Transient fibrosis resolves via fibroblast inactivation in the regenerating zebrafish heart

Sánchez-Iranzo, Héctor; Galardi-Castilla, María; Sanz-Morejón, Andrés; González‐Rosa, Juan Manuel; Costa, Ricardo; Ernst, Alexander; Aja, Julio Sainz de; Langa, Xavier; Mercader, Nadia

doi:10.1073/pnas.1716713115

Cited by 153 publications

(217 citation statements)

References 43 publications

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“…In addition, we found that the Runx1-Citrine positive thrombocytes that make up a large proportion of the wound express Myh11. Surprisingly, we observed most collagen deposition in the wound localised adjacent to the Myh11 expressing endocardial cells and thrombocytes, and to a much lesser extent near the epicardium, despite the fact that the epicardium is considered the main source of myofibroblasts and collagen deposition in the heart (37,40). This suggests that while these cells retain the characteristics of endocardial cells and thrombocytes, they can function analogously to myofibroblasts.…”

Section: Discussionmentioning

confidence: 70%

“…Absence of these cells could, therefore, explain the different wound composition as well as the enhanced regeneration in the runx1 mutant. This is a novel and surprising finding, as the epicardium is considered the main source of myofibroblasts and collagen deposition in the heart (37,39,40).…”

Section: Smooth Muscle Genes Are Expressed In the Endocardium And Thrmentioning

confidence: 91%

“…5a). Upregulation of collagens in the wound endocardium has been observed before (36,37), but has not previously been analysed using single cell transcriptomics. Clustering of the citrine/mcherry double positive cells showed 2 clusters (C4 and C5) appearing after injury, with upregulation of genes involved in extracellular matrix formation ( Fig.…”

Section: Runx1-positive Endocardial Cells Express Smooth Muscle Genesmentioning

confidence: 99%

“…As the epicardium has been shown to contribute myofibroblasts to the wound in zebrafish (37,40), and we observed activation of Runx1-Citrine in the epicardium, we next compared the epicardial cluster to the myofibroblast/smooth muscle cluster (C8 and C10, Fig. 5b-c, 8a).…”

Section: Changes In Runx1-citrine Positive Epicardial Cells After Injurymentioning

confidence: 99%

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Runx1 promotes scar deposition and inhibits myocardial proliferation and survival during zebrafish heart regeneration

Koth

Wang

Killen

et al. 2019

Preprint

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Runx1 is a transcription factor that plays a key role in determining the proliferative and differential state of multiple cell-types, during both development and adulthood. Here, we report how runx1 is specifically upregulated at the injury site during zebrafish heart regeneration, but unexpectedly, absence of runx1 results in enhanced regeneration. Using single cell sequencing, we found that the wild-type injury site consists of Runx1-positive endocardial cells and thrombocytes that induce expression of smooth muscle and collagen genes without differentiating into myofibroblasts. Both these populations are absent in runx1 mutants, resulting in a less collagenous and fibrinous scar. The reduction in fibrin in the mutant is further explained by reduced myofibroblast formation and by upregulation of components of the fibrin degradation pathway, including plasminogen receptor Annexin 2A as well as downregulation of plasminogen activator inhibitor serpine1 in myocardium and endocardium, resulting in increased levels of Plasminogen. In addition, we find enhanced myocardial proliferation as well as increased myocardial survival in the mutant. Our findings suggest that Runx1 controls the regenerative response of multiple cardiac cell-types and that targeting Runx1 is a novel therapeutic strategy to induce endogenous heart repair.

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Section: Discussionmentioning

confidence: 70%

Section: Smooth Muscle Genes Are Expressed In the Endocardium And Thrmentioning

confidence: 91%

Section: Runx1-positive Endocardial Cells Express Smooth Muscle Genesmentioning

confidence: 99%

Section: Changes In Runx1-citrine Positive Epicardial Cells After Injurymentioning

confidence: 99%

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Runx1 promotes scar deposition and inhibits myocardial proliferation and survival during zebrafish heart regeneration

Koth

Wang

Killen

et al. 2019

Preprint

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“…These include maturation of cardiac fibroblasts, activity of macrophages and other immune cells, ECM composition and rigidity, as well as physiological hypoxia and hormonal regulation. 14,28,41,42 Investigating the discordance in timing of cardiac maturation and regenerative capacity in pigs could be useful to define relative contributions of multiple cell types and physiological factors in heart regeneration. Here, we show that ECM remodeling is significant by P7 in pigs, contributing to increased rigidity of the matrix, while maturational collagen remodeling continues to 6mo.…”

Section: What Dictates Postnatal Regenerative Capacity Of the Mammalimentioning

confidence: 99%

Cardiomyocyte cell cycling, maturation, and growth by multinucleation in postnatal swine

Velayutham

Alfieri

Agnew

et al. 2019

Preprint

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words)Aims: Cardiomyocyte (CM) cell cycle arrest, decline of mononucleated-diploid CMs, sarcomeric maturation, and extracellular matrix remodeling are implicated in loss of cardiac regenerative potential in mice after birth. Recent studies show a 3-day neonatal regenerative capacity in pig hearts similar to mice, but postnatal pig CM growth dynamics are unknown. We examined cardiac maturation in postnatal pigs and mice, to determine the relative timing of developmental events underlying heart growth and regenerative potential in large and small mammals. Methods and Results:Left ventricular tissue from White Yorkshire-Landrace pigs at postnatal day (P)0 to 6 months (6mo) was analyzed to span birth, weaning, and adolescence in pigs, compared to similar physiological timepoints in mice. Collagen remodeling increases by P7 in postnatal pigs, but sarcomeric and gap junctional maturation only occur at 2mo. Also, there is no postnatal transition to beta-oxidation metabolism in pig hearts. Mononucleated CMs, predominant at birth, persist to 2mo in swine, with over 50% incidence of mononucleated-diploid CMs at P7-P15. Extensive multinucleation with 4-16 nuclei per CM occurs beyond P30. Pigs also exhibit increased CM length relative to multinucleation, preceding increase in CM width at 2mo-6mo. Further, robust CM mitotic nuclear pHH3 activity and cardiac cell cycle gene expression is apparent in pig left ventricles up to 2mo. By contrast, in mice, these maturational events occur concurrently in the first two postnatal weeks alongside loss of cardiac regenerative capacity. Conclusions:Cardiac maturation occurs over a 6mo postnatal period in pigs, despite a similar early-neonatal heart regenerative window as mice. Postnatal pig CM growth includes increase in CM length alongside multinucleation, with CM cell cycle arrest and loss of mononucleated-diploid CMs occurring at 2mo-6mo. These CM characteristics are important to consider for pig preclinical studies and may offer opportunities to study aspects of heart regeneration unavailable in other models.

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Finding Solutions for Fibrosis: Understanding the Innate Mechanisms Used by Super‐Regenerator Vertebrates to Combat Scarring

Durant

Whited

2021

Advanced Science

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Soft tissue fibrosis and cutaneous scarring represent massive clinical burdens to millions of patients per year and the therapeutic options available are currently quite limited. Despite what is known about the process of fibrosis in mammals, novel approaches for combating fibrosis and scarring are necessary. It is hypothesized that scarring has evolved as a solution to maximize healing speed to reduce fluid loss and infection. This hypothesis, however, is complicated by regenerative animals, which have arguably the most remarkable healing abilities and are capable of scar‐free healing. This review explores the differences observed between adult mammalian healing that typically results in fibrosis versus healing in regenerative animals that heal scarlessly. Each stage of wound healing is surveyed in depth from the perspective of many regenerative and fibrotic healers so as to identify the most important molecular and physiological variances along the way to disparate injury repair outcomes. Understanding how these powerful model systems accomplish the feat of scar‐free healing may provide critical therapeutic approaches to the treatment or prevention of fibrosis.

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Transient fibrosis resolves via fibroblast inactivation in the regenerating zebrafish heart

Cited by 153 publications

References 43 publications

Runx1 promotes scar deposition and inhibits myocardial proliferation and survival during zebrafish heart regeneration

Runx1 promotes scar deposition and inhibits myocardial proliferation and survival during zebrafish heart regeneration

Cardiomyocyte cell cycling, maturation, and growth by multinucleation in postnatal swine

Finding Solutions for Fibrosis: Understanding the Innate Mechanisms Used by Super‐Regenerator Vertebrates to Combat Scarring

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