Stem cell-derived 'organoids' help predict neural toxicity

September 21, 2015 by Brian Mattmiller, Morgridge Institute for Research
Confocal microscopy image illustrating long range organization for neurons (green) and nuclei (blue) within a developing neural construct. The neural tissues were removed from the inserts and placed on a glass bottom petri dish for imaging. Credit: Michael Schwartz, UW-Madison Department of Biomedical Engineering

A new system developed by scientists at the Morgridge Institute for Research and the University of Wisconsin-Madison may provide a faster, cheaper and more biologically relevant way to screen drugs and chemicals that could harm the developing brain.

Reporting in the Sept. 21, 2015 issue of the Proceedings of the National Academy of Sciences (PNAS), the team describes a new approach for predicting developmental neurotoxicity that uses stem cells to model features of the developing that could be targeted by toxic chemicals or drugs.

The research also is important to addressing growing concerns about the rising incidence worldwide of neurodevelopmental disorders such as autism and the potential role of environmental chemicals.

First, the team produced a model human by culturing stem cell-derived , , and microglia on engineered hydrogels. These precursor cells self-assembled into three-dimensional neural tissue constructs with features that resemble the developing human brain. Such tissues are often referred to as "organoids."

"Several things about this project surprised us," says Michael Schwartz, an assistant scientist in biomedical engineering at UW-Madison and co-lead author of the study with Zhonggang Hou of the Morgridge Institute (now a researcher at Harvard University). "In the beginning, we weren't expecting the kind of complex neural tissues that were ultimately developed."

RNA-sequencing data was collected from neural tissue constructs that were individually exposed to 60 different "training" chemicals—both safe compounds and known toxins—and machine learning was used to build a predictive model from these results. The algorithm proved remarkably accurate: After training with known chemicals using duplicate samples and two time points (240 neural constructs in total), the model correctly classified nine out of 10 additional chemicals in a blinded trial.

Confocal microscopy image illustrating neurons (green), glial cells (red), and nuclei (blue) within a developing neural construct. The neural tissues were removed from the inserts and placed on a glass bottom petri dish for imaging. Credit: Michael Schwartz, Department of Biomedical Engineering, UW-Madison

Schwartz says that this new screening method offers a valuable bridge between testing a single layer of cells in a dish and testing on animals. "These model neural tissues capture a lot more of the complexity than you would find in a monolayer of cells," he says. "They also mimic human physiology, and should be more relevant for predicting toxicity than animal models. The fact that we could apply a machine learning model to achieve 90 percent accuracy this early in the process is fantastic."

This project reflects a diverse collaboration between the Morgridge Institute's regenerative biology team, led by stem cell pioneer James Thomson, and leading UW-Madison experts in tissue engineering and machine learning.

Biomedical Engineering Professor William Murphy led the development of synthetic "hydrogels," or matrices that enable stem cells to grow naturally and self-assemble into a complex network of tissues. And Biostatistics and Medical Informatics Professor David Page developed the using two types of holdout-testing methods.

Thomson says the Wisconsin project has potential to improve drug testing, but with more than 100,000 mostly untested chemical compounds used in commerce, the impact could be even greater for screening chemicals.

"The current toxicity screening tests use multi-generational rat studies and cost about $1 million to test one chemical," he says. "So we need a really high-throughput way to test these compounds, figure out which ones may be the bad actors, then focus on those with more traditional methods."

Three-dimensional organization within the neural constructs: Confocal microscopy image illustrating endothelial cells (green), glial cells (red), and nuclei (blue). The neural tissues were removed from the inserts and placed on a glass bottom petri dish for imaging. Credit: Michael Schwartz, UW-Madison Department of Biomedical Engineering

Schwartz says the RNA sequencing data generated by this study will be beneficial to future studies by helping to identify potential toxic profiles or fingerprints. "These datasets provide valuable information about changes in gene expression that researchers can mine to better understand mechanisms that might be disrupted during human brain development," he says.

One unique element of the project is the level of consistency achieved across hundreds of samples—especially given the cellular diversity of the neural tissue model, which included neurons, glial cells, interconnected vascular networks, and microglia, which is the immune cell of central nervous system. The neural tissue constructs developed in this project are the first to incorporate vascular and microglial components into a 3D model of brain development derived from human pluripotent .

The synthetic material used to help the tissues grow was a key part of the early success of this work. "These hydrogels are minimally complex in that they only present peptides that allow the cells to attach and degrade the matrix. The cells will do the rest of the work on their own—biology does a better job forming tissues than we do," Schwartz says.

In the original proposal, Thomson notes that "if appropriately specified, are brought together in the right environment, a degree of self-assembly, differentiation, and maturation will occur." The synthetic materials used to culture the were key to achieving the consistency needed to successfully screen so many samples.

Explore further: Developing 'tissue chip' to screen neurological toxins

More information: Human pluripotent stem cell-derived neural constructs for predicting neural toxicity, www.pnas.org/cgi/doi/10.1073/pnas.1516645112

Related Stories

Developing 'tissue chip' to screen neurological toxins

September 23, 2014
A multidisciplinary team at the University of Wisconsin-Madison and the Morgridge Institute for Research is creating a faster, more affordable way to screen for neural toxins, helping flag chemicals that may harm human development.

Most complete human brain model to date is a 'brain changer'

August 18, 2015
Scientists at The Ohio State University have developed a nearly complete human brain in a dish that equals the brain maturity of a five-week-old fetus.

New way to repair nerves: Using exosomes to hijack cell-to-cell communication

September 15, 2015
Regenerative medicine using stem cells is an increasingly promising approach to treat many types of injury. Transplanted stem cells can differentiate into just about any other kind of cell, including neurons to potentially ...

Reconstructing 3D neural tissue with biocompatible nanofiber scaffolds and hydrogels

April 1, 2015
Damage to neural tissue is typically permanent and causes lasting disability in patients, but a new approach has recently been discovered that holds incredible potential to reconstruct neural tissue at high resolution in ...

New advancements in 3D designs for neural tissue engineering

April 6, 2015
It is well known that neurological diseases and injuries pose some of the greatest challenges in modern medicine, with few if any options for effectively treating such diagnoses, but recent work suggests a unique approach ...

Recommended for you

Scientists discover the region of the brain that registers excitement over a preferred food option

October 19, 2018
At holiday buffets and potlucks, people make quick calculations about which dishes to try and how much to take of each. Johns Hopkins University neuroscientists have found a brain region that appears to be strongly connected ...

Gene plays critical role in noise-induced deafness

October 19, 2018
In experiments using mice, a team of UC San Francisco researchers has discovered a gene that plays an essential role in noise-induced deafness. Remarkably, by administering an experimental chemical—identified in a separate ...

How clutch molecules enable neuron migration

October 19, 2018
The brain can discriminate over 1 trillion odors. Once entering the nose, odor-related molecules activate olfactory neurons. Neuron signals first accumulate at the olfactory bulb before being passed on to activate the appropriate ...

Brain cells called astrocytes have unexpected role in brain 'plasticity'

October 18, 2018
When we're born, our brains have a great deal of flexibility. Having this flexibility to grow and change gives the immature brain the ability to adapt to new experiences and organize its interconnecting web of neural circuits. ...

Weight loss success linked with active self-control regions of the brain

October 18, 2018
New research suggests that higher-level brain functions have a major role in losing weight. In a study among 24 participants at a weight-loss clinic, those who achieved greatest success in terms of weight loss demonstrated ...

How the brain makes rapid, fine adjustments in motor activity

October 18, 2018
Short-term motor learning appears not to require physical change in the brain Brain's premotor cortex may use a 'neural scratch pad' to calculate fine adjustments Brain can try different things in simulation without 'screwing ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.