The cell-cycle state of stem cells determines cell fate propensity.
Self-renewal and differentiation of stem cells are fundamentally associated with cell-cycle progression to enable tissue specification, organ homeostasis, and potentially tumorigenesis. However, technical challenges have impaired the study of the molecular interactions coordinating cell fate choice and cell-cycle progression. Here, we bypass these limitations by using the FUCCI reporter system in human pluripotent stem cells and show that their capacity of differentiation varies during the progression of their cell cycle. These mechanisms are governed by the cell-cycle regulators cyclin D1-3 that control differentiation signals such as the TGF-β-Smad2/3 pathway. Conversely, cell-cycle manipulation using a small molecule directs differentiation of hPSCs and provides an approach to generate cell types with a clinical interest. Our results demonstrate that cell fate decisions are tightly associated with the cell-cycle machinery and reveal insights in the mechanisms synchronizing differentiation and proliferation in developing tissues.
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine and Department of Surgery, University of Cambridge, Cambridge CB2 0SZ, UK. Electronic address: sp579@cam.ac.uk.
Siim
S
Pauklin
Ludovic
L
Vallier
D002453:Cell Cycle; D002454:Cell Differentiation; D056741:Cyclin D / Q000235:genetics / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D016193:G1 Phase; D055785:Gene Knockdown Techniques; D006801:Humans; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics; D051900:Smad3 Protein / Q000235:genetics
D056741:Cyclin D; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein