Fgf16 is required for cardiomyocyte proliferation in the mouse embryonic heart

Hotta, Yuhei; Sasaki, Sayaka; Konishi, Morichika; Kinoshita, Hideyuki; Kuwahara, Koichiro; Nakao, Kazuwa; Itoh, Nobuyuki

doi:10.1002/dvdy.21726

Cited by 62 publications

(80 citation statements)

References 29 publications

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“…Of these, epicardial derived FGF9 and FGF16 are factors that directly signal to FGFRs expressed in cardiomyocytes during midgestation. Although myocardial proliferation is reduced in mice lacking FGF9 (Lavine et al, 2005) or FGF16 (Hotta et al, 2008), proliferation is clearly not arrested. This indicates that other factors must act in parallel to FGF9/16 to regulate myocardial proliferation.…”

Section: Research Articlementioning

confidence: 97%

“…Other members of the FGF9 subfamily have also been shown to function during heart development. For example, FGF16 is expressed in the midgestation heart (Lavine et al, 2005) and functions to regulate myocardial proliferation (Hotta et al, 2008). Several studies have identified expression of Fgf7 and Fgf10 in the developing myocardium, and one study showed that mice lacking the b splice variant of Fgfr2 (Fgfr2b -/-) developed a thin-walled heart (Morabito et al, 2001;Marguerie et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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FGF10/FGFR2b signaling is essential for cardiac fibroblast development and growth of the myocardium

et al. 2011

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SUMMARYThe epicardium serves as a source of growth factors that regulate myocardial proliferation and as a source of epicardial-derived cells (EPDC), which give rise to interstitial cardiac fibroblasts and perivascular cells. These progenitors populate the compact myocardium to become part of the mature coronary vasculature and fibrous skeleton of the heart. Little is known about the mechanisms that regulate EPDC migration into the myocardium or the functions carried out by these cells once they enter the myocardium. However, it has been proposed that cardiac fibroblasts are important for growth of the heart during late gestation and are a source of homeostatic factors in the adult. Here, we identify a myocardial to epicardial fibroblast growth factor (FGF) signal, mediated by FGF10 and FGFR2b, that is essential for movement of cardiac fibroblasts into the compact myocardium. Inactivation of this signaling pathway results in fewer epicardial derived cells within the compact myocardium, decreased myocardial proliferation and a resulting smaller thin-walled heart.

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Section: Research Articlementioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

FGF10/FGFR2b signaling is essential for cardiac fibroblast development and growth of the myocardium

et al. 2011

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“…FGF16 belongs to the FGF9 subfamily and is the only cardiac-specific member of the FGF family. FGF16 is mainly expressed in cardiomyocytes and has been shown to be secreted from cardiomyocytes after birth, suggesting its specific role in the postnatal heart (Hotta et al, 2008). A previous study showed that FGF16 is required for cardiomyocyte replication during development (Lu et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

GATA4 regulates Fgf16 to promote heart repair after injury

Huang

Tian

et al. 2016

Development

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Although the mammalian heart can regenerate during the neonatal stage, this endogenous regenerative capacity is lost with age. Importantly, replication of cardiomyocytes has been found to be the key mechanism responsible for neonatal cardiac regeneration. Unraveling the transcriptional regulatory network for inducing cardiomyocyte replication will, therefore, be crucial for the development of novel therapies to drive cardiac repair after injury. Here, we investigated whether the key cardiac transcription factor GATA4 is required for neonatal mouse heart regeneration. Using the neonatal mouse heart cryoinjury and apical resection models with an inducible loss of GATA4 specifically in cardiomyocytes, we found severely depressed ventricular function in the Gata4-ablated mice (mutant) after injury. This was accompanied by reduced cardiomyocyte replication. In addition, the mutant hearts displayed impaired coronary angiogenesis and increased hypertrophy and fibrosis after injury. Mechanistically, we found that the paracrine factor FGF16 was significantly reduced in the mutant hearts after injury compared with littermate controls and was directly regulated by GATA4. Cardiac-specific overexpression of FGF16 via adeno-associated virus subtype 9 (AAV9) in the mutant hearts partially rescued the cryoinjuryinduced cardiac hypertrophy, promoted cardiomyocyte replication and improved heart function after injury. Altogether, our data demonstrate that GATA4 is required for neonatal heart regeneration through regulation of Fgf16, suggesting that paracrine factors could be of potential use in promoting myocardial repair.

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“…2002;Usui et al, 2004;Hung et al, 2007). Fgf16 knockout mice on a C57BL/6 genetic background are viable, but have impaired embryonic cardiomyocyte proliferation (Hotta et al, 2008). Fgf16 knockout phenotypes may be more severe on a Black Swiss genetic background where they die at embryonic day (E) 10.5 with severely impaired cardiac and facial development (Lu et al, 2008;Lu et al, 2010).…”

Section: Paracrine Fgfsmentioning

confidence: 99%