Induced pluripotent stem
cells (iPSCs), stem cells created from skin cells that can be transformed
into any type of cell in the body, revolutionized biomedical science.
They have contributed to breakthroughs in regenerative medicine and drug
discovery, surpassing what researchers once thought possible.
any new technology, there is room for improvement. How do you improve a Nobel Prize-winning discovery? Add a debilitating disease-causing gene mutation.
‘The efficiency of stem cell reprogramming has been enhanced with a gene mutation that causes 'stone man syndrome', revealed scientists.’
In a study published in the journal Proceedings of the National Academy of Sciences
Shinya Yamanaka, who first created induced iPSCs, and his colleagues at the Gladstone Institutes found a
way to increase the efficiency of stem cell reprogramming through
research on a rare genetic disease.
existing techniques, fewer than 1% of adult skin cells are
reprogrammed into iPSCs.
"Inefficiency in creating iPSCs is a major roadblock toward applying
this technology to biomedicine," said Yamanaka, a senior investigator
at Gladstone and director of the Center for iPSC Research and
Application (CiRA) in Japan. "Our study identified a surprising way to
increase the number of iPSCs that we can generate."
The scientists started with a very different goal: to create a
cellular model to study fibrodysplasia ossificans progressiva (FOP).
This extremely rare genetic disease causes muscle, tendons, and
ligaments to turn into bone, earning it the nickname "stone man
syndrome." It is caused by a mutation in the ACVR1 gene, which
over-activates a cellular signaling process that is important for embryo
development and involves a protein called BMP.
Surprisingly, the scientists discovered that they could create more
iPSCs from cells taken from FOP patients than those taken from healthy
individuals. They believe this is because BMP signaling enhances cell
renewal - a cell's ability to replicate - and keeps them in a pluripotent
state, able to turn into any type of cell.
These two traits are key
characteristics of stem cells. To confirm their hunch, the researchers
prevented BMP signaling, which resulted in fewer iPSCs being generated
from FOP patients' cells. Conversely, activating the signaling pathway
yielded more iPSCs.
"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, a former postdoctoral
scholar with Shinya Yamanaka. "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
"This is is the first reported case showing that a naturally
occurring genetic mutation improves the efficiency of iPSC generation,"
added co-author Bruce Conklin, a senior investigator at Gladstone.
"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."