Using stem cells from patients with ALS (amyotrophic lateral sclerosis), Cedars-Sinai has created a lifelike model of the mysterious and fatal disease that could help identify a cause of the illness as well as effective treatments.
In a study published in the peer-reviewed journal Cell Stem Cell , investigators detail how they created "ALS on a chip" and the clues the specialized laboratory chip has already produced about nongenetic causes of the disease, also known as Lou Gehrig's disease.
The work builds on previous studies where adult cells from ALS patients were reverted into stem cells. The cells were then pushed forward to produce motor neurons, which die in the disease, causing progressive loss of the ability to move, speak, eat and breathe.
In this study, the motor neurons from ALS patients were seeded into the top channels of microengineered chips. Cells that make up the blood-brain barrier were seeded into the bottom channels of the chips. The two channels are connected through a porous membrane that allows investigators to flow fluids through the chips in order to mimic blood flow.
Investigators created a second group of the specialized chips using cells from individuals who did not have ALS, then used advanced technologies to analyze more than 10,000 genes in the motor neurons in both groups of chips.
"In our early work, we couldn't detect many differences between the motor neurons of patients with ALS and those from healthy individuals," said Clive Svendsen, PhD , executive director of the Board of Governors Regenerative Medicine Institute at Cedars-Sinai and senior author of the study. "But those studies employed traditional lab culture that is static like a pond. In the body, blood vessels provide constant fluid flow to bring in nutrients and take away waste—and may even provide other types of support to motor neurons."
In the specialized chips, the motor neurons matured more completely than they would in a static dish, and investigators could detect distinct differences in the cells from patients with ALS.
"We were intrigued to find that signaling for glutamate, a chemical that sends excitatory messages between neurons, was altered in the ALS motor neurons," Svendsen said. "Excessive release of glutamate has long been considered a possible cause of ALS, and one of the few drugs approved to treat the disease targets this neurotransmitter. The changes we found don't seem to cause any issues for the motor neurons when they are young, but over many years it is possible that this increased glutamate signaling may be part of why motor neurons die in ALS."
Svendsen said that while these results are exciting, the team's next task is to determine whether this increased glutamate signaling directly leads to the dysfunction or death of the cells. He also noted that glutamate is likely only one piece in a much larger puzzle that underlies the cause of ALS.
"These models allow us to better understand the very earliest stages of the disease process," Svendsen said. "We haven't connected all the dots yet, but based on these findings we have a model that will allow us to test our theories. If we can show that glutamate signaling eventually makes the ALS motor neurons sick, for instance, we can apply drugs to the blood vessel side of the chip to mimic a clinical trial. Those experiments are underway."
Additional authors include Deepti Lall, Michael Workman, Samuel Sances, Briana N. Ondatje, Shaughn Bell, George Lawless, Amanda Woodbury, Dylan West, Amanda Meyer, Andrea Matlock, Vineet Vaibhav, and Jennifer E. Van Eyk.
Funding: This work was supported by NIH-NCATS grants 1UG3NS105703-01 and 1UG3TR003264-01, and funding from The ALS Association.
Cedars-Sinai owns a minority stock interest in Emulate, the company that produces the study's microfluidic Organ-Chips. An officer of Cedars-Sinai also serves on Emulate's Board of Directors. C.N.S serves on the advisory board of Cell Stem Cell.
