CIRM-funded scientists track the steps that take an adult cell back in time

The ability to transform an adult cell back into a stem cell has been heralded as one of the greatest achievements of the 21st century. Scientists have lauded this discovery, made by Nobel Prize-winning scientist Shinya Yamanaka, as a game changer for the future of medicine.

Despite this extraordinary advance, the method remains inefficient. And even the top experts still don’t quite understand how it works.

But now, a team of stem cell scientists from the University of California, Los Angeles (UCLA) has mapped the precise series of steps that an adult skin cell must go through to become a stem cell. The results, published online in the journal Cell, represent a much-needed step towards bringing cellular reprogramming forward.

A colony of iPSC's obtained by reprogramming a specialized cell for two weeks. The starting specialized cells can only make more of themselves, while the reprogrammed cells obtained from them can give rise to all cells of the body.

A colony of iPSC’s obtained by reprogramming a specialized cell for two weeks. The starting specialized cells can only make more of themselves, while the reprogrammed cells obtained from them can give rise to all cells of the body.

In this study, co-first authors Vincent Pasque and Jason Tchieu initiated the reprogramming process, whereby adult cells are reprogrammed back into embryonic-like stem cells. Yamanaka called these cells induced pluripotent stem cells, or iPSCs.

In order to map the steps being taken to reprogram these cells, the team devised a detailed time-course analysis whereby they would observe and analyze the cells each day as they transformed over a period of two weeks.

Importantly, the team found that no matter what type of adult cells were involved, the specific steps it took during reprogramming were the same. This revelation, that all adult cell types follow the same road map, is one of the most exciting discoveries. Said Pasque in a news release:

“The exact stage of reprogramming of any cell can now be determined. This study signals a big change in our thinking, because it provides simple and efficient tools for scientists to study stem cell creation in a stage-by-stage manner.”

The research team, led by CIRM grantee Katherin Plath, also uncovered some interesting information about the sequence of steps taken by these reprogrammed cells.

When an adult cell is reprogrammed back into an iPSC, it is not simply that all the steps that normally take an embryonic stem cell into an adult cell are reversed. Some may be reversed in the correct order, but others are not. And some steps are put off until the very end—indicating strong resistance against reprogramming.

“This reflects how cells do not like to change from one specialized cell type into another and resist a change in cellular identity,” said Pasque.

With future work, the team hopes to continue to investigate the reprogramming process. They are also hopeful that this newfound insight will bring robust iPSC-based therapies to the clinic.

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