Onward and upward with organoids

UTRECHT, The Netherlands—The promise of lab-grown tissues, especially organs, has captivated scientists to a large degree over the years. Model organs, also known as organoids, could offer a variety of potential uses: they can enable researchers to more accurately test the toxicity of compounds before risking participants in human trials, allow closer study of disease progression and possibly represent a new solution to the great need for transplant organs.

And a pair of papers featuring research out of the Hubrecht Institute and University Medical Center Utrecht (UMC Utrecht) could offer a new avenue for exploring that potential.

This research began several years ago when, in 2009, a research group led by Prof. Hans Clevers, professor of molecular genetics at the Hubrecht Institute/UMC Utrecht and president of the Royal Dutch Academy of Arts and Sciences, detailed a revolutionary culturing method that enabled the culturing of mini-guts from single mouse intestine stem cells. The organoids are functional miniature organs that can be grown in tissue culture.

That same group of researchers has now announced the development of a culturing system for liver stem cells and stem cells from pancreatic cancer. Both sets of research appeared recently in Cell.

The culturing system for liver stem cells is detailed in the paper “Long-Term Culture of Genome-Stable Bipotent Stem Cells from Adult Human Liver,” specifically the conditions that allow “long-term expansion of adult bile duct-derived bipotent progenitor cells from human liver.” The paper notes that the expanded cells are highly stable at both the chromosome and structural levels, and the cells “can readily be converted into functional hepatocytes in vitro and, upon transplantation, in vivo.” The resulting organoids grown from cells from patients with α1-antitrypsin deficiency and Alagille syndrome—an inherited disorder that can lead to liver disease and/or cirrhosis and a genetic disorder characterized by liver damage due to abnormalities in the bile ducts, respectively—accurately represent the in-vivo pathology of the disorders.

This approach, which enables long-term replication of harvested liver tissue, makes it possible to culture the equivalent of a full-grown liver from a single liver cell over the course of four months, and the cultured tissue is genetically similar to healthy liver tissue and very stable. Human “mini-livers” cultured in the lab have been successfully transplanted into mouse models with liver damage.

The second paper, “Organoid Models of Human and Mouse Ductal Pancreatic Cancer,” details the team’s development of a technology enabling long-term laboratory culturing of healthy and diseased pancreatic stem cells. The work was co-led by Clevers and Dr. David Tuveson, professor at Cold Spring Harbor Laboratory and director of research for The Lustgarten Foundation.

Culturing either healthy or cancerous pancreatic cells in the lab has failed in the past, in part due to the fact that the normal ductal cells that can become cancerous represent about 10 percent of the cells in the pancreas. The organoids generated from this culturing method consist entirely of ductal cells, excluding the other cell types that can contaminate pancreas samples. The organoids are grown as hollow spheres in a gel-like substance full of growth-inducing factors and connecting fibers, and once grown, they can be transplanted back into mice, where they accurately duplicate pancreatic cancer.

As noted in the paper, these organoids “can be rapidly generated from resected tumors and biopsies, survive cryopreservation and exhibit ductal- and disease-stage-specific characteristics. Orthotopically transplanted neoplastic organoids recapitulate the full spectrum of tumor development by forming early-grade neoplasms that progress to locally invasive and metastatic carcinomas.”

“We now have a model for each stage in the progression of the disease,” said Dr. Chang-Il Hwang, one of the lead authors of the second paper working in The Lustgarten Foundation’s Pancreatic Cancer Research Lab at CSHL directed by Tuveson.

Dr. Dannielle Engle of Cold Spring Harbor, another lead author, added that while biopsies are the current standard for cancer diagnosis, “We can now rapidly generate organoids from any patient, which offers us the potential to study the disease in a much wider population.”

The researchers found that thanks to this method, the tumor tissue samples from individual patients can be tested to determine their sensitivity or resistance to different cancer drugs.

The technology was also used to create a ‘Living Biobank’ of cultured pancreatic tumors from a large group of patients with pancreatic tumors, which was established with support from the Dutch Cancer Society/Stand up to Cancer. The biobank is open to cancer researchers and companies worldwide to aid in the development of new drugs and therapies for cancer.