How ‘Dancing Molecules’ Can Improve the Way We Study Neurodegenerative Disease

The Context: Turning patient stem cells into the different cell types of the brain offers immense promise for studying and treating neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and multiple sclerosis. However, a brain cell made from a stem cell is a bit more like a baby brain cell than an adult one. To better use stem cell-derived brain cells in research and treatment, scientists need tools to make these cells ‘mature in a dish.’

The Study: Researchers have developed a technique that employs ‘dancing molecules’ to create more mature neurons from stem cells than standard methods have achieved. The study, led by NYSCF – Robertson Stem Cell Investigator Evangelos Kiskinis, PhD, of Northwestern University appears in Cell Stem Cell.

The Importance: These mature cells provide a more accurate window into neurodegenerative diseases, and the ‘dancing molecules’ technique could one day be leveraged to treat patients by replacing damaged neurons with healthy ones.

“When you have an iPSC that you manage to turn into a neuron, it’s going to be a young neuron,” added Samuel Stupp, PhD, co-corresponding author of the study in an article from Northwestern. “But, in order for it to be useful in a therapeutic sense, you need a mature neuron. Otherwise, it is like asking a baby to carry out a function that requires an adult human being.” 

“This is the first time we have been able to trigger advanced functional maturation of human induced pluripotent stem cell (iPSC)-derived neurons by plating them on a synthetic matrix,” said Dr. Kiskinis.

“It’s important because there are many applications that require researchers to use purified populations of neurons. Most stem cell-based labs use mouse or rat neurons co-cultured with human stem cell-derived neurons. But that does not allow scientists to investigate what happens in human neurons because you end up working with a mixture of mouse and human cells.”

Dancing Molecules Make Mature Neurons

The team decided to employ a technique Dr. Stupp developed last year to create mature neurons from stem cells. First, the team turned the stem cells into two types of neurons – motor and cortical neurons – then stationed them on synthetic nanofibers containing the ‘dancing molecules.’ These rapidly moving molecules are meant to simulate the environment of the central nervous system, allowing the cells to mature how they would in the body.

Excitingly, the neurons showed features of mature cells, including enhanced abilities to branch out and form connections. The cells also managed not to clump together: a common issue with stem cell-derived neurons that can make them challenging to maintain.

“We have confirmed that neurons coated with our nanofibers achieve more maturity than other methods, and mature neurons are better able to establish the synaptic connections that are fundamental to neuronal function,” noted Dr. Stupp.

Creating Aged ALS Neurons

The scientists then tested the method on stem cell-derived motor neurons – the cells impacted by ALS – created from an ALS patient. The cells matured in the dancing molecules, and the team found that they still exhibited hallmarks of ALS, including protein aggregation in the neurons that normally occurs in adulthood. This provides a clearer window into how mature neurons are impacted in this disease, which typically manifests in individuals over 55. 

“For the first time, we have been able to see adult-onset neurological protein aggregation in the stem cell-derived ALS patient motor neurons. This represents a breakthrough for us,” said Dr. Kiskinis. “It’s unclear how the aggregation triggers the disease. It’s what we are hoping to find out for the first time.”

What’s Next?

The team hopes their technique will help labs create neurons that can be used to study neurodegenerative diseases more accurately and comprehensively. 

They also believe that with more development, the mature neurons could be potentially used to treat conditions of the central nervous system like Alzheimer’s, ALS, Parkinson’s, multiple sclerosis, or spinal cord injury.

“We could integrate our coating into large-scale manufacturing of patient-derived neurons for cell transplantation therapies without immune rejection,” remarked Dr. Stupp.

“Cell replacement therapy can be very challenging for a disease like ALS, as transplanted motor neurons in the spinal cord will need to project their long axons to the appropriate muscle sites in the periphery but could be more straightforward for Parkinson’s disease,” said Dr. Kiskinis. “Either way this technology will be transformative.” 

Journal Article

Artificial extracellular matrix scaffolds of mobile molecules enhance maturation of human stem cell-derived neurons
Zaida Álvarez, J. Alberto Ortega, Kohei Sato, Ivan R. Sasselli, Alexandra N. Kolberg-Edelbrock, Ruomeng Qiu, Kelly A. Marshall, Thao Phuong Nguyen, Cara S. Smith, Katharina A. Quinlan, Vasileios Papakis, Zois Syrgiannis, Nicholas A. Sather, Chiara Musumeci, Elisabeth Engel, Samuel I. Stupp, Evangelos Kiskinis. Cell Stem Cell. 2023. DOI: https://doi.org/10.1016/j.stem.2022.12.010

Cover image: Fluorescent images of human neurons (stained with red, green and blue) growing on coatings with fast-moving molecules (left) or conventional laminin (right) for 60 days. Neurons spread homogenously and showed more complex branching on the highly mobile coating. Credit: Northwestern University