Human cell dedifferentiation in mesenchymal condensates through controlled autophagy

Pennock, Rebecca; Bray, Elen; Pryor, Paul; James, Sally; McKeegan, Paul; Sturmey, Roger; Genever, Paul

Abstract

Tissue and whole organ regeneration is a dramatic biological response to injury that occurs across different plant and animal phyla. It frequently requires the dedifferentiation of mature cells to a condensed mesenchymal blastema, from which replacement tissues develop. Human somatic cells cannot regenerate in this way and differentiation is considered irreversible under normal developmental conditions. Here, we sought to establish in vitro conditions to mimic blastema formation by generating different three-dimensional (3D) condensates of human mesenchymal stromal cells (MSCs). We identified specific 3D growth environments that were sufficient to dedifferentiate aged human MSCs to an early mesendoderm-like state with reversal of age-associated cell hypertrophy and restoration of organized tissue regenerating capacity in vivo. An optimal auophagic response was required to promote cytoplasmic remodeling, mitochondrial regression, and a bioenergetic shift from oxidative phosphorylation to anaerobic metabolism. Our evidence suggests that human cell dedifferentiation can be achieved through autonomously controlled autophagic flux.

Citation

Pennock, R., Bray, E., Pryor, P., James, S., McKeegan, P., Sturmey, R., & Genever, P. (2015). Human cell dedifferentiation in mesenchymal condensates through controlled autophagy. Scientific reports, 5(1), Article ARTN 13113. https://doi.org/10.1038/srep13113

• Acceptance Date: Jul 15, 2015
• Online Publication Date: Aug 20, 2015
• Publication Date: 2015-10
• Deposit Date: Nov 18, 2015
• Publicly Available Date: Nov 23, 2017
• Journal: Scientific reports
• Print ISSN: 2045-2322
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 5
• Issue: 1
• Article Number: ARTN 13113
• DOI: https://doi.org/10.1038/srep13113
• Keywords: Autophagy; Cell biology; Condensed mesenchymal blastema
• Public URL: https://hull-repository.worktribe.com/output/381584
• Publisher URL: http://www.nature.com/articles/srep13113
• Additional Information: Copy of article first published in: Scientific reports, 2015, v.5.
• Contract Date: Nov 23, 2017