Coronary Revascularization During Heart Regeneration Is Regulated by Epicardial and Endocardial Cues and Forms a Scaffold for Cardiomyocyte Repopulation

Marín-Juez, Rubén; El-Sammak, Hadil; Helker, Christian S. M.; Kamezaki, Aosa; Mullapuli, Sri Teja; Bibli, Sofia-Iris; Foglia, Matthew J.; Fleming, Ingrid; Poss, Kenneth D.; Stainier, Didier Y.R.

doi:10.1016/j.devcel.2019.10.019

Cited by 100 publications

(175 citation statements)

References 70 publications

(82 reference statements)

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“…This process results in gradual myocardial regeneration and complete LV functional recovery by 3 weeks post-MI. Future studies aimed at elucidating the mechanisms involved with natural heart regeneration are necessary, including the role of angiogenesis [26,39,41], the immune system [42,43], the endocrine system [44], and the nervous system [45].…”

Section: Discussionmentioning

confidence: 99%

Natural Heart Regeneration in a Neonatal Rat Myocardial Infarction Model

Wang

Paulsen

Hironaka

et al. 2020

Cells

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Newborn mice and piglets exhibit natural heart regeneration after myocardial infarction (MI). Discovering other mammals with this ability would provide evidence that neonatal cardiac regeneration after MI may be a conserved phenotype, which if activated in adults could open new options for treating ischemic cardiomyopathy in humans. Here, we hypothesized that newborn rats undergo natural heart regeneration after MI. Using a neonatal rat MI model, we performed left anterior descending coronary artery ligation or sham surgery in one-day-old rats under hypothermic circulatory arrest (n = 74). Operative survival was 97.3%. At 1 day post-surgery, rats in the MI group exhibited significantly reduced ejection fraction (EF) compared to shams (87.1% vs. 53.0%, p < 0.0001). At 3 weeks post-surgery, rats in the sham and MI groups demonstrated no difference in EF (71.1% vs. 69.2%, respectively, p = 0.2511), left ventricular wall thickness (p = 0.9458), or chamber diameter (p = 0.7801). Masson’s trichome and picrosirius red staining revealed minimal collagen scar after MI. Increased numbers of cardiomyocytes positive for 5-ethynyl-2′-deoxyuridine (p = 0.0072), Ki-67 (p = 0.0340), and aurora B kinase (p = 0.0430) were observed within the peri-infarct region after MI, indicating ischemia-induced cardiomyocyte proliferation. Overall, we present a neonatal rat MI model and demonstrate that newborn rats are capable of endogenous neocardiomyogenesis after MI.

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Section: Discussionmentioning

confidence: 99%

Natural Heart Regeneration in a Neonatal Rat Myocardial Infarction Model

Wang

Paulsen

Hironaka

et al. 2020

Cells

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“…Adult zebrafish hearts do regenerate, and coronary revascularization initiates within hours of injury. After cryoinjury, new coronaries regenerate both superficially around the injured area and intra-ventricularly toward the cardiac lumen, and act as a scaffold for proliferating cardiomyocytes ( 33 ). Epicardial cells express Cxcl12b after injury, as a consequence of hypoxia and HIF-1α activation.…”

Section: Cxcr4 and Cxcl12 In Tissue Regenerationmentioning

confidence: 99%

The Chemokine Receptor CXCR4 in Cell Proliferation and Tissue Regeneration

2020

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The CXCR4 receptor upon binding its ligands triggers multiple signaling pathways that orchestrate cell migration, hematopoiesis and cell homing, and retention in the bone marrow. However, CXCR4 also directly controls cell proliferation of non-hematopoietic cells. This review focuses on recent reports pointing to its pivotal role in tissue regeneration and stem cell activation, and discusses the connection to the known role of CXCR4 in promoting tumor growth. The mechanisms may be similar in all cases, since regeneration often recapitulates developmental processes, and cancer often exploits developmental pathways. Moreover, cell migration and cell proliferation appear to be downstream of the same signaling pathways. A deeper understanding of the complex signaling originating from CXCR4 is needed to exploit the opportunities to repair damaged organs safely and effectively.

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“…Cryoinjury results in cell death within the ventricle wall (with apoptotic cells also detectable in the lumen of coronary vessels) which peaks at approximately 4 dpi and decreases progressively to below 0.5% at 60 dpi (Chablais et al 2011 ; González-Rosa et al 2011 ; Schnabel et al 2011 ). This apoptotic peak is concomitant with the initial inflammatory response and the commencement of neovascularisation with existing coronary vessels sprouting into the injury area (González-Rosa et al 2011 ; Marín-Juez et al 2019 ). Extensive fibrin accumulation in the injury areas is also seen at 4 dpi (Chablais et al 2011 ; Schnabel et al 2011 ) but is mostly eliminated by 14–21 dpi (Chablais et al 2011 ; González-Rosa et al 2011 ; Schnabel et al 2011 ).…”

Section: Zebrafish As a Model For Repair And Regenerationmentioning

confidence: 99%

“…Extensive CM (and other cell) proliferation is observed during these initial phases of the injury response, peaking within the first week (Chablais et al 2011 ; González-Rosa et al 2011 ; Schnabel et al 2011 ). By 21 dpi, vessel coverage of the injured area is complete, and this re-vascularisation of the injured area is so rapid that a mere 40 days after injury the vessels are indistinguishable between controls and injured hearts (González-Rosa et al 2011 ; Marín-Juez et al 2019 ).…”

Section: Zebrafish As a Model For Repair And Regenerationmentioning

confidence: 99%

“…A study of the revascularisation that occurs post-injury has also revealed that there are two kinds of coronary sprouting that have separate mechanistic controls, with superficial sprouting (within the regenerating epicardium) regulated by chemokines cxcl12 and cxcr4, whereas intraventricular sprouting (towards the activated endocardium) is controlled by vegfa. These then combine to provide a scaffold for CM repopulation of the injured heart; however, inhibition of early revascularisation via a dominant negative form of vegfaa reduces CM proliferation and inhibits regeneration (Marín-Juez et al 2019 ). Consistently, knockout of cxcr4a also inhibits regeneration (Harrison et al 2015 ).…”

Section: Extracellular Vesicles Cilia and Signalling Networkmentioning

confidence: 99%

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Zebrafish cardiac regeneration—looking beyond cardiomyocytes to a complex microenvironment

Ryan

Moyse

Richardson

2020

Histochem Cell Biol

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The study of heart repair post-myocardial infarction has historically focused on the importance of cardiomyocyte proliferation as the major factor limiting adult mammalian heart regeneration. However, there is mounting evidence that a narrow focus on this one cell type discounts the importance of a complex cascade of cell–cell communication involving a whole host of different cell types. A major difficulty in the study of heart regeneration is the rarity of this process in adult animals, meaning a mammalian template for how this can be achieved is lacking. Here, we review the adult zebrafish as an ideal and unique model in which to study the underlying mechanisms and cell types required to attain complete heart regeneration following cardiac injury. We provide an introduction to the role of the cardiac microenvironment in the complex regenerative process and discuss some of the key advances using this in vivo vertebrate model that have recently increased our understanding of the vital roles of multiple different cell types. Due to the sheer number of exciting studies describing new and unexpected roles for inflammatory cell populations in cardiac regeneration, this review will pay particular attention to these important microenvironment participants.

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Coronary Revascularization During Heart Regeneration Is Regulated by Epicardial and Endocardial Cues and Forms a Scaffold for Cardiomyocyte Repopulation

Cited by 100 publications

References 70 publications

Natural Heart Regeneration in a Neonatal Rat Myocardial Infarction Model

Natural Heart Regeneration in a Neonatal Rat Myocardial Infarction Model

The Chemokine Receptor CXCR4 in Cell Proliferation and Tissue Regeneration

Zebrafish cardiac regeneration—looking beyond cardiomyocytes to a complex microenvironment

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