What Can A Rare Disease Teach Us About Stem Cell Reprogramming?

New research on the disease fibrodysplasia ossificans progressiva (FOP) from the team that created the first induced pluripotent stem cells (iPSCs), has discovered a pathway that improves iPSC production efficiency

Fibrodysplasia ossificans progressiva (FOP), nicknamed ‘Stone Man Syndrome’, is an extremely rare disease in which connective tissue and muscle gradually turn into bone. The disease is caused by a mutation in , the gene ACVR1, which over activates an important cellular pathway involving the signalling protein BMP (bone morphogenetic protein), which is crucial to embryonic development. 

“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”

All about BMP

In a study led by Shinya Yamanaka, who won a Nobel Prize for his work on iPSCs, cells from patients with FOP were found to form iPSC cells much more easily than those from ‘ordinary’ individuals. iPSC generation efficiency is notoriously poor, with only around 1% of adult cells successfully transformed into iPSCs. This is a roadblock to treatments and progress, because it makes producing large numbers of iPSCs much more challenging. 

Shinya Yamanaka (centre)

After further analysis, the reason for FOP cells’ increased ability to turn into pluripotent stem cells was determined to be increased levels of BMP. BMP is a potent signalling protein and is known to be involved with stem cell renewal and maintenance of a plastic, pluripotent state – the ability to form other types of cells. Unfortunately for FOP sufferers raised BMP is also critical for bone formation, which leads to a progressive hardening of ligaments, muscles and tendons. When the research team began to modulate levels of BMP in healthy cells they found that activating the pathway increased iPSC cell generation, which dampening it prevented it from occurring. 

“Originally, we wanted to establish a disease model for FOP that might help us understand how specific gene mutations affect bone formation,” said first author Yohei Hayashi, PhD, a former postdoctoral scholar with Shinya Yamanaka, PhD. “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.”

“This is 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”

Read more at Phys.org