If epigenetics has taught us anything, it is that not all genetically identical beings are created equal. A team of stem-cell researchers from Tel Aviv University led by Iftach Nachman now apply this principle to populations of cells undergoing reprogramming to induced pluripotent stem cells (iPSCs) and show that some cells have a higher chance of reprogramming success than others.
Reprogramming to pluripotency with Yamanaka’s typical recipe (let’s call it OSKM for short) is very inefficient. Different models have been proposed to explain this phenomenon. In the ‘stochastic’ model of reprogramming, all of the cells in the population are equally likely to reprogram at any given cell division (think of a lottery where each player buys one ticket). In the ‘deterministic’ model, particular cells within the population are predisposed to reprogramming (now think of a lottery where John Smith buys 5000 tickets, and holds up the line in the convenience store for so long that he stops you from buying yours).
To distinguish between these two possibilities, Nachman’s team used simple mathematics and a new take on an old idea: the Luria-Delbrück experiment of the 1940s, which was designed to test Darwin’s ideas of natural selection in bacteria. In Nachman’s modified version, his team plated Mouse Embryonic Fibroblasts containing identical integrations of dox-inducible OSKM at a low density in 96 well plates and allowed cells to divide several times before factor induction. If reprogramming potential is pre-determined (i.e. deterministic) then the fraction of wells containing iPSCs will depend on the initial population size (assuming that reprogramming potential is heritable). However, in a post-determined (i.e. stochastic) model, reprogramming will depend on the number of cells at the time of induction.
Here’s what they found after some number crunching:
- Cells are predisposed to reprogramming and this characteristic is heritable.
- Reprogramming potential is independent of neighboring cells and early OSKM levels.
- Inhibition of Ezh2 (a H3K27 methylase) or Lsd1 a (H3K4 demethylase) substantially improves reprogramming efficiency.
What’s more, Ezh2 inhibition appeared to work by increasing the number of cells that generate iPSC-forming lineages (and not by speeding up the process in already predisposed cells). Thus, the reprogramming lottery is rigged, with epigenetically privileged cells taking home the jackpot.
Try your luck at EMBO reports, January 2015.