An essential step in growing human livers

I bring great news from the world of stem-cell research. Japanese scientists published a paper in the science journal Nature on July 3rd demonstrating "proof of concept" that a working human liver can be built in the laboratory from stem cells. The work was carried out by a team led by Takanori Takebe at Yokohama City University.

This work is the first step in growing replacement livers from stem cells for transplants. There is a serious scarcity of livers for transplant. In 2011 more than 16,000 people in the US were on a waiting list for a liver transplant, 5,805 transplants were carried out and 2,938 people either died that year waiting for a new liver or became too ill to remain on the list.

It will take about 10 years, all going well, to develop the initial work of Takebe’s team before livers grown from stem cells can be transplanted into humans.

I’m particularly pleased by Takebe’s work because this breakthrough was made using human-induced pluripotent stem cells (IPSC) and human adult stem cells derived from umbilical cords. No ethical problems necessarily attend the use of such stem cells – unlike with human embryonic stem cells – whose preparation entails killing human embryos.

The human body contains more than 200 differentiated (specialised) cell types organised into tissues and organs. A stem cell is an undifferentiated cell that can change into one, several or many types of specialised cells. The two most flexible stem-cell types are IPSC and embryonic stem cells derived from embryos. IPSCs are made by genetically reprogramming specialised adult cells, for example skin cells, transforming them into stem cells that resemble embryonic stem cells.

Work is ongoing on developing methods to reliably coax these stem cells into differentiated cells of choice. Adult stem cells are derived from umbilical cords or adult tissues. They are not as flexible as the other two types of stem cells but they are more easily and reliably manipulated.

Every bodily organ or tissue is made of a number of cell types. The predominant cell type carries out the function of the tissue/organ; connective tissue cells hold the tissue/organ together, giving it strength and coherence; cells of the vasculature provide a nourishing blood supply to the tissue/organ. Tissues/organs form during embryological development when stem-cell precursors of their differentiated cells mix together and differentiate into a 3D organ/tissue.

Takebe’s group mimicked this embryological development process in a laboratory dish by mixing three types of cells: human IPSC cells that had been coaxed to differentiate into a cell type that expresses liver genes; human blood-vessel precursor cells (endothelial cells); and connective- tissue precursor cells (mesenchymal stem cells). The latter two types of precursor cells were harvested from umbilical cords.

Cell cocktail
To the delight of the research team this cell cocktail organised itself into 3D tissue clusters called "liver buds" within 48 hours. These liver buds look very like the developing liver inside the embryo after five or six weeks' gestation, and were threaded through with blood vessels (vascularised), a crucial characteristic of complex tissue structure.

The research group transplanted liver buds into mice, where they matured and performed several functions characteristic of human liver: they secreted two proteins characteristic of human liver and were able to detoxify two human drugs (a key liver function). In a fascinating experiment, the team showed that such liver buds transplanted into a mouse, whose own liver was experimentally disabled, kept it alive for a month.

The next step is to scale up laboratory production of liver buds so that tens of thousands can be routinely produced. Successful scaling up could take five to six years. It is likely that the first humans to be treated with liver buds will be newborn babies or children with liver damage who would otherwise die without treatment.

In the meantime, liver buds could be used to test drugs before they are sold to the public. They should produce more reliable results than the current method of testing drugs on animal models. Takebe’s group is also working on building other human organs in the lab such as pancreases and kidneys. Much work remains to develops this breakthrough to the point of routine use in human medicine, but an essential first step has been achieved.

William Reville is an emeritus professor of biochemistry and public awareness of science officer at UCC. understandingscience.ucc.ie