A ‘cocktail’ recipe for brain cells

Jeffrey Macklis.

Photo by Grace DuVal

Science & Tech
A ‘cocktail’ recipe for brain cells

Kermit Pattison

Harvard Staff Writer

February 10, 2026 5 min read

Stem cell biologists discover how to regenerate type damaged in ALS, spinal cord injuries

Harvard stem cell biologists have discovered a way to grow the type of brain cells that degenerate in patients with amyotrophic lateral sclerosis (ALS) and suffer damage in spinal cord injuries.

In a paper published in the journal eLife, researchers engineered a cocktail of molecular signals to coax some “progenitor cells” — precursors that can differentiate into other cell types — to generate corticospinal neurons (CSNs), brain cells vital to voluntary motor control.

“The exciting thing about this progenitor population is that it’s already distributed throughout the brain,” said Jeffrey Macklis, Max and Anne Wien Professor of Life Sciences in the Department of Stem Cell and Regenerative Biology and Center for Brain Science. “They’re sitting there — resident stem cells.”

The new study offers the first-ever model for growing corticospinal neurons in the lab, opening new windows for researching and potentially regenerating neurons for two devastating neurological afflictions.

In ALS, also known as Lou Gehrig’s disease, these neurons die for reasons that remain unknown and eventually patients become paralyzed. The disease afflicts some 30,000 people in the U.S.

In spinal cord injuries, CSNs suffer damage when the long axons — which extend up to one meter long from the brain to the lower spinal cord — are crushed. About 300,000 Americans currently live with spinal cord injuries.

Many tissues such as skin, bones, and blood can regenerate themselves throughout the lifespan. Most regions in the brain and the spinal cord, however, cannot replace lost or damaged neurons, making neurodegenerative diseases and spinal cord injuries irreversible.

Derived from stem cell lineages, progenitors are “multipotent” cells that develop into other types of cells within specific body parts such as muscles, blood, or organs.

In contrast to embryonic stem cells — which theoretically can give rise to any cell type —progenitor cells are much more advanced on the path to becoming specific cell types with a more limited range of outcomes. That also provides an advantage: Progenitors are already partially programmed and close to their appropriate locations.

“They’re poised,” said Macklis, who is also a professor of neurology at Harvard Medical School. “They’ve already gone through a range of developmental steps that we don’t need to orchestrate in a dish or in a brain for regeneration in future experiments.”

In the new study, the researchers worked with a newly discovered subset of progenitor known as NG2 cells in the cerebral cortex that normally produce oligodendroglia, a cell that wraps a fatty substance called myelin around nerve axons that serves like insulation on electrical wires.

A lab-grown neuron engineered by the Macklis lab shows the cell body top extending a long axon.

Photo by Ozkan Padmanabhan

Unlike neurons, oligodendrocytes can renew themselves throughout adulthood. For years, biologists have suspected that some unknown subset of these NG2 progenitor cells might retain the dormant capacity to produce neurons, but this capability remains repressed in adult brains.

The Macklis team sought to reawaken this capability. First, researchers purified cultures of cells called SOX6+/NG2+ progenitors. Then they introduced a set of molecular signals (some that stimulated certain cellular responses and others that blocked undesired responses) to reproduce how the neurons formed during embryonic development.

“And lo and behold,” said Macklis, “unlike anything that people have published before, they send out one long axon, and they look like the right kind of neuron.”

“And lo and behold, unlike anything that people have published before, they send out one long axon, and they look like the right kind of neuron.”
Jeffrey D. Macklis

In subsequent tests, these cells bore all the morphological, molecular, electrophysiological characteristics of normal CSN cells and expressed the same genes. A separate commentary in the journal called the new approach a “perfect recipe” for making these neurons and reprogramming cells “with the goal to repair the brain.”

These cells provide the best-yet model for researching the mechanisms of diseases involving corticospinal neurons. Brain cells are extraordinarily specialized, which creates “selective vulnerability” — diseases that afflict only specific types of neurons. Consequently, specific cellular models are essential for deciphering how brain cells go wrong.

“There are thousands of different types of neurons in the brain,” said co-lead author Kadir Ozkan, a former postdoc in the Macklis Lab. “Each cell type has a different vulnerability to a given gene mutation. Because of that, we cannot study a disease using just any neuron we are able to generate — we need the right neuron type.”

The study demonstrates this cellular reprogramming only in vitro, and further research will determine whether these approaches can be transferred to the brains of living model animals and to human stem cell-derived neurons.

“This is by no means the most fully optimized cocktail,” said co-lead author Hari Padmanabhan, a former postdoc in the Macklis lab. “This is our first-generation approach — and it works. I’m confident that the Macklis Lab and others will be able to tweak both the composition of the cocktail, the dosing, the timing, and all these things, to make it even better.”

The new approach also opens a path to potential regenerative therapies, such as transplantation of lab-grown neurons or stimulated neurogenesis in living brains. Macklis says he can foresee such experiments in mice within a few years and, in the more distant future, perhaps humans too.

“If Aladdin came out of the lamp and asked me for my scientific wish,” said Macklis, “my dream experiment would not be to build these neurons in a dish and transplant them. It would to be to bring these types of regulatory controls to bear and activate desired neuron birth and circuit regeneration in situ — right in the brain.”