A team of HSCI stem cell researchers has succeeded in reprogramming adult mouse skin cells directly into the type of motor neurons damaged in amyotrophic lateral sclerosis (ALS), best known as Lou Gehrig’s disease, and spinal muscular atrophy (SMA). These new cells, which researchers are calling induced motor neurons (iMNs), can be used to study the development of the paralyzing diseases and to develop treatments for them.
Producing motor neurons this way is much less labor intensive than having to go through the process of creating induced pluripotent stem (iPS) cells, and is so much faster than the iPS method that it potentially could reduce by a year the time it eventually takes to produce treatments for ALS and SMA, according to HSCI Principal Faculty member Kevin Eggan, PhD, leader of the Harvard team.
The work builds on and advances work by Douglas Melton, PhD, Co-Director of HSCI, who pioneered direct cellular reprogramming, and Marius Wernig, MD, PhD, of Stanford, who used direct reprogramming to produce generalized neurons.
In a paper published in the scientific journal Cell Stem Cell, the Eggan team reports that the cells they are calling iMNs appear to be fully functional. When placed in the spinal cord of a chicken embryo, the iMNs settle into the cord and send out their projections to connect with muscles.
“That’s a unique thing,” Eggan said. “We showed [that] they have contact with muscle cells and make synapses with them.”
“When the iMN cells were placed in a lab dish with muscle cells, they made what appeared to be normal contact,” Eggan said, “and when we add curare to the dish, that contact stops over time — which is exactly what curare (a paralyzing agent) does in nature; it is an antagonist to the receptors on the muscle cells.”
“One of the utilities [of this new method for producing motor neurons] is it makes a much more rapid way to grow motor neurons. This could allow us to test very rapidly whether a new therapeutic is likely to be effective,” Eggan said. “Realistically, it takes about a year for us to create an iPS cell line; this [approach] takes weeks.”
Explaining how this success was built on previous discoveries and how scientists build on each other’s work, Eggan said, “We had been taking fibroblasts from mouse embryos and were able occasionally, rarely, ... to turn those cells into motor neurons using a set of factors we developed. We were struggling. And at that moment, Marius Wernig came up with a system for what I would call making generic neurons; they were electrically active, they looked like neurons, but they didn’t have the properties you could assign to any neural cell type. But when we combined our factors with his factors, it allowed us to go on and make motor neurons.”