iPS cell smack down

Pity the iPS cell -- it's had quite a ride this year. On the upside, cells reprogrammed from people with autism, Parkinson's disease and schizophrenia were used to create the first ever models of those diseases in a dish. Those models could provide a way of testing drugs on actual human cells. That's good.

But in the same year, a number of studies found significant genetic differences between reprogrammed iPS cells and their embryonic counterparts (here's our blog entry). Today, a paper published in Nature by CIRM grantee Yang Xu at the University of California, San Diego found that the cells can also be rejected by the body.

This finding is a bit of a blow. When Shinya Yamanaka and colleagues first reprogrammed human skin to an embryonic-like state in 2007 the stem cell world was aflutter. These cells were seen by some as a possible replacement for embryonic stem cells, with the advantage that because they could be generated from a person's own skin they would be genetically identical and not get rejected by the immune system.

It turns out the immune system is smarter than that, at least in mice. The mice were able to detect and subsequently reject genetically identical iPS cells.

A New York Times story quotes George Daley of Boston Children's Hospital:

“As with any new technology, there is always this initial phase of infatuation, and then the reality sets in,” said Dr. George Q. Daley, director of the stem cell transplantation program at Children’s Hospital Boston. “I think it goes to the heart of the issue of how ignorant we really are in understanding these cells.”

Apparently what made the cells visible to the immune system were the genes that were activated in order to reprogram the cells. The immune reaction varied depending on how the cells were made. This work isn't exactly the death knell for iPS cells, but it does mean that the path to the clinic could be a tricky one.

May 13, Nature
CIRM Funding: Yang Xu (TR1-01277)

A.A.

Reducing teratoma risk from transplanted stem cells

By Paul Knoepfler

The two most serious obstacles to regenerative medicine therapies are potential immune rejection of transplanted cells and the possibility that such cells could form a type of tumor called teratoma.

CIRM grant recipient and professor of Biology at UC San Diego, Yang Xu, is tackling both of these hurdles. He and his colleagues have recently discovered a method to reduce the ability of embryonic stem cells to form teratoma. The approach involves interfering with the function of a key gene, called Nanog, that is involved in maintaining stem cells. Nanog is one of several genes known as plurpotency factors, which work together to keep cells in their embryonic state.

The paper describing this work, entitled “Phosphorylation stabilizes Nanog by promoting its interaction with Pin1”, was published this week in the Proceedings of the National Academies of Science. Xu and colleagues found that by inhibiting Nanog function in stem cells, those cells still formed teratoma, but they were only about one-third the size of tumors that formed by control cells.

Xu was quoted in a press release by UCSD as saying the method is only partially effective because “we are targeting only one pathway” and he speculates that targeting multiple pathways simultaneously might provide a more robust inhibition of teratoma formation.

Some important unanswered questions remain. Would inhibition of any key pluripotency factor, for example Oct3, produce the same effect? Are cells with reduced levels of pluripotency factors still able to give rise to normal differentiated cells of diverse types and in sufficient numbers to be useful for therapies? Could a similar effect be achieved by withdrawing growth factors, such as removing LIF from the media of mouse stem cells or FGF from the media of human stem cells?

Despite these remaining gaps in our understanding, this study provides an exciting foundation for improving the safety of regenerative medicine therapies, any area in the stem field that requires more attention.



PNAS, July 5, 2010
CIRM Funding: Yang Xu (RC1-00148)

Paul Knoepfler is assistant professor of Cell Biology and Human Anatomy at UC Davis School of Medicine. He publishes a blog about stem cell research.

Genetic Brake Key to Stem Cell Fate

Researchers at UC, Santa Barbara, have mapped the role of a genetic signal that puts the breaks on the ability of stem cells to self renew. The finding could eventually shed light on self-renewal that has run amuck as in cancer, and can immediately be put to use in managing the balancing act between self-renewal and differentiation—the process through which stem cells mature into more specific cell types such as neurons or muscle.  Specifically, they found that a microRNA, a single-stranded RNA whose function is to decrease gene expression, lowers the activity of three key genes needed for embryonic stem cell self-renewal. Conversely, they found that when this microRNA, miR-145, is lost the stem cells are prevented from differentiating into more mature cells.

Cell: April 30, 2009
CIRM funding: Na Xu (T3-00009)

Related Information: Press release, University of California, Santa Barbara