Complex organ models grown in the lab

Complex organ models

In 2006, Japanese researchers came up with a new way of creating pluripotent stem cells through epigenetic reprogramming of connective tissue cells. Their discovery has yielded a highly valuable cell type which scientists can use to grow all cells of the human body in a Petri dish.

When culturing these so-called "induced pluripotent stem cells" (iPS cells) as three-dimensional cell aggregates, functional miniature versions of human organs, the so-called organoids, can be created by selectively adding growth factors. In the past years, this technique has been used to create cell culture models of the intestines, the lung, liver, kidneys and the brain, for example.

Previous organoids remained incomplete

Such organoid models are often surprisingly similar to real embryonic tissues. However, most remained incomplete because they lacked stromal cells and structures, the supportive framework of an organ composed of connective tissue. For instance, the tissues lacked blood vessels and immune cells. During embryonic development, all these cell types and structures are engaged in a process of constant exchange, they influence each other and thereby boost the development and maturation of the tissue and of the organ. Diseases, too, usually evolve in the tissue context with the involvement of different cell types. The selective incorporation of stromal components, and especially of functioning blood vessels, would therefore promote the maturation of already established organoid models.

Scientists from the University of Würzburg have now taken a major step towards developing such complex organoids. The anatomists, Dr. Philipp Wörsdörfer and Professor Süleyman Ergün, the head of the Institute of Anatomy and Cell Biology, were in charge of the project. In an article published in the journal "Scientific Reports" in early November 2019, the two researchers present the results of their work.

Mesodermal stem cells make miniature organs complete

"We used a trick to achieve our goal," explains Philipp Wörsdörfer. "First we created so-called mesodermal progenitor cells from pluripotent stem cells." Under the right conditions, such progenitor cells are capable of producing blood vessels, immune cells and connective tissue cells.

To demonstrate the potential of the mesodermal progenitor cells, the scientists then mixed these cells with tumour cells as well as with brain stem cells that had previously been generated from human iPS cells. This mixture grew to form complex three-dimensional tumour or brain organoids in the Petri dish featuring functional blood vessels, connective tissue, and in the case of the brain tissue, also brain-specific immune cells, the so-called microglia cells.

"In the future, the miniature organ models generated with this new technique can help scientists shed light on the processes involved in the genesis of diseases and analyse the effect of therapeutic substances in more detail before using them on animals and human patients," says Süleyman Ergün. This would allow the number of animal experiments to be reduced. Moreover, the organ models could contribute to gaining a better understanding of embryonic development processes and grow tissue that can be transplanted efficiently since they already have a functional vascular system.

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Materials provided by University of Würzburg. Note: Content may be edited for style and length.

Brain waves detected in mini-brains grown in a dish

Brain waves detected

Scientists have created miniature brains from stem cells that developed functional neural networks. Despite being a million times smaller than human brains, these lab-grown brains are the first observed to produce brain waves that resemble those of preterm babies. The study, published August 29 in the journal Cell Stem Cell, could help scientists better understand human brain development.

"The level of neural activity we are seeing is unprecedented in vitro," says Alysson Muotri, a biologist at the University of California, San Diego. "We are one step closer to have a model that can actually generate these early stages of a sophisticated neural network."

The pea-sized brains, called cerebral organoids, are derived from human pluripotent stem cells. By putting them in culture that mimics the environment of brain development, the stem cells differentiate into different types of brain cells and self-organize into a 3D structure resembling the developing human brain.

Scientists have successfully grown organoids with cellular structures similar to those of human brains. However, none of the previous models developed human-like functional neural networks. Networks appear when neurons are mature and become interconnected, and they are essential for most brain activities.

"You can use brain organoids for several things, including understand normal human neurodevelopment, disease modeling, brain evolution, drug screening, and even to inform artificial intelligence," Muotri says.

Muotri and colleagues designed a better procedure to grow stem cells, including optimizing the culture medium formula. These adjustments allowed their organoids to become more mature than previous models. The team grew hundreds of organoids for 10 months and used multi-electrode arrays to monitor their neural activities.

The team began to detect bursts of brain waves from organoids at about two months. The signals were sparse and had the same frequency, a pattern seen in very immature human brains. As the organoids continued to grow, they produced brain waves at different frequencies, and the signals appeared more regularly. This suggests the organoids have further developed their neural networks.

"This is a result of having more functional synapses, and you are forming more connections between the neurons," Muotri says. The interactions between neurons contribute to signals at various frequencies, he says.

To compare the brain wave patterns of organoids with those of human brains early in development, the team trained a machine learning algorithm with brain waves recorded from 39 premature babies between six and nine-and-a-half months old. The algorithm was able to predict how many weeks the organoids have developed in culture, which suggests these organoids and human brain share a similar growth trajectory.

However, it's not likely these organoids have mental activities, such as consciousness, Muotri says. "The organoid is still a very rudimentary model -- we don't have other brain parts and structures. So these brain waves might not have anything to do with activities in real brains."

"It might be that in the future, we will get something that is really close to the signals in the human brains that control behaviors, thoughts, or memory," Muotri says. "But I don't think we have any evidence right now to say we have any of those."

Looking forward, the team aims to further improve the organoids and use them to understand diseases associated with neural network malfunctioning, such as autism, epilepsy, and schizophrenia.

"As a scientist, I want to get closer and closer to the human brain," Muotri says. "I want to do that because I see the good in it. I can help people with neurological conditions by giving them better treatments and better quality of life. But it's up to us to decide where the limit is. It might be that the technology is not ready yet, or we don't know how to control the technology. This is the same kind of discussion around CRISPR in babies, and that's why we have ethics committees to represent all parts of the society."

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Materials provided by Cell Press. Note: Content may be edited for style and length.