Ccn2a/Ctgfa is an injury-induced matricellular factor that promotes cardiac regeneration in zebrafish

Mukherjee, Debanjan; Wagh, Ganesh; Mokalled, Mayssa H.; Kontarakis, Zacharias; Dickson, Amy L.; Rayrikar, Amey; Günther, Stefan; Poss, Kenneth D.; Stainier, Didier Y.R.; Patra, Chinmoy

doi:10.1242/dev.193219

Cited by 18 publications

(30 citation statements)

References 77 publications

(81 reference statements)

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“…Similar to mammals, we found increased expressions of fn1a, fn1b, loxa, and tnc transcripts in AngII-induced zebrafish hearts, while spp1 expression remained unaltered. In contrast, our previous study identified ~15 fold increased expression of spp1 in injured zebrafish hearts [75]. These findings put forward that regulation of spp1 expression in cardiac fibrosis is context dependent.…”

Section: Discussioncontrasting

confidence: 65%

Zebrafish Model to Study Angiotensin II-Mediated Pathophysiology

Joshi

Wagh

Kaur

et al. 2021

Biology

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Hypertension, a common chronic condition, may damage multiple organs, including the kidney, heart, and brain. Thus, it is essential to understand the pathology upon ectopic activation of the molecular pathways involved in mammalian hypertension to develop strategies to manage hypertension. Animal models play a crucial role in unraveling the disease pathophysiology by allowing incisive experimental procedures impossible in humans. Zebrafish, a small freshwater fish, have emerged as an important model system to study human diseases. The primary effector, Angiotensin II of the RAS pathway, regulates hemodynamic pressure overload mediated cardiovascular pathogenesis in mammals. There are various established mammalian models available to study pathophysiology in Angiotensin II-induced hypertension. Here, we have developed a zebrafish model to study pathogenesis by Angiotensin II. We find that intradermal Angiotensin II injection every 12 h can induce cardiac remodeling in seven days. We show that Angiotensin II injection in adult zebrafish causes cardiomyocyte hypertrophy and enhances cardiac cell proliferation. In addition, Angiotensin II induces ECM protein-coding gene expression and fibrosis in the cardiac ventricles. Thus, this study can conclude that Angiotensin II injection in zebrafish has similar implications as mammals, and zebrafish can be a model to study pathophysiology associated with AngII-RAS signaling.

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Section: Discussioncontrasting

confidence: 65%

Zebrafish Model to Study Angiotensin II-Mediated Pathophysiology

Joshi

Wagh

Kaur

et al. 2021

Biology

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“…Secreted factors, including ECM proteins, have been shown to strongly influence CM regeneration after injury (53)(54)(55)(56). il11ra mutant hearts, after injury, display EndoMT-mediated fibrosis, a lack of transitional matrix deposition, and CM repopulation defects.…”

Section: Il-11 Signaling In Endothelial Cells Allows CM Repopulation After Cardiac Injurymentioning

confidence: 99%

Interleukin-11 signaling promotes cellular reprogramming and limits fibrotic scarring during tissue regeneration

et al. 2021

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Damage-induced fibrotic scarring limits tissue regeneration in mammals and is a leading cause of morbidity. In contrast, species like zebrafish can regenerate damaged tissues without excessive fibrosis. However, whether specific signaling pathways can both limit fibrosis and promote regeneration is unclear. Here, we show that interleukin-11 (Il-11)/Stat3 signaling has such a dual function. Zebrafish lacking Il-11 receptor function display severely compromised heart, fin, and scale regeneration. Deep phenotyping and transcriptional analysis of adult hearts and fins show that Il-11 signaling drives cellular reprogramming to orchestrate global and tissue-specific regenerative programs and broadly antagonizes hallmarks of adult mammalian scarring. Mechanistically, our data indicate that IL-11 signaling in endothelial cells antagonizes profibrotic transforming growth factor- signaling and endothelial-to-mesenchymal transition, limiting scarring and promoting cardiomyocyte repopulation, after injury. Overall, our findings position damage-induced Il-11/Stat3 signaling in a key role limiting fibrosis and promoting regeneration, revealing novel targets for regenerative therapies.

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Section: Extracellular Matrixmentioning

confidence: 99%

“…Connective tissue growth factor (CTGF), also known as communication network factor 2a (Ccn2a), is a matricellular protein that is synthesized and secreted from endocardial cells after cardiac injuries (156). In zebrafish, CTGF has been reported necessary for heart regeneration by inducing cardiomyocyte proliferation and infiltration (156). CTGF triggers cardiomyocyte cell cycle activity also in neonatal mammals (135), however, its potential impact on adult cardiomyocyte proliferation and heart regeneration has not been explored thus far.…”

Section: Extracellular Matrixmentioning

confidence: 99%

Reawakening the Intrinsic Cardiac Regenerative Potential: Molecular Strategies to Boost Dedifferentiation and Proliferation of Endogenous Cardiomyocytes

Bongiovanni

Sacchi

Pra

et al. 2021

Front. Cardiovasc. Med.

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Despite considerable efforts carried out to develop stem/progenitor cell-based technologies aiming at replacing and restoring the cardiac tissue following severe damages, thus far no strategies based on adult stem cell transplantation have been demonstrated to efficiently generate new cardiac muscle cells. Intriguingly, dedifferentiation, and proliferation of pre-existing cardiomyocytes and not stem cell differentiation represent the preponderant cellular mechanism by which lower vertebrates spontaneously regenerate the injured heart. Mammals can also regenerate their heart up to the early neonatal period, even in this case by activating the proliferation of endogenous cardiomyocytes. However, the mammalian cardiac regenerative potential is dramatically reduced soon after birth, when most cardiomyocytes exit from the cell cycle, undergo further maturation, and continue to grow in size. Although a slow rate of cardiomyocyte turnover has also been documented in adult mammals, both in mice and humans, this is not enough to sustain a robust regenerative process. Nevertheless, these remarkable findings opened the door to a branch of novel regenerative approaches aiming at reactivating the endogenous cardiac regenerative potential by triggering a partial dedifferentiation process and cell cycle re-entry in endogenous cardiomyocytes. Several adaptations from intrauterine to extrauterine life starting at birth and continuing in the immediate neonatal period concur to the loss of the mammalian cardiac regenerative ability. A wide range of systemic and microenvironmental factors or cell-intrinsic molecular players proved to regulate cardiomyocyte proliferation and their manipulation has been explored as a therapeutic strategy to boost cardiac function after injuries. We here review the scientific knowledge gained thus far in this novel and flourishing field of research, elucidating the key biological and molecular mechanisms whose modulation may represent a viable approach for regenerating the human damaged myocardium.

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Ccn2a/Ctgfa is an injury-induced matricellular factor that promotes cardiac regeneration in zebrafish

Cited by 18 publications

References 77 publications

Zebrafish Model to Study Angiotensin II-Mediated Pathophysiology

Zebrafish Model to Study Angiotensin II-Mediated Pathophysiology

Interleukin-11 signaling promotes cellular reprogramming and limits fibrotic scarring during tissue regeneration

Reawakening the Intrinsic Cardiac Regenerative Potential: Molecular Strategies to Boost Dedifferentiation and Proliferation of Endogenous Cardiomyocytes

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