Perspectives on human micro liver structures made from iPS cells

The big stem cell buzz the last day or two has been the news exploding across mainstream media outlets about laboratory-produced human liver grown from stem cells.

It’s good news to be sure as it would seem we might be one important step closer to a new reality for millions of people suffering from liver disease. There are not enough livers to go around for transplants.

However, this advance is just one small even if important step and many more remain.

What was the science behind this excitement?

A team led by Hideki Taniguchi  in Japan has for the first time produced structures that appear to be akin to micro-livers from induced pluripotent stem (iPS) cells. Others have tried this using iPS cells and embryonic stem cells as a starting material, but the efforts always failed.

More broadly, this may be the first time that human iPS cells have ever been used to make anything close to a functional solid organ.

The researchers at Yokohama City University Graduate School of Medicine reported their work in a letter in Nature, Takebe, et al.

Monya Baker has an excellent piece in Nature on the story and Gina Kolata has a great piece in the NYT on the discovery as well, quoting both researchers who seem wowed by this research and other scientists who were more cautious. Dan Vergano at USA Today also has a piece on this liver bud story that I highly recommend.

How big a deal is this finding? What are the implications? Hurdles remaining?

I’m excited by this development and it is important, but at the same time there are some reasons for caution and certain complexities to it.

The team made human iPS cells from skin cells and then differentiated the iPS cells into human liver cells. Not much new here.

Most teams have failed in attempts to make livers at this point.

The Japanese team then “stumbled upon their solution” according to Kolata with a very complicated approach.

They took the human iPS cell-derived liver cells and grew them along with human umbilical cords and also human connective tissue.

This mixture of cells and tissues developed into primitive blobs or “buds” that have some features resembling human fetal liver.

The primordial human microliver-like structures were then transplanted into mice allowing further development.

The new murine homes for the liver-like tissues were mouse brain or abdomen. The human primitive liver buds, just about 1/6 of an inch in diameter, were able to perform some metabolic functions attributable to human livers in the mice and reportedly kept the mice from dying of liver disease.

Are these structures (see image above from USA Today of the micro-livers in culture from Takebe’s lab) really tiny human livers? More study is needed.

The function of these human micro-liver-like structures is quite notable, but the complexity of the protocol and the ultimate development of the micro-organs inside of mice are serious limiting factors of the paper’s clinical relevance for humans. This finding may have more liver basic science than direct clinical relevance. Takebe is quoted in USA Today by Vergano providing the appropriate context:

“Despite the effort’s success, Takebe warned that implants of such tissues in human patients are at least a decade away, after tests of their long-term growth and safety. Concerns linger about cancer risks from stem cells implanted into patients. The liver buds also lacked immune cells that filter toxins from the bloodstream and structural cells that send digestive enzymes into the gut from a real liver.”

The team also only followed the micro-livers for a few months in the mice, which is also a limitation. Could the human tissues become tumorous? Might they simply fade away? Future studies will address these questions. The Kolata NYT piece also highlights these concerns:

“They were letting nature do its thing rather than trying to conceive of what the right signals might be,” Dr. Zaret said. But, he said, the mice were studied for only a couple of months. He would like to see what happens over a longer time.

“We don’t know if the cells will grow out of control or will poop out,” Dr. Zaret said.

Additional research will teach us how big a deal this really is (or not) for treating human liver disease and for the regenerative medicine field more generally. It is encouraging, but it could still be a decade or more before this kind of work directly helps people.