Researchers chart human glial cell maturation

A new study published in Nature Communications shows that human glial progenitor cells are a promising and safe cell product for transplantation. The research also defines the transcriptional and epigenetic signatures of these cells as they mature into astrocytes and oligodendrocytes, two essential support cell types in the brain.

“We believe that glia are particularly divergent compared to other species,” said lead study author John Mariani, Ph.D., a neuroscientist with University of Rochester Medicine and the first author of the new paper.

“For this study, we grow these cells in vitro, and then we transplant them. We wanted to know what they look like before we transplant them and what they look like after. This sets the stage for long-term manipulation of these cells to engraft better, to respond better to the cues, and understand this process better, since it is an approach we are pursuing for cell therapies.”

This transplantation model may have implications for disorders such as multiple sclerosis, leukodystrophies, and Huntington’s disease, in which myelination, the insulating process that helps nerve cells communicate efficiently, is disrupted.

Glial progenitor cells as a cell therapy

The loss of functional astrocytes and oligodendrocytes can lead to a variety of neurological disorders. Glial progenitor cells (GPCs) are precursor cells that can differentiate into mature astrocytes and oligodendrocytes. Because of this potential, GPCs have been studied as a potential cell therapy for glial diseases, and Steve Goldman, MD, Ph.D., and his lab have long been leaders in this area.

Transplanting pluripotent stem cells directly into mice or humans can be dangerous, causing a teratoma to form, a benign tumor that can cause severe neurological complications by occupying critical space in the brain.

In the new study, the GPCs showed no pluripotent signatures in culture, and mature identity persisted after transplantation into mice, indicating that the cells were highly specified, functional, and safe.

A transcriptional and epigenetic map

Researchers began by growing GPCs in vitro and used single-cell RNA and ATAC sequencing to create a comprehensive, genome-wide molecular blueprint of these cells. They found that the GPCs in culture were mature, as evidenced by their lack of pluripotent markers and by remodeling of gene expression as the cells transitioned into specific cell types, thereby activating the cells’ proper function.

The researchers then transplanted the cells into a chimeric, immunodeficient, myelin-deficient mouse model developed in Goldman’s lab, placing the cells in the corpus callosum, the brain’s largest white matter structure. The human glial cells eventually outcompeted and replaced the dysfunctional mouse glial cells and began remyelinating the brain.

Remarkably, the human GPCs extracted back from the mice after engraftment showed a pronounced shift in identity. The GPCs showed strong differentiation and mature astrocyte and oligodendrocyte cell profiles, suggesting that “the cues in the mouse are very good at tightening these cells up to behave,” explained Mariani.

Within the tissue microenvironment, the researchers also identified genes, pathways, and networks that may be responsible for the maturation of the cells to astrocytes and oligodendrocytes.

These networks have strong implications for future studies aimed at understanding how cells respond post-transplantation and how to modulate these cells for the treatment of glial diseases.

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Sadie Harley

BSc Life Sciences & Ecology. Microbiology lab background with pharmaceutical news experience in oil, gas, and renewable industries.

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Andrew Zinin

Master’s in physics with research experience. Long-time science news enthusiast. Plays key role in Science X’s editorial success.

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