. 2. Cardiac regenerative capacity is reduced then permanently lost after metamorphosis. (A) Cardiac resection was performed at different developmental stages before, during, and after TH-dependent metamorphosis: prometamorphic stages (NF57–58), climax (NF61–62), end (NF65–66), and just after metamorphosis (froglet), and in 6-mo-old juveniles. Hearts were collected 6 mpa for metamorphic stages (NF57 to froglet), and ≥1 ypa for juveniles. (B) Using PSR histological staining, hearts were categorized and quantified according to different heart phenotypes observed: fully regenerated (green: no fibrotic tissue present at the amputated site), partially regenerated (orange: fibrotic tissue remaining present at the amputated site), and those displaying an absence of regeneration (red: strong appearance of a fibrotic scar at the amputated site); arrowheads indicate the amputation site. All samples were obtained from more than four independent experiments: NF57–58, n = 4; NF61–62, n = 15; NF65–66, n = 8; froglet, n = 6, juvenile, n = 7. Immunolabeling (C and D) fibronectin (green), tropomyosin (red), and PSR staining (E) of a juvenile heart at 1 ypa (n = 5) displaying a clear presence of invasive fibrotic tissue at the amputation site (arrowhead). Immunolabeling (F) and PSR staining (G) of a juvenile heart at 3.3 ypa (n = 2) still showing a strong presence of fibrotic tissue and, hence, a persistent scar at the amputation site (arrowhead). (Scale bars, 1 mm inC and 0.5 mm in D–G.)|
References [+] :
Alameddine, Matrix Metalloproteinases and Tissue Inhibitor of Metalloproteinases in Inflammation and Fibrosis of Skeletal Muscles. 2018, Pubmed