Human cell dedifferentiation in mesenchymal condensates through controlled autophagy.
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.
Department of Biology, University of York, York, YO10 5DD, UK.
Rebecca
R
Pennock
Department of Biology, University of York, York, YO10 5DD, UK.
Elen
E
Bray
Department of Biology, University of York, York, YO10 5DD, UK.
Paul
P
Pryor
Department of Biology, University of York, York, YO10 5DD, UK.
Sally
S
James
Centre for Cardiovascular and Metabolic Research, Hull York Medical School, University of Hull, Hull, HU6 7RX, UK.
Paul
P
McKeegan
Centre for Cardiovascular and Metabolic Research, Hull York Medical School, University of Hull, Hull, HU6 7RX, UK.
Roger
R
Sturmey
Department of Biology, University of York, York, YO10 5DD, UK.
Paul
P
Genever
D000368:Aged; D001343:Autophagy; D018929:Cell Culture Techniques; D054337:Cell Dedifferentiation; D003593:Cytoplasm / Q000378:metabolism; D004707:Endoderm / Q000166:cytology; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D008875:Middle Aged; D012038:Regeneration