A team at the Weizmann Institute of Science in Israel led by Jacob Hanna reports today near perfect reprogramming efficiency to make induced pluripotent stem cells (iPSCs) by eliminating a single factor called Mbd3 from the cellular equation. On first glance, the Nature article (Rais, et al.) seems to be all about boosting cellular reprogramming efficiency to close to 100%. If that were the whole story of this paper then it would likely not draw major interest and probably would not have been published in Nature. Why? The last few years there has been some definite fatigue for an earlier enthusiastic mantra in the reprogramming field: let’s boost efficiency!
While in the first few years of the iPS cell field there were many papers–really methodological papers without providing significant insight into molecular mechanisms of cell fate–published in top journals focused simply on boosting reprogramming and iPS cell production efficiency, more recently enthusiasm for such papers that mainly report different ways of making iPS cells or increased efficiency has substantially waned. The reality is that even poor efficiency of reprogramming may still be clinically just fine as we may only need one high quality iPS cell line per patient, right?
As a result, the portion of this new paper that in essence provides a super-efficient iPS cell production protocol is in some sense not that big a deal. However, the specific method that the authors used to so powerfully boost iPS cell production efficiency also provides some valuable insight into molecular mechanisms by which cellular fate and pluripotency are controlled. That’s what got me more excited and interested.
The fact that disrupting NuRD complex function and specifically that of the Mbd3 component boosts efficiency and conversely that NuRD normally suppresses pluripotency is quite intriguing.
The notion explored in this paper that reprogramming can be forced to become more deterministic rather than stochastic is also important and seems to be an emerging area of interest in the field. I really enjoy that kind of conceptual modeling of cell behavior.
However, the paper has some limitations as well.
Where this paper is relatively less convincing is on explaining the mechanisms by which Mbd3 and NuRD influence reprogramming and pluripotency (focused on in their Figure 5, shown above).
The authors argue that Mbd3 protein interacts with key pluripotency-related factors including OCT4, SOX2, KLF4, and c-Myc as well as to a lesser extent the fellow NuRD complex member HDAC1. However, these studies were conducted only on exogenously expressed proteins present at hyperphysiological levels. Frankly, I am surprised the Nature reviewers did not require this team to demonstrate interaction of the endogenous proteins, particularly endogenous Mbd3 with exogenous reprogramming factors. As a result, their model in Fig. 5f has not got me convinced.
I’m just curious how the mechanism will play out with more investigation over time.
What did you think of the paper?