Metabolic remodeling in early development and cardiomyocyte maturation

Kreipke, Rebecca Ellen; Wang, Yuliang; Miklas, Jason W.; Mathieu, Julie

doi:10.1016/j.semcdb.2016.02.004

Cited by 66 publications

(63 citation statements)

References 79 publications

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“…The EMBO Journal Mitophagy regulates cell differentiation Lorena Esteban-Martínez et al associated with increased mitochondrial activity (Agathocleous et al, 2012;Wagatsuma & Sakuma, 2013;Agostini et al, 2016;Cedikova et al, 2016;Ellen Kreipke et al, 2016). However, in agreement with our observations in RGCs, this view has been recently challenged (Forni et al, 2016).…”

Section: Discussionsupporting

confidence: 90%

“…The importance of metabolic regulation for stem cell function has been well described, and as a general rule stem cells predominantly rely on glycolytic metabolism (Chandel et al , ). On the other hand, the differentiation of most cell types is typically associated with increased mitochondrial activity (Agathocleous et al , ; Wagatsuma & Sakuma, ; Agostini et al , ; Cedikova et al , ; Ellen Kreipke et al , ). However, in agreement with our observations in RGCs, this view has been recently challenged (Forni et al , ).…”

Section: Discussionmentioning

confidence: 99%

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Programmed mitophagy is essential for the glycolytic switch during cell differentiation

et al. 2017

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Retinal ganglion cells (RGCs) are the sole projecting neurons of the retina and their axons form the optic nerve. Here, we show that embryogenesis-associated mouse RGC differentiation depends on mitophagy, the programmed autophagic clearance of mitochondria. The elimination of mitochondria during RGC differentiation was coupled to a metabolic shift with increased lactate production and elevated expression of glycolytic enzymes at the mRNA level. Pharmacological and genetic inhibition of either mitophagy or glycolysis consistently inhibited RGC differentiation. Local hypoxia triggered expression of the mitophagy regulator BCL2/adenovirus E1B 19-kDa-interacting protein 3-like (BNIP3L, best known as NIX) at peak RGC differentiation. Retinas from NIX-deficient mice displayed increased mitochondrial mass, reduced expression of glycolytic enzymes and decreased neuronal differentiation. Similarly, we provide evidence that NIX-dependent mitophagy contributes to mitochondrial elimination during macrophage polarization towards the proinflammatory and more glycolytic M1 phenotype, but not to M2 macrophage differentiation, which primarily relies on oxidative phosphorylation. In summary, developmentally controlled mitophagy promotes a metabolic switch towards glycolysis, which in turn contributes to cellular differentiation in several distinct developmental contexts.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Programmed mitophagy is essential for the glycolytic switch during cell differentiation

et al. 2017

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“…200 This metabolic transition coincides with an increase in mitochondrial density, as well as a mitochondrial shift in shape from small and round to large and ovoid. 201, 202 Positional differences are also observed, with mitochondria of mature CMs being located in closer proximity with myofibrils and the sarcoplasmic reticulum.…”

Section: Maturationmentioning

confidence: 84%

Cardiac Regeneration

Galdos

Guo

Paige

et al. 2017

Circulation Research

125

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Palliative surgery for congenital heart disease has allowed patients with previously lethal heart malformations to survive and, in most cases, to thrive. However, these procedures often place pressure and volume loads on the heart, and over time these chronic loads can cause heart failure. Current therapeutic options for initial surgery and chronic heart failure that results from failed palliation are limited, in part, by the mammalian heart’s low inherent capacity to form new cardiomyocytes (CMs). Surmounting the heart regeneration barrier would transform the treatment of congenital, as well as acquired, heart disease, and likewise would enable development of personalized, in vitro cardiac disease models. Although these remain distant goals, studies of heart development are illuminating the path forward and suggest unique opportunities for heart regeneration, particularly in fetal and neonatal periods. Here we review major lessons from heart development that inform current and future studies directed at enhancing cardiac regeneration.

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“…Metabolic 14 and functional 15,4 maturation have been demonstrated in aged pluripotent stem cell-derived cardiomyocytes, however, a change in three-dimensional shape has not been described. Cardiomyocytes increase in volume during fetal development, 28 and this study demonstrates that the same phenomena occurs in long-term in vitro culture of hiPSC-cardiomyocytes, with volume increasing more than 2-fold in aged 12-month-old cardiomyocytes versus 2-week-old control cells.…”

Section: Discussionmentioning

confidence: 99%

Hypertrophy Changes 3D Shape of hiPSC-Cardiomyocytes: Implications for Cellular Maturation in Regenerative Medicine

2016

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Advances in the use of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes for heart regeneration and in vitro disease models demand a greater understanding of how these cells grow and mature in 3-dimensional space. In this study, we developed an analysis methodology of single cardiomyocytes plated on 2D surfaces to assess their 3D myofilament volume and its zheight distribution, or shape, upon hypertrophic stimulation via phenylephrine (PE) treatment or long-term culture ("aging"). Cardiomyocytes were fixed and labeled with α-actinin for confocal microscopy imaging to obtain z-stacks for 3D myofilament volume analysis. In primary neonatal rat ventricular myocytes (NRVMs), area increased 72% with PE, while volume increased 31%. In hiPSC-cardiomyocytes, area increased 70% with PE and 4-fold with aging; however, volume increased significantly only with aging by 2.3-fold. Analysis of z-height myofilament volume distribution in hiPSC-cardiomyocytes revealed a shift from a fairly uniform distribution in control cells to a basally located volume in a more flat and spread morphology with PE and even more so with aging, a shape that was akin to all NRVMs analyzed. These results suggest that 2D area is not a sufficient measure of hiPSC-cardiomyocyte growth and maturation, and that changes in 3D volume and its distribution are essential for understanding hiPSC-cardiomyocyte biology for disease modeling and regenerative medicine applications.

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Metabolic remodeling in early development and cardiomyocyte maturation

Cited by 66 publications

References 79 publications

Programmed mitophagy is essential for the glycolytic switch during cell differentiation

Programmed mitophagy is essential for the glycolytic switch during cell differentiation

Cardiac Regeneration

Hypertrophy Changes 3D Shape of hiPSC-Cardiomyocytes: Implications for Cellular Maturation in Regenerative Medicine

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