Liao S et al. (2017), Heart regeneration in adult Xenopus tropicalis ...

XB-ART-54386

Cell Biosci 2017 Dec 13;7:70. doi: 10.1186/s13578-017-0199-6.

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Heart regeneration in adult Xenopus tropicalis after apical resection.

Liao S , Dong W , Lv L , Guo H , Yang J , Zhao H , Huang R , Yuan Z , Chen Y , Feng S , Zheng X , Huang J , Huang W , Qi X , Cai D .

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Background: Myocardium regeneration in adult mammals is very limited, but has enormous therapeutic potentials. However, we are far from complete understanding the cellular and molecular mechanisms by which heart tissue can regenerate. The full functional ability of amphibians to regenerate makes them powerful animal models for elucidating how damaged mature organs are naturally reconstituted in an adult organism. Like other amphibians, such as newts and axolotls, adult Xenopus displays high regenerative capacity such as retina. So far, whether the adult frog heart processes regenerative capacity after injury has not been well delineated. Results: We examined the regeneration of adult cardiac tissues of Xenopus tropicalis after resection of heart apex. We showed, for the first time, that the adult X. tropicalis heart can regenerate perfectly in a nearly scar-free manner approximately 30 days after injury via apical resection. We observed that the injured heart was sealed through coagulation immediately after resection, which was followed by transient fibrous tissue production. Finally, the amputated area was regenerated by cardiomyocytes. During the regeneration process, the cardiomyocytes in the border area of the myocardium adjacent to the wound exhibited high proliferation after injury, thus contribute the newly formed heart tissue. Conclusions: Establishing a cardiac regeneration model in adult X. tropicalis provides a powerful tool for recapitulating a perfect regeneration phenomenon and elucidating the underlying molecular mechanisms of cardiac regeneration in an adult heart, and findings from this model may be applicable in mammals.

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Species referenced: Xenopus tropicalis
Genes referenced: acta1 h3-3a
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	Fig. 1. Apical resection of the X. tropicalis heart and rapid blood coagulation after resection. a The heart was exposed for apical resection. The dash line shows the resection plane, corresponding to approximately 10% of the ventricle. b The heart immediate after surgical amputation. c Bleeding after ventricle amputation. d Rapid blood coagulation in the amputated heart after approximately 5 s of pressure with sterile cotton. e Outer surface of the amputated apex. The asterisk indicates the end of the apex on the outer surface. f Inner surface of the amputated apex. The circle with the dotted line indicates the bottom of the ventricle. g Lateral view of the amputated apex. The arrow indicates the bottom of the apex on the outer surface

	Fig. 3. Adult X. tropicalis heart has capacity for regeneration after resection. A1 Longitudinal section of an adult heart from the non-amputated sham control. Bar = 400 μm. A2 High magnification of the region outlined by rectangle in A1. Bar = 100 μm. A3 High magnification of the rectangle region in A2. Bar = 20 μm. B1–B3 An amputated heart at 0 daar (approximately 30 min after amputation), showing activated inflammation and hyperemia at the border of the injury. C1–C3 An amputated heart at 1 daar, showing a membrane-like structure (arrow) close to the outer surface of the scar tissue which exhibited with inflammatory cell infiltration, and red blood cells accumulation below the membrane-like structure. C2′ High power of the membrane-like structure which is consisted of cellular or some extracellular matrix. D1–D3 An amputated heart at 2 daar, showing more inflammatory cells in the regenerated area compared with 1 daar. E1–E3 An amputated heart at 4 daar, showing an increase of inflammatory cells and a decrease of red blood cells in the regenerated area compared with 2 daar. F1–F3 An amputated heart at 8 daar, showing the disappearance of most infiltrated red blood cells and a significant decrease of the inflammatory cell intensity in the regenerated area. g1–g3 Most of the fibrous tissue production was replaced with newly regenerated cardiomyocytes and some of the newly regenerated cardiac myocytes are matured, as indicated by a more regular cardiac-specific cross-striated morphology at 16 daar (G3′). H1–H3, I1–I3 An amputated heart regenerated with a perfect morphology and nearly perfect morphology at 30 daar. The amputated area was regenerated with mature cardiomyocytes. In addition, the regenerated myocardium has an intact epicardium (arrow). J1–J3, K1–K3 An amputated heart regenerated with a perfect morphology and nearly perfect morphology at 60 daar. The amputated area was regenerated with mature cardiomyocytes. An intact epicardial structure (arrow) in the regenerated myocardium. R regenerated area, B border area. White star: showing red blood cells; White arrows: showing inflammation cells. Six frogs were inspected for 30 and 60 daar, while three frogs were inspected for other time points respectively

	Fig. 5. α-SA/PH3 positive cells exist in the border area of the amputated site and regenerated area. a1 Longitudinal section of the apical area from a sham control. High magnification of the square region is shown (a2). Longitudinal sections of an amputated heart at 0 daar (b1, b2), 1 daar (c1, c2), 2 daar (d1, d2), 4 daar (e1, e2), 8 daar (f1, f2), 16 daar (g1, g2), 30 daar (h1, h2; perfect regeneration), 30 daar (i1, i2; nearly perfect regeneration), and 60 daar (j1; perfect regeneration). The amputated apex was regenerated by newly cardiomyocytes within approximately 30 days after amputation, as demonstrated by the presence of many α-SA+ cardiomyocytes in the regenerated zone (area between the red dotted line and white dotted line). In addition, the density of α-SA+/PH3+ cardiac myocytes in the border area of the regenerated zone at 2–8 daar and in the regenerated zone at 16–30 daar is significantly higher than those in the sham control and in 0–2 daar groups, suggesting that the proliferation of endogenous cardiomyocytes in the border area of the amputated site might be an important mechanism for regeneration of the damaged myocardium. α-SA alpha skeletal muscle actin, PH3 phospho-histone H3, DAPI 4′,6-diamidino-2-phenylindole. White arrow: PH3+ nucleus. White dotted line, outer surface of the epicardium. Area between the red dotted line and white dotted line, regenerated area after amputation. 30-daar-n: amputated heart with nearly perfect regeneration at 30 daar. Bar in a1–j1 = 50 μm. Bar in a2–j2 = 10 μm. Six frogs were inspected for 30 and 60 daar, while three frogs were inspected for other time points respectively

	Fig. 7. The regeneration of the injured adult X. tropicalis heart is nearly scar-free manner. a1 Longitudinal section of an adult heart from a sham control. Bar = 400 μm (scale bar for a1–k1). a2 High magnification of the rectangle with a dotted line from a1. Bar = 100 μm (scale bar for A2–K2). A3 High magnification of rectangle with the dotted line from A2. Bar = 20 μm (scale bar for a3–k3). Longitudinal sections from amputated heart at 0 daar (B1–B3), 1 daar (C1–C3), 2 daar (D1–D3), 4 daar (E1–E3), 8 daar (F1–F3), 16 daar (G1–G3), 30 daar (H1–H3; an amputated heart regenerated with a perfect morphology), 30 daar (i1–i3; an amputated heart regenerated with a nearly perfect morphology), 60 daar (J1–J3; an amputated heart regenerated with a perfect morphology) and 60 daar (K1–K3; an amputated heart regenerated with a nearly perfect morphology). Fibrosis-like structures were stained in blue. In the hearts that were regenerated with a nearly perfect morphology, fibrosis-like structures was only observed in adhesion tissue, but not in the regenerated myocardium between 30 and 60 daar. B border area. R regenerated area. Six frogs were inspected for 30 and 60 daar, while three frogs were inspected for other time points respectively
	Fig. 8. Time course of infiltration of red blood cell and inflammation, and fibrosis during the regeneration of amputated myocardium. a Images represent various degrees of infiltration of red blood cell and inflammation cells, and fibrous tissue production during heart regeneration. b Comparison of time courses for infiltration of red blood cell and inflammation cells, and fibrous tissue production

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Ali, Existing cardiomyocytes generate cardiomyocytes at a low rate after birth in mice. 2014, Pubmed