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Can Organoids Yield Answers to Fatty Liver Disease?

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Liver Organoid
Confocal microscope image shows liver organoid made from iPS cells derived from children with Wolman disease. The hepatocyte cells (red) accumulate fat (blue). Credit: Cincinnati Children’s Hospital Medical Center

With advances in induced pluripotent stem cell (iPSC) technology, it’s now possible to reprogram adult skin or blood cells to form miniature human organs in a lab dish. While these “organoids” closely mimic the structures of the liver and other vital organs, it’s been tough to get them to represent inflammation, fibrosis, fat accumulation, and many other complex features of disease.

Fatty liver diseases are an increasingly serious health problem. So, I’m pleased to report that, for the first time, researchers have found a reliable way to make organoids that display the hallmarks of those conditions. This “liver in a dish” model will enable the identification and preclinical testing of promising drug targets, helping to accelerate discovery and development of effective new treatments.

Previous methods working with stem cells have yielded liver organoids consisting primarily of epithelial cells, or hepatocytes, which comprise most of the organ. Missing were other key cell types involved in the inflammatory response to fatty liver diseases.

To create a better organoid, the team led by Takanori Takebe, Cincinnati Children’s Hospital Medical Center, focused its effort on patient-derived iPSCs. Takebe and his colleagues devised a special biochemical “recipe” that allowed them to grow liver organoids with sufficient cellular complexity.

As published in Cell Metabolism, the recipe involves a three-step process to coax human iPSCs into forming multi-cellular liver organoids in as little as three weeks. With careful analysis, including of RNA sequencing data, they confirmed that those organoids contained hepatocytes and other supportive cell types. The latter included Kupffer cells, which play a role in inflammation, and stellate cells, the major cell type involved in fibrosis. Fibrosis is the scarring of the liver in response to tissue damage.

Now with a way to make multi-cellular liver organoids, the researchers put them to the test. When exposed to free fatty acids, the organoids gradually accumulated fat in a dose-dependent manner and grew inflamed, which is similar to what happens to people with fatty liver diseases.

The organoids also showed telltale biochemical signatures of fibrosis. Using a sophisticated imaging method called atomic force microscopy (AFM), the researchers found as the fibrosis worsened, they could measure a corresponding increase in an organoid’s stiffness.

Next, as highlighted in the confocal microscope image above, Takebe’s team produced organoids from iPSCs derived from children with a deadly inherited form of fatty liver disease known as Wolman disease. Babies born with this condition lack an enzyme called lysosomal acid lipase (LAL) that breaks down fats, causing them to accumulate dangerously in the liver. Similarly, the miniature liver shown here is loaded with accumulated fat lipids (blue).

That brought researchers to the next big test. Previous studies had shown that LAL deficiency in kids with Wolman disease overactivates another signaling pathway, which could be suppressed by targeting a receptor known as FXR. So, in the new study, the team applied an FXR-targeted compound called FGF19, and it prevented fat accumulation in the liver organoids derived from people with Wolman disease. The organoids treated with FGF19 not only were protected from accumulating fat, but they also survived longer and had reduced stiffening, indicating a reduction in fibrosis.

These findings suggest that FGF19 or perhaps another compound that acts similarly might hold promise for infants with Wolman disease, who often die at a very early age. That’s encouraging news because the only treatment currently available is a costly enzyme replacement therapy. The findings also demonstrate a promising approach to accelerating the search for new treatments for a variety of liver diseases.

Takebe’s team is now investigating this approach for non-alcoholic steatohepatitis (NASH), a common cause of liver failure and the need for a liver transplant. The hope is that studies in organoids will lead to promising new treatments for this liver condition, which affects millions of people around the world.

Ultimately, Takebe suggests it might prove useful to grow liver organoids from individual patients with fatty liver diseases, in order to identify the underlying biological causes and test the response of those patient-specific organoids to available treatments. Such evidence could one day help doctors to select the best available treatment option for each individual patient, and bring greater precision to treating liver disease.

Reference:

[1] Modeling steatohepatitis in humans with pluripotent stem cell-derived organoids. Ouchi R, Togo S, Kimura M, Shinozawa T, Koido M, Koike H, Thompson W, Karns RA, Mayhew CN, McGrath PS, McCauley HA, Zhang RR, Lewis K, Hakozaki S, Ferguson A, Saiki N, Yoneyama Y, Takeuchi I, Mabuchi Y, Akazawa C, Yoshikawa HY, Wells JM, Takebe T. Cell Metab. 2019 May 14. pii: S1550-4131(19)30247-5.

Links:

Wolman Disease (Genetic and Rare Diseases Information Center/NIH)

Nonalcoholic Fatty Liver Disease & NASH (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)

Stem Cell Information (NIH)

Tissue Chip for Drug Screening (National Center for Advancing Translational Sciences/NIH)

Takebe Lab (Cincinnati Children’s Hospital Medical Center)

NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases


Studying Color Vision in a Dish

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Credit: Eldred et al., Science

Researchers can now grow miniature versions of the human retina—the light-sensitive tissue at the back of the eye—right in a lab dish. While most “retina-in-a-dish” research is focused on finding cures for potentially blinding diseases, these organoids are also providing new insights into color vision.

Our ability to view the world in all of its rich and varied colors starts with the retina’s light-absorbing cone cells. In this image of a retinal organoid, you see cone cells (blue and green). Those labelled with blue produce a visual pigment that allows us to see the color blue, while those labelled green make visual pigments that let us see green or red. The cells that are labeled with red show the highly sensitive rod cells, which aren’t involved in color vision, but are very important for detecting motion and seeing at night.


Regenerative Medicine: Making Blood Stem Cells in the Lab

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Endothelial cells becoming hematopoietic stem cells

Caption: Arrow in first panel points to an endothelial cell induced to become hematopoietic stem cell (HSC). Second and third panels show the expansion of HSCs over time.
Credit: Raphael Lis, Weill Cornell Medicine, New York, NY

Bone marrow transplants offer a way to cure leukemia, sickle cell disease, and a variety of other life-threatening blood disorders.There are two major problems, however: One is many patients don’t have a well-matched donor to provide the marrow needed to reconstitute their blood with healthy cells. Another is even with a well-matched donor, rejection or graft versus host disease can occur, and lifelong immunosuppression may be needed.

A much more powerful option would be to develop a means for every patient to serve as their own bone marrow donor. To address this challenge, researchers have been trying to develop reliable, lab-based methods for making the vital, blood-producing component of bone marrow: hematopoietic stem cells (HSCs).

Two new studies by NIH-funded research teams bring us closer to achieving this feat. In the first study, researchers developed a biochemical “recipe” to produce HSC-like cells from human induced pluripotent stem cells (iPSCs), which were derived from mature skin cells. In the second, researchers employed another approach to convert mature mouse endothelial cells, which line the inside of blood vessels, directly into self-renewing HSCs. When these HSCs were transplanted into mice, they fully reconstituted the animals’ blood systems with healthy red and white blood cells.


LabTV: Curious About Parkinson’s Disease

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Kinsley Belle

When the young scientist featured in this LabTV video first learned about induced pluripotent stem (iPS) cells a few years ago as an undergrad, he thought it would be cool if he could someday work with this innovative technology. Today, as a graduate student, Kinsley Belle is part of a research team that’s using iPS cells on a routine basis to gain a deeper understanding of Parkinson’s disease.

Derived from genetically reprogrammed skin cells or white blood cells, iPS cells have the potential to develop into many different types of cells, providing scientists with a powerful tool to model a wide variety of diseases in laboratory dishes.  At the University of Miami’s John P. Hussman Institute for Human Genomics, Belle and his colleagues are taking advantage of an iPS model of Parkinson’s disease to explore its molecular roots. Their goal? To use that information to develop better treatments or maybe even a cure for the neurodegenerative disorder that affects at least a half-million Americans.


Bioengineering: Big Potential in Tiny 3D Heart Chambers

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iPS human heart

Caption: Heart microchamber generated from human iPS cells; cardiomyocytes (red), myofibroblasts (green), cell nuclei (blue) 
Credit: Zhen Ma, University of California, Berkeley

The adult human heart is about the size of a large fist, divided into four chambers that beat in precise harmony about 100,000 times a day to circulate blood throughout the body. That’s a very dynamic system, and also a very challenging one to study in real-time in the lab. Understanding how the heart forms within developing human embryos is another formidable challenge. So, you can see why researchers are excited by the creation of tiny, 3D heart chambers with the ability to exist (see image above) and even beat (see video below) in a lab dish, or as scientists  say “in vitro.”

iPS heart cells video

Credit: Zhen Ma et al., Nature Communications

To achieve this feat, an NIH-funded team from University of California, Berkeley, and Gladstone Institute of Cardiovascular Disease, San Francisco turned to human induced pluripotent stem (iPS) cell technology. The resulting heart chambers may be miniscule—measuring no more than a couple of hair-widths across—but they hold huge potential for everything from improving understanding of cardiac development to speeding drug toxicity screening.


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