Gladstone Institutes

Joint Gladstone-UCSF study highlights novel reprogramming method; offers new hope for treating liver failure

SAN FRANCISCO, CAFebruary 23, 2014 The power of regenerative medicine now allows scientists to transform skin cells into cells that closely resemble heart cells, pancreas cells and even neurons. However, a method to generate cells that are fully maturea crucial prerequisite for life-saving therapieshas proven far more difficult. But now, scientists at the Gladstone Institutes and the University of California, San Francisco (UCSF), have made an important breakthrough: they have discovered a way to transform skin cells into mature, fully functioning liver cells that flourish on their own, even after being transplanted into laboratory animals modified to mimic liver failure.

In previous studies on liver-cell reprogramming, scientists had difficulty getting stem cell-derived liver cells to survive once being transplanted into existing liver tissue. But the Gladstone-UCSF team figured out a way to solve this problem. Writing in the latest issue of the journal Nature, researchers in the laboratories of Gladstone Senior Investigator Sheng Ding, PhD, and UCSF Associate Professor Holger Willenbring, MD, PhD, reveal a new cellular reprogramming method that transforms human skin cells into liver cells that are virtually indistinguishable from the cells that make up native liver tissue.

These results offer new hope for the millions of people suffering from, or at risk of developing, liver failurean increasingly common condition that results in progressive and irreversible loss of liver function. At present, the only option is a costly liver transplant. So, scientists have long looked to stem cell technology as a potential alternative. But thus far they have come up largely empty-handed.

Earlier studies tried to reprogram skin cells back into a pluripotent, stem cell-like state in order to then grow liver cells, explained Dr. Ding, one of the papers senior authors, who is also a professor of pharmaceutical chemistry at UCSF, with which Gladstone is affiliated. However, generating these so-called induced pluripotent stem cells, or iPS cells, and then transforming them into liver cells wasnt always resulting in complete transformation. So we thought that, rather than taking these skin cells all the way back to a pluripotent, stem cell-like state, perhaps we could take them to an intermediate phase.

This research, which was performed jointly at the Roddenberry Center for Stem Cell Research at Gladstone and the Broad Center of Regeneration Medicine and Stem Cell Research at UCSF, involved using a cocktail of reprogramming genes and chemical compounds to transform human skin cells into cells that resembled the endoderm. Endoderm cells are cells that eventually mature into many of the bodys major organsincluding the liver.

Instead of taking the skin cells back to the beginning, we took them only part way, creating endoderm-like cells, added Gladstone and CIRM Postdoctoral Scholar Saiyong Zhu, PhD, one of the papers lead authors. This step allowed us to generate a large reservoir of cells that could more readily be coaxed into becoming liver cells.

Next, the researchers discovered a set of genes and compounds that can transform these cells into functioning liver cells. And after just a few weeks, the team began to notice a transformation.

The cells began to take on the shape of liver cells, and even started to perform regular liver-cell functions, said UCSF Postdoctoral Scholar Milad Rezvani, MD, the papers other lead author. They werent fully mature cells yetbut they were on their way.

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Scientists Transform Skin Cells Into Functioning Liver Cells