Somatic Oxidative Bioenergetics Transitions into Pluripotency-Dependent Glycolysis to Facilitate Nuclear Reprogramming

Folmes, Clifford D.L.; Nelson, Timothy J.; Martinez‐Fernandez, Almudena; Arrell, D. Kent; Lindor, Jelena Zlatkovic; Dzeja, Petras P.; Ikeda, Yasuhiro; Perez‐Terzic, Carmen; Terzic, André

doi:10.1016/j.cmet.2011.06.011

Cited by 871 publications

(986 citation statements)

References 42 publications

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“…60 Reprogramming of somatic cells into "induced pluripotent stem cells" (iPSCs) is accompanied by a reduction in mitochondria and a switch to glycolysis. 61 Thus, changes in cell function and differentiation are coupled to changes in cell metabolism.…”

Section: Discussionmentioning

confidence: 99%

Nanofiber scaffolds influence organelle structure and function in bone marrow stromal cells

Tutak

Giri

Bajcsy

et al. 2016

J. Biomed. Mater. Res.

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Tutak, Wojtek; Jyotsnendu, Giri; Bajcsy, Peter; and Simon, Carl G. Jr., "Nanofiber scaffolds influence organelle structure and function in bone marrow stromal cells" (2016 Abstract: Recent work demonstrates that osteoprogenitor cell culture on nanofiber scaffolds can promote differentiation. This response may be driven by changes in cell morphology caused by the three-dimensional (3D) structure of nanofibers. We hypothesized that nanofiber effects on cell behavior may be mediated by changes in organelle structure and function. To test this hypothesis, human bone marrow stromal cells (hBMSCs) were cultured on poly(e-caprolactone) (PCL) nanofibers scaffolds and on PCL flat spuncoat films. After 1 dayculture, hBMSCs were stained for actin, nucleus, mitochondria, and peroxisomes, and then imaged using 3D confocal microscopy. Imaging revealed that the hBMSC cell body (actin) and peroxisomal volume were reduced during culture on nanofibers. In addition, the nucleus and peroxisomes occupied a larger fraction of cell volume during culture on nanofibers than on films, suggesting enhancement of the nuclear and peroxisomal functional capacity. Organelles adopted morphologies with greater 3D-character on nanofibers, where the Z-Depth (a measure of cell thickness) was increased. Comparisons of organelle positions indicated that the nucleus, mitochondria, and peroxisomes were closer to the cell center (actin) for nanofibers, suggesting that nanofiber culture induced active organelle positioning. The smaller cell volume and more centralized organelle positioning would reduce the energy cost of inter-organelle vesicular transport during culture on nanofibers. Finally, hBMSC bioassay measurements (DNA, peroxidase, bioreductive potential, lactate, and adenosine triphosphate (ATP)) indicated that peroxidase activity may be enhanced during nanofiber culture. These results demonstrate that culture of hBMSCs on nanofibers caused changes in organelle structure and positioning, which may affect organelle functional capacity and transport.

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Section: Discussionmentioning

confidence: 99%

Nanofiber scaffolds influence organelle structure and function in bone marrow stromal cells

Tutak

Giri

Bajcsy

et al. 2016

J. Biomed. Mater. Res.

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“…The generation of iPSCs is accompanied by an extensive restructuring of mitochondria and energy metabolism (Folmes et al, 2011;Prigione et al, 2010). A hierarchical clustering of genes involved in energy metabolism (Prigione et al, 2011b) identified differences in the metabolic regulation of PSCs and NPCs (including NI NPCs, rNPCs, and eNPCs) ( Figure 1J).…”

Section: Ni Npcs Exhibit Mitochondrial Maturation and Neuronal-like Ementioning

confidence: 99%

Human iPSC-Derived Neural Progenitors Are an Effective Drug Discovery Model for Neurological mtDNA Disorders

et al. 2017

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SUMMARYMitochondrial DNA (mtDNA) mutations frequently cause neurological diseases. Modeling of these defects has been difficult because of the challenges associated with engineering mtDNA. We show here that neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (iPSCs) retain the parental mtDNA profile and exhibit a metabolic switch toward oxidative phosphorylation. NPCs derived in this way from patients carrying a deleterious homoplasmic mutation in the mitochondrial gene MT-ATP6 (m.9185T>C) showed defective ATP production and abnormally high mitochondrial membrane potential (MMP), plus altered calcium homeostasis, which represents a potential cause of neural impairment. High-content screening of FDA-approved drugs using the MMP phenotype highlighted avanafil, which we found was able to partially rescue the calcium defect in patient NPCs and differentiated neurons. Overall, our results show that iPSC-derived NPCs provide an effective model for drug screening to target mtDNA disorders that affect the nervous system.

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“…The metabolic profile of differentiated cells, which favors oxidative phosphorylation, is reset to a glycolysis-dependent ESC-like state after reprogramming [176][177][178][179][180]. This metabolic resetting takes place before pluripotency is established [179].…”

Section: Gaining Epithelial Properties and Accelerating Cell Cyclementioning

confidence: 99%

Embryonic stem cell and induced pluripotent stem cell: an epigenetic perspective

2012

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Somatic Oxidative Bioenergetics Transitions into Pluripotency-Dependent Glycolysis to Facilitate Nuclear Reprogramming

Cited by 871 publications

References 42 publications

Nanofiber scaffolds influence organelle structure and function in bone marrow stromal cells

Nanofiber scaffolds influence organelle structure and function in bone marrow stromal cells

Human iPSC-Derived Neural Progenitors Are an Effective Drug Discovery Model for Neurological mtDNA Disorders

Embryonic stem cell and induced pluripotent stem cell: an epigenetic perspective

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