Abstract
A close relationship between proliferation and cell fate specification has been well documented in many developmental systems. In addition to the gradual cell fate changes accompanying normal development and tissue homeostasis, it is now commonly appreciated that cell fate could also undergo drastic changes, as illustrated by the induction of pluripotency from many differentiated somatic cell types during the process of Yamanaka reprogramming. Strikingly, the drastic cell fate change induced by Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc) is preceded by extensive cell cycle acceleration. Prompted by our recent discovery that progression toward pluripotency from rare somatic cells could bypass the stochastic phase of reprogramming and that a key feature of these somatic cells is an ultrafast cell cycle (~8 h/cycle), we assess whether cell cycle dynamics could provide a general framework for controlling cell fate. Several potential mechanisms on how cell cycle dynamics may impact cell fate determination by regulating chromatin, key transcription factor concentration, or their interactions are discussed. Specific challenges and implications for studying and manipulating cell fate are considered.
Highlights
The ability to faithfully maintain cell fate or cell identity is critical for the function of highly specialized cell types in multicellular organisms
The length of gap 1 phase (G1) phase might be less critical when the cell identity only needs to be copied but becomes more relevant upon exiting from pluripotency, as longer G1 may allow lineage-specific transcription factors to bind their target sites after being displaced from condensing chromatin during mitosis [41]
PU.1 accumulates which drives a myeloid fate [10]. While this was demonstrated for PU.1, it is conceivable that similar mechanisms may contribute to the effectiveness of other key fate specifying transcription factors, with their steady state concentration being a function of the multipotent progenitor cell cycle length as well as their inherent messenger RNA and/or protein stability
Summary
The ability to faithfully maintain cell fate or cell identity is critical for the function of highly specialized cell types in multicellular organisms. Using a direct live-cell imaging approach [24] in attempt to identify this rate-limiting event, we observed that a specific somatic cell type existing in the bone marrow did not display the usual stochastic reprogramming behavior.
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