How research on a rare disease turned into a faster way to make stem cells

Forest Gump. (Paramount Pictures)

Forest Gump. (Paramount Pictures)

If Forest Gump were a scientist, I’d like to think he would have said his iconic line a little differently. Dr. Gump would have said, “scientific research is like a box of chocolates – you never know what you’re gonna get.”

A new CIRM-funded study coming out of the Gladstone Institutes certainly proves this point. Published yesterday in the Proceedings of the National Academy of Sciences, the study found that a specific genetic mutation known to cause a rare disease called fibrodysplasia ossificans progressiva (FOP) makes it easier to reprogram adult skin cells into induced pluripotent stem cells (iPSCs).

Shinya Yamanaka received the Nobel Prize in medicine in 2012 for his seminal discovery of the iPSC technology, which enabled scientists to generate patient specific pluripotent stem cell lines from adult cells like skin and blood. These iPSC lines are useful for modeling disease in a dish, identifying new therapeutic drugs, and potentially for clinical applications in patients. However, one of the rate-limiting steps to this technology is the inefficient process of making iPSCs.

Yamanaka, a senior investigator at Gladstone, knows this problem all too well. In a Gladstone news release he commented, “inefficiency in creating iPSCs is a major roadblock toward applying this technology to biomedicine. Our study identified a surprising way to increase the number of iPSCs that we can generate.”

So how did Yamanaka and his colleagues discover this new trick for making iPSCs more efficiently? Originally, their intentions were to model a rare genetic disease called FOP. It’s commonly known as “stone man syndrome” because the disease converts normal muscle and connective tissue into bone either spontaneously or spurred by injury. Bone growth begins at a young age starting at the neck and progressively moving down the body. Because there is no treatment or cure, patients typically have a lifespan of only 40 years.

The Gladstone team wanted to understand this rare disease better by modeling it in a dish using iPSCs generated from patients with FOP. These patients had a genetic mutation in the ACVR1 gene, which plays an important role in the development of the embryo. FOP patients have a mutant form of ACVR1 that overstimulates this developmental pathway and boosts the activity of a protein called BMP (bone morphogenic protein). When BMP signaling is ramped up, they discovered that they could produce significantly more iPSCs from the skin cells of FOP patients compared to normal, healthy skin cells.

First author on the study, Yohei Hayashi, explained their hypothesis for why this mutation makes it easier to generate iPSCs:

“Originally, we wanted to establish a disease model for FOP that might help us understand how specific gene mutations affect bone formation. We were surprised to learn that cells from patients with FOP reprogrammed much more efficiently than cells from healthy patients. We think this may be because the same pathway that causes bone cells to proliferate also helps stem cells to regenerate.”

To be sure that enhanced BMP signaling caused by the ACVR1 mutation was the key to generating more iPSCs, they blocked this signal and discovered that much fewer iPSCs were made from FOP patient skin cells.

Senior Investigator Bruce Conklin, who was a co-author on this study, succinctly summarized the importance of their findings:

“This is the first reported case showing that a naturally occurring genetic mutation improves the efficiency of iPSC generation. Creating iPSCs from patient cells carrying genetic mutations is not only useful for disease modeling, but can also offer new insights into the reprogramming process.”

Gladstone investigators Bruce Conklin and Shinya Yamanaka. (Photo courtesy of Chris Goodfellow, Gladstone Institutes)

Gladstone investigators Bruce Conklin and Shinya Yamanaka. (Photo courtesy of Chris Goodfellow, Gladstone Institutes)

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