Redefining Pluripotent Stem Cells: A Cell Cycle Perspective

As it is classically defined, the term stem cell seems at odds with the process of early development where, at least initially, there are no discernable cell fates. However, a paradox exists: not all pluripotent cells found the embryo, whether that cell is an epiblast cell or its in vitro counterpart, the ES cell. In this thesis, the supposition that all pluripotent cells are intrinsically equivalent from a functional perspective is challenged. We provide evidence that not all ES cells are by definition bona fide stem cells. In addition, we show that the two hallmark features of a stem cell are independent and dissociable fate decisions: proliferative competency (founding capacity) and lineage competency (potency). Founding capacity, which is a behavioural output of proliferative competency, is not biased or modified by either cell cycle position or cell cycle regulation during G2/M. This is in stark contrast to cell fate decisions pertaining to lineage, which are influenced by both cell cycle position and direct cell cycle governance during G2/M. Variation in cell cycle time may therefore serve as a mechanistic platform for creating heterogeneities within a relatively equivalent group of cells. Dissociation of founding capacity (proliferative competency) and potency (lineage competency) within the pluripotent population in vitro implores the field to redefine the population, our ideology of stem cells during early development, and how we functionally define them. Acknowledgement of a subpopulation of bona fide stem cells shifts our perception on the type and nature of cell fate decisions that can or have occurred. This shift in perception is relevant not only during normal development but also during processes such as regeneration and cellular reprogramming, which rely on the presence of plasticity within fate decisions that are characteristic of a stem cell.Ph.D