Nonstochastic reprogramming from a privileged somatic cell state.
Reprogramming somatic cells to induced pluripotency by Yamanaka factors is usually slow and inefficient and is thought to be a stochastic process. We identified a privileged somatic cell state, from which acquisition of pluripotency could occur in a nonstochastic manner. Subsets of murine hematopoietic progenitors are privileged whose progeny cells predominantly adopt the pluripotent fate with activation of endogenous Oct4 locus after four to five divisions in reprogramming conditions. Privileged cells display an ultrafast cell cycle of ∼8 hr. In fibroblasts, a subpopulation cycling at a similar ultrafast speed is observed after 6 days of factor expression and is increased by p53 knockdown. This ultrafast cycling population accounts for >99% of the bulk reprogramming activity in wild-type or p53 knockdown fibroblasts. Our data demonstrate that the stochastic nature of reprogramming can be overcome in a privileged somatic cell state and suggest that cell-cycle acceleration toward a critical threshold is an important bottleneck for reprogramming. PAPERCLIP:
Department of Cell Biology, Yale University, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA. Electronic address: shangqin.guo@yale.edu.
Shangqin
S
Guo
Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA; Department of Cell Biology, Second Military Medical University, Shanghai 200433, China.
Xiaoyuan
X
Zi
Department of Pediatrics, Yale University, New Haven, CT 06520, USA.
Vincent P
VP
Schulz
Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA; Department of Genetics, Yale University, New Haven, CT 06520, USA.
Jijun
J
Cheng
Department of Cell Biology, Yale University, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA.
Mei
M
Zhong
Department of Cell Biology, Yale University, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA.
Sebastian H J
SH
Koochaki
Department of Cell Biology, Yale University, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA.
Cynthia M
CM
Megyola
Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA; Department of Genetics, Yale University, New Haven, CT 06520, USA.
Xinghua
X
Pan
Department of Immunobiology, Yale Flow Cytometry Core Facility, Yale University, New Haven, CT 06520, USA.
Kartoosh
K
Heydari
Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA; Department of Genetics, Yale University, New Haven, CT 06520, USA; Yale Comprehensive Cancer Center, Yale University, New Haven, CT 06520, USA.
Sherman M
SM
Weissman
Department of Pediatrics, Yale University, New Haven, CT 06520, USA; Department of Genetics, Yale University, New Haven, CT 06520, USA; Department of Pathology, Yale University, New Haven, CT 06520, USA.
Patrick G
PG
Gallagher
Department of Cell Biology, Yale University, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA; Department of Laboratory Medicine, Yale University, New Haven, CT 06520, USA.
Diane S
DS
Krause
Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA; Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA; Yale Comprehensive Cancer Center, Yale University, New Haven, CT 06520, USA.
Rong
R
Fan
Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA; Department of Genetics, Yale University, New Haven, CT 06520, USA; Yale Comprehensive Cancer Center, Yale University, New Haven, CT 06520, USA.
Jun
J
Lu
D000818:Animals; D001854:Bone Marrow Cells; D002454:Cell Differentiation; D065150:Cellular Reprogramming; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D055785:Gene Knockdown Techniques; D016158:Genes, p53; D055014:Granulocyte-Macrophage Progenitor Cells / Q000166:cytology* / Q000378:metabolism; D057026:Induced Pluripotent Stem Cells; D051379:Mice