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Bioengineering 2018, 5(1), 22; https://doi.org/10.3390/bioengineering5010022

Metabolic Reprogramming and the Recovery of Physiological Functionality in 3D Cultures in Micro-Bioreactors

1
Tissue Culture Engineering Laboratory, Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense, Denmark
2
CelVivo IVS, 5491 Blommenslyst, Denmark
This article is dedicated to the memory of Vasco Botelho Carvalho.
*
Author to whom correspondence should be addressed.
Received: 22 January 2018 / Revised: 21 February 2018 / Accepted: 24 February 2018 / Published: 7 March 2018
(This article belongs to the Special Issue Advances in Micro-Bioreactor Design for Organ Cell Studies)
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Abstract

The recovery of physiological functionality, which is commonly seen in tissue mimetic three-dimensional (3D) cellular aggregates (organoids, spheroids, acini, etc.), has been observed in cells of many origins (primary tissues, embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and immortal cell lines). This plurality and plasticity suggest that probably several basic principles promote this recovery process. The aim of this study was to identify these basic principles and describe how they are regulated so that they can be taken in consideration when micro-bioreactors are designed. Here, we provide evidence that one of these basic principles is hypoxia, which is a natural consequence of multicellular structures grown in microgravity cultures. Hypoxia drives a partial metabolic reprogramming to aerobic glycolysis and an increased anabolic synthesis. A second principle is the activation of cytoplasmic glutaminolysis for lipogenesis. Glutaminolysis is activated in the presence of hypo- or normo-glycaemic conditions and in turn is geared to the hexosamine pathway. The reducing power needed is produced in the pentose phosphate pathway, a prime function of glucose metabolism. Cytoskeletal reconstruction, histone modification, and the recovery of the physiological phenotype can all be traced to adaptive changes in the underlying cellular metabolism. These changes are coordinated by mTOR/Akt, p53 and non-canonical Wnt signaling pathways, while myc and NF-kB appear to be relatively inactive. Partial metabolic reprogramming to aerobic glycolysis, originally described by Warburg, is independent of the cell’s rate of proliferation, but is interwoven with the cells abilities to execute advanced functionality needed for replicating the tissues physiological performance. View Full-Text
Keywords: bioreactors; 3D cell culture; spheroids; organoids; hypoxia; aerobic glycolysis; glutaminolysis; metabolic reprogramming; physiological performance; Warburg bioreactors; 3D cell culture; spheroids; organoids; hypoxia; aerobic glycolysis; glutaminolysis; metabolic reprogramming; physiological performance; Warburg
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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    Doi: 10.1371/journal.pone.0106973
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Wrzesinski, K.; Fey, S.J. Metabolic Reprogramming and the Recovery of Physiological Functionality in 3D Cultures in Micro-Bioreactors. Bioengineering 2018, 5, 22.

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