July 10, 2014 12:00 am JST

Researchers work in 3-D to grow organs for regenerative medicine

MASARU YAMAMOTO, Nikkei staff writer

TOKYO -- The use of 3-D technology for movies, games and TV is a matter of taste. But when it comes to regenerative medicine, 3-D is all but essential.

     To treat diseases and restore lost functionality by transplanting grown-to-order organs requires complex, three-dimensional masses of tissue with the cells all working in concert. Cells grown in flat sheets simply cannot do this.

     Scientists have managed to culture 3-D masses of cells of such organs as the kidney, pancreas and liver. They call these "organ buds," or "organoids."

     Japan's Yokohama City University has become known for its experiments in which researchers have transplanted organoids to mice, where the masses successfully developed into more complex tissues.

     It may be years before this kind of science is ready for the clinic, but the pace is picking up, particularly with an eye toward the treatment of liver problems using regenerative medicine.

Two methods
There are two main approaches to making organoids. The first is to start with a mass of cells in the lab and then grow the organs inside an animal. This is efficient because the growth is effectively hitching a ride on the process by which animals develop from fertilized eggs. The snag is that it is hard to control what shape the tissue becomes.

     The second is to do it all in the lab, engineering the organs with tools such as 3-D printers. The shape is easy to control, but producing organs in sizes suitable for transplant is still difficult.

     The successes reported by Yokohama City University uses the first approach.

     Last year, the American academic journal Science listed the creation of organoids as one of the top 10 breakthroughs of 2013. Yokohama City University associate professor Takanori Takebe and professor Hideki Taniguchi created liver buds and transplanted them into mice, where they developed into functioning mini livers.

     Their team then developed a basic technology to create organoids for the pancreas, cartilage and kidneys. "It looks like this method can be applied to any organ," Takebe said.

     To create their kidney organoids, the team starts with a mix of blood vessel-forming endothelial cells, mesenchymal stem cells, precursors to the cells that form the glomerulus to filter the blood, and precursors to the cells that form the connecting tubule. Grown together for two to three days in a culture dish in an environment mimicking the body, these cells form into a thriving kidney bud. Transplanted to a mouse, this organoid develops over a month into a functioning mini kidney measuring 4-5mm wide.

     Similar work is being done at the University of Tokyo, where a team managed to grow a rat pancreas inside a mouse in 2010, and a pancreas inside a pig last year.

Body doubles

Organ therapy as a goal of regenerative medicine depends on an elaborate partnership of tissues inside the body. Cells need to build up and form connections with blood vessels and other organs. Cells cultured as a flat sheet in a dish cannot pull this off.

     Research using human iPS cells will be used in future efforts. Because these are stem cells that can proliferate indefinitely, their use should contribute to the development of technologies for mass production of organoids.

     Takebe and his collaborators are now studying a number of different organoids. But their studies with the liver are furthest along. Their goal is to conduct clinical research using liver organoids within the next 10 years.

     The team is nailing down the details of organoid growth for liver transplants. And in partnership with the private sector, they are working out the technologies for mass production.