Journal Club: Stem Cells/Immunology

Wednesday, January 16, 2013

Presentation: “Serendipity 3: The Role of TLR3 in Nuclear Reprogramming”

Presenter: Avantika Chitre  (second-year BMS student)

Paper: Lee J, et al. Activation of innate immunity is required for efficient nuclear reprogramming. Cell. 2012 Oct 26;151(3):547-58.

In a nutshell:

Arguably one of the most remarkable feats of modern medicine is organ transplantation. Who could have imagined centuries ago that we would someday be able to remove a patient’s damaged kidney or liver and replace it with that of another human being? 

This process, however, carries significant risks, including the limited availability of donor organs and possible rejection of the foreign tissue.  What if we could bypass all of that by growing and using the patient’s own healthy tissue? 

What if we could grow a new liver for a patient using his or her skin cells?  What if we could regrow neurons in patients with degenerative diseases such as Alzheimer’s? This is the hope of regenerative medicine – developing the ability to replace damaged tissue or stimulate its healing. 

Ground-breaking progress in the field was made in the lab of UCSF’s own Nobel-prize-winning Shinya Yamanaka.  It was found that four proteins (the transcription factors Oct4, Sox2, Klf4 and c-Myc) could be used to reprogram mature cells into induced pluripotent stem cells, or iPS cells. 

Not only does this discovery allow researchers to bypass the ethical concerns of experimentation with embryonic stem cells, but it also introduces the possibility of taking mature cells in the body and reprogramming them into another cell type for regenerative purposes. 

Something that works well in the laboratory, however, does not always translate into success in the clinic.  One of the reprogramming methods is introducing these proteins, now dubbed the Yamanaka factors, into cells, using a virus.

This poses the risk of turning on cancer-causing genes — is it worth it to get a new kidney only to develop cancer shortly afterwards?  Another technique is the use of purified proteins, but this has proven to be significantly less effective than the use of viruses. 

The authors of this paper set out to determine the reason for this decreases in reprogramming efficiency.  They found that using any virus, not just one that introduces (one of) the Yamanaka factors, improved efficiency and hypothesized that this might be due to activation of the immune system by the virus.  Indeed, they uncovered a possible role for the immune component TLR3.  Stimulating the TLR3 pathway allowed for more efficient reprogramming.

In support of the role of the immune system was the observation that the TLR3 pathway induced epigenetic changes, which are necessary for cellular reprogramming.  Perhaps by stimulating the immune system, then, we can reprogram cells into iPS cells more safely and efficiently and come one step closer to the goals of regenerative medicine.