is at the top, with the nucleus in yellow-green (green fluorescent protein overlaid by red) and the soma cytoplasm and multiple spiky dendrites in red. The extremely long, red axon can be seen meandering toward the bottom, led by its growth cone (green). Credit: Ozkan, Padmanabhan et al. (CC BY 4.0)“) A progenitor-derived corticospinal-like neuron in cell culture, extending its long axon, even in isolation. The cell body (or "soma"; immunolabeled by Tuj1 antibody in red) is at the top, with the nucleus in yellow-green (green fluorescent protein overlaid by red) and the soma cytoplasm and multiple spiky dendrites in red. The extremely long, red axon can be seen meandering toward the bottom, led by its growth cone (green). Credit: Ozkan, Padmanabhan et al. (CC BY 4.0)

Researchers have developed a way to grow a highly specialized subset of brain nerve cells that are involved in motor neuron disease and damaged in spinal injuries. Their study, published today in eLife, presents fundamental findings on the directed differentiation of a rare population of special brain progenitors—also known as adult or parent stem cells—into corticospinal-like neurons. The editors note that the work provides compelling data demonstrating the success of this new approach.

The findings set the stage for further research into whether these molecularly directed neurons can form functional connections in the body, and to explore their potential use in human diseases where corticospinal neurons are compromised.

Why these vulnerable neurons matter

The nervous system comprises diverse neurons with many distinctive features including shape, anatomical position, connections to other neurons (their circuitry), the genes they express, patterns of electrical conductivity, and ultimately their function. These unique subpopulations of neurons arise from tightly controlled and precise differentiation processes that direct them to transition from immature nerve stem cells to fully mature, specialized neurons. Because they are so specialized, such distinct "subtypes" of neurons are often particularly vulnerable to, or associated with neurodegenerative injuries or diseases.

"To realistically model diseases and screen for potential treatments, or to regenerate neurons that are damaged in spinal injuries, we need reliable approaches to accurately differentiate progenitor cells into these specific types of neurons," explains co-lead author Kadir Ozkan, who at the time of the study was a Postdoctoral Fellow in senior author Jeffrey Macklis’ lab at the Department of Stem Cell and Regenerative Biology, and Center for Brain Science, Harvard University, Cambridge, US.

"Generic or regionally similar neurons do not adequately reflect the selective vulnerability of neuron subtypes in most human neurodegenerative diseases or injuries."

Corticospinal neurons in disease and injury

Corticospinal neurons are crucial cells that degenerate in amyotrophic lateral sclerosis (ALS), the most common form of motor neuron disease. Damage to these cells’ long axons—the extensions that connect from the cell bodies in the brain through the spinal cord to their target spinal motor neurons—underlies the loss of voluntary and skilled movement seen in people with spinal cord injuries.

"There are currently no appropriate in vitro models for investigating the selective vulnerability and degeneration of corticospinal neurons in ALS or to explore potential routes to regeneration in spinal cord injury," says senior author Jeffrey Macklis, the Max and Anne Wien Professor of Life Sciences in the Department of Stem Cell and Regenerative Biology, and Center for Brain Science, Harvard University. "This critically limits the relevance of much existing research."

Building on earlier cortical circuitry work

Previous work from the Macklis Lab and others has identified central molecular programs that first broadly, and then with increasing precision, control and regulate the specification, diversity and connectivity of specific neuron subtypes in the cerebral cortex during the period of their differentiation. Building on that work, the team has identified a subset of progenitor cells in the postnatal and adult cortex that can be captured and differentiated in the lab into neurons with unique characteristics of corticospinal neurons.

"Knowing that a subset of early progenitors and glial cells in the cortex share a common ancestry with cortical ‘projection neurons,’ we hypothesized that some of these progenitors might retain dormant neurogenic potential—that is, the potential to differentiate into neurons," explains co-lead author Hari Padmanabhan, who was also a Postdoctoral Fellow in the Macklis Lab at the time of the study.

The team found that a subset of progenitor cells producing two important regulatory molecules, Sox6 and Neuron/Glia Antigen 2 (Sox6+/NG2+ cells), are poised to develop into neurons. "We wanted to grow these cortical SOX6+/NG2+ progenitors in the lab and see if we could direct their differentiation into corticospinal neurons."

A new gene-programming strategy in the lab

To achieve this, the team designed a multi-component gene-expression system termed "NVOF" to precisely fine tune the regulatory signals the progenitor cells require. The system enabled them to drive cells down a highly specific differentiation route where they acquire the hallmark characteristics of corticospinal neurons, rather than the features of other types of central nervous system neurons.

As they anticipated, the NVOF programming produced mature neurons from the progenitors with the same distinct shape, key cell markers, molecular-gene expression, and electrical connectivity as seen in native corticospinal neurons. By contrast, a widely employed approach to differentiate neuron-like cells by switching on just the Neurogenin2 gene resulted in cells of a mixed identity with abnormal forms (morphology) and molecular features.

Next steps toward therapies and models

eLife’s editors note that, as the study demonstrates reprogramming in vitro only—that is, not using living model organisms—future research is needed to assess how these reprogrammed corticospinal neurons integrate and function under physiological conditions and in models of trauma or neurodegeneration.

"We have identified a subset of cortical progenitor cells with strong potential to differentiate into specialized neurons for disease modeling in ALS and spinal cord injury, and for regenerative therapies," concludes Macklis.

"Importantly, SOX6+/NG2+ progenitor cells are widely distributed in the cortex, already positioned near sites of degeneration or pathology. This adds substantially to their therapeutic potential, pending further study, including with human pluripotent stem cell-derived cortical progenitors."

Publication details

Directed differentiation of functional corticospinal-like neurons from endogenous SOX6+/NG2+ cortical progenitors, eLife (2026). DOI: 10.7554/eLife.100340.3

Journal information: eLife

Clinical categories

Neurology

Citation: Scientists grow specialized nerve cells that degenerate in ALS and are damaged in spinal cord injury (2026, January 27) retrieved 27 January 2026 from https://medicalxpress.com/news/2026-01-scientists-specialized-nerve-cells-degenerate.html

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