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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.


[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.


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

Moving Closer to a Stem Cell-Based Treatment for AMD

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In recent years, researchers have figured out how to take a person’s skin or blood cells and turn them into induced pluripotent stem cells (iPSCs) that offer tremendous potential for regenerative medicine. Still, it’s been a challenge to devise safe and effective ways to move this discovery from the lab into the clinic. That’s why I’m pleased to highlight progress toward using iPSC technology to treat a major cause of vision loss: age-related macular degeneration (AMD).

In the new work, researchers from NIH’s National Eye Institute developed iPSCs from blood-forming stem cells isolated from blood donated by people with advanced AMD [1]. Next, these iPSCs were exposed to a variety of growth factors and placed on supportive scaffold that encouraged them to develop into healthy retinal pigment epithelium (RPE) tissue, which nurtures the light-sensing cells in the eye’s retina. The researchers went on to show that their lab-grown RPE patch could be transplanted safely into animal models of AMD, preventing blindness in the animals.

This preclinical work will now serve as the foundation for a safety trial of iPSC-derived RPE transplants in 12 human volunteers who have already suffered vision loss due to the more common “dry” form of AMD, for which there is currently no approved treatment. If all goes well, the NIH-led trial may begin enrolling patients as soon as this year.

Risk factors for AMD include a combination of genetic and environmental factors, including age and smoking. Currently, more than 2 million Americans have vision-threatening AMD, with millions more having early signs of the disease [2].

AMD involves progressive damage to the macula, an area of the retina about the size of a pinhead, made up of millions of light-sensing cells that generate our sharp, central vision. Though the exact causes of AMD are unknown, RPE cells early on become inflamed and lose their ability to clear away debris from the retina. This leads to more inflammation and progressive cell death.

As RPE cells are lost during the “dry” phase of the disease, light-sensing cells in the macula also start to die and reduce central vision. In some people, abnormal, leaky blood vessels will form near the macula, called “wet” AMD, spilling fluid and blood under the retina and causing significant vision loss. “Wet” AMD has approved treatments. “Dry” AMD does not.

But, advances in iPSC technology have brought hope that it might one day be possible to shore up degenerating RPE in those with dry AMD, halting the death of light-sensing cells and vision loss. In fact, preliminary studies conducted in Japan explored ways to deliver replacement RPE to the retina [3]. Though progress was made, those studies highlighted the need for more reliable ways to produce replacement RPE from a patient’s own cells. The Japanese program also raised concerns that iPSCs derived from people with AMD might be prone to cancer-causing genomic changes.

With these challenges in mind, the NEI team led by Kapil Bharti and Ruchi Sharma have designed a more robust process to produce RPE tissue suitable for testing in people. As described in Science Translational Medicine, they’ve come up with a three-step process.

Rather than using fibroblast cells from skin as others had done, Bharti and Sharma’s team started with blood-forming stem cells from three AMD patients. They reprogrammed those cells into “banks” of iPSCs containing multiple different clones, carefully screening them to ensure that they were free of potentially cancer-causing changes.

Next, those iPSCs were exposed to a special blend of growth factors to transform them into RPE tissue. That recipe has been pursued by other groups for a while, but needed to be particularly precise for this human application. In order for the tissue to function properly in the retina, the cells must assemble into a uniform sheet, just one-cell thick, and align facing in the same direction.

So, the researchers developed a specially designed scaffold made of biodegradable polymer nanofibers. That scaffold helps to ensure that the cells orient themselves correctly, while also lending strength for surgical transplantation. By spreading a single layer of iPSC-derived RPE progenitors onto their scaffolds and treating it with just the right growth factors, the researchers showed they could produce an RPE patch ready for the clinic in about 10 weeks.

To test the viability of the RPE patch, the researchers first transplanted a tiny version (containing about 2,500 RPE cells) into the eyes of a rat with a compromised immune system, which enables human cells to survive. By 10 weeks after surgery, the human replacement tissue had integrated into the animals’ retinas with no signs of toxicity.

Next, the researchers tested a larger RPE patch (containing 70,000 cells) in pigs with an AMD-like condition. This patch is the same size the researchers ultimately would expect to use in people. Ten weeks after surgery, the RPE patch had integrated into the animals’ eyes, where it protected the light-sensing cells that are so critical for vision, preventing blindness.

These results provide encouraging evidence that the iPSC approach to treating dry AMD should be both safe and effective. But only a well-designed human clinical trial, with all the appropriate prior oversights to be sure the benefits justify the risks, will prove whether or not this bold approach might be the solution to blindness faced by millions of people in the future.

As the U.S. population ages, the number of people with advanced AMD is expected to rise. With continued progress in treatment and prevention, including iPSC technology and many other promising approaches, the hope is that more people with AMD will retain healthy vision for a lifetime.


[1] Clinical-grade stem cell-derived retinal pigment epithelium patch rescues retinal degeneration in rodents and pigs. Sharma R, Khristov V, Rising A, Jha BS, Dejene R, Hotaling N, Li Y, Stoddard J, Stankewicz C, Wan Q, Zhang C, Campos MM, Miyagishima KJ, McGaughey D, Villasmil R, Mattapallil M, Stanzel B, Qian H, Wong W, Chase L, Charles S, McGill T, Miller S, Maminishkis A, Amaral J, Bharti K. Sci Transl Med. 2019 Jan 16;11(475).

[2] Age-Related Macular Degeneration, National Eye Institute.

[3] Autologous Induced Stem-Cell-Derived Retinal Cells for Macular Degeneration. Mandai M, Watanabe A, Kurimoto Y, Hirami Y, Takasu N, Ogawa S, Yamanaka S, Takahashi M, et al. N Engl J Med. 2017 Mar 16;376(11):1038-1046.


Facts About Age-Related Macular Degeneration (National Eye Institute/NIH)

Stem Cell-Based Treatment Used to Prevent Blindness in Animal Models of Retinal Degeneration (National Eye Institute/NIH)

Kapil Bharti (NEI)

NIH Support: National Eye Institute; Common Fund

Creative Minds: Mapping the Biocircuitry of Schizophrenia and Bipolar Disorder

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Bruce Yankner

Bruce Yankner

As a graduate student in the 1980s, Bruce Yankner wondered what if cancer-causing genes switched on in non-dividing neurons of the brain. Rather than form a tumor, would those genes cause neurons to degenerate? To explore such what-ifs, Yankner spent his days tinkering with neural cells, using viruses to insert various mutant genes and study their effects. In a stroke of luck, one of Yankner’s insertions encoded a precursor to a protein called amyloid. Those experiments and later ones from Yankner’s own lab showed definitively that high concentrations of amyloid, as found in the brains of people with Alzheimer’s disease, are toxic to neural cells [1].

The discovery set Yankner on a career path to study normal changes in the aging human brain and their connection to neurodegenerative diseases. At Harvard Medical School, Boston, Yankner and his colleague George Church are now recipients of an NIH Director’s 2016 Transformative Research Award to apply what they’ve learned about the aging brain to study changes in the brains of younger people with schizophrenia and bipolar disorder, two poorly understood psychiatric disorders.

Creative Minds: A Transcriptional “Periodic Table” of Human Neurons

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neuronal cell

Caption: Mouse fibroblasts converted into induced neuronal cells, showing neuronal appendages (red), nuclei (blue) and the neural protein tau (yellow).
Credit: Kristin Baldwin, Scripps Research Institute, La Jolla, CA

Writers have The Elements of Style, chemists have the periodic table, and biomedical researchers could soon have a comprehensive reference on how to make neurons in a dish. Kristin Baldwin of the Scripps Research Institute, La Jolla, CA, has received a 2016 NIH Director’s Pioneer Award to begin drafting an online resource that will provide other researchers the information they need to reprogram mature human skin cells reproducibly into a variety of neurons that closely resemble those found in the brain and nervous system.

These lab-grown neurons could be used to improve our understanding of basic human biology and to develop better models for studying Alzheimer’s disease, autism, and a wide range of other neurological conditions. Such questions have been extremely difficult to explore in mice and other animal models because they have shorter lifespans and different brain structures than humans.

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.

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