As technologies go, induced pluripotent stem (iPS) cells have had a relatively rapid road to the clinic. They were first described in the scientific literature in 2007. (See BioWorld Today, Nov. 21, 2007.)

And by the summer of 2013, the Riken Institute began recruiting for the world’s first clinical trial. Six patients are being treated for wet age-related macular degeneration with iPS-cell derived retinal pigment epithelial cells.

With clinical trials progressing, scientists are working on ways to make iPS cell derivation faster and more efficient, which will be important for them to fulfill their clinical potential on a large scale.

IMPROVING EFFICIENCY

A number of studies have recently explored ways to improve the efficiency of generating iPS cells, which is typically around 1 percent – a rate that, while high enough to continue working with such cells, will clearly cause problems if their successes end up translating into a greater demand for the cells.

The generation of therapeutically useful cells entails two basic steps: adult cells from patients need to be turned into pluripotent cells, which are then coaxed into the desired cell type. Two separate teams have discovered ways to increase the efficacy of the first step.

One team combined reprogramming factors with proteins that are responsible for keeping embryonic cells in a totipotent state – that is, able to turn into any cell type of the body – through their first few divisions. The proteins TH2A/TH2B, keep chromatin in an open state, leaving DNA accessible to the transcription machinery. In mature cells, much of the DNA is inaccessible to transcription, and that inaccessibility closes of most potential fates to mature cells.

Another group showed that increasing the speed of the cell cycle to two to three times its normal level doubled the yield of iPS cells from blood cell progenitors.

Neither of the two groups approached the efficiency reported last fall by scientists who made iPS cell generation nearly 100 percent efficient by knocking out a single gene, Mbd3. (See BioWorld Today, Sept. 19, 2013.)

But collectively, the studies are turning iPS cell generation into less of an art and more of an engineering feat. Yale University’s Shangqin Guo, whose team made reprogramming more efficient by speeding the cell cycle, told BioWorld Today that the epigenome, which is critical for determining cell fate, has “a consistency or texture that we are beginning to understand . . . we’re learning what we can do to this texture for a desired result.”

In the most practical of the recent crop of papers, scientists including Shinya Yamanaka – who first described the technique that is now known as Yamanaka reprogramming, and won the 2012 Novel Prize for his work – showed that they could combine c-Myc, which is part of the classical Yamanaka cocktail, and the overexpression of anti-apoptotic proteins to generate large numbers of platelet progenitors.

Halting the overexpression of those factors, in turn, let the progenitors differentiate into platelets. The authors hope their work will ultimately spell the end of the looming shortages that are a near-constant companion of deriving platelets from blood donations.

THE OTHER END OF THE SPECTRUM

Perhaps on the other end of the practicality spectrum was a paper describing the generation of pluripotent stem cells without the use of any Yamanaka factors at all. Instead, researchers made pluripotent stem cells purely by manipulating the cellular environment in the form of subjecting cells to stress. By subjecting cells to either an acidic environment or (mild) mechanical stress, the team was able to essentially induce amnesia in mature cells, returning them to a pluripotent state. (See BioWorld Today, Jan. 30, 2014.)

For now, the pluripotent potential of such cells –which their creators have named stimulus-acquired pluripotency (STAP) cells – is lower than that of other types of stem cells. Haruko Obokata of the Riken Center for Developmental Biology told reporters that “they can be passaged only four to five times, and we can culture them for only two weeks or so.”

The technique also works better for both newborn cells and older ones, though Obokata predicted that “in the future, I think we will be able to modify the conversion conditions or culture conditions. I think that it will work for older animals.”

And though STAP cells are less pluripotent than other stem cell types in some respects, they are able to generate cells of both the embryo and the placenta, showing that they may be in “an even more immature state” in other ways.