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Single-Cell, Spatial Genomics Studies Unravel Development of Fetal Spinal Cord

NEW YORK — A pair of new studies by independent research teams has shed light on the different cell types that come together to form the fetal human spinal cord and how the fates of these cell types are decided. The two groups also uncovered how the human spinal cord development process differs from that of rodents.

The human spinal cord is part of the central nervous system and is essential to communication between the brain and the body. Studies on its development can help in understanding disorders that result from spinal cord injury and some forms of pediatric cancers.

For the first of the studies, published in Nature Neuroscience on Monday, researchers from Stanford University and their colleagues performed single-cell and single-nucleus RNA sequencing on four samples of developing human spinal cords from gestational weeks 17 and 18. They obtained transcriptomes for 112,554 cells and 34,884 nuclei.

"A common theme that emerged through our analysis was the existence of a transcriptional positional identity code governing cell diversity," the authors wrote. "Our data suggest that the acquisition of positional identity is a common fundamental principle guiding patterning in the spinal cord beyond neuronal specification."

While it has been known that astrocytes in rodent spinal cords are spatially and functionally heterogeneous, the researchers wanted to learn if the same holds true for humans.

Using immunohistochemistry, they found nine clusters of astrocytes along two axes of developing human spinal cords. While the first axis of diversity corresponded to dorso-ventral positioning, the second axis corresponded to white matter and gray matter astrocytes.

They also found different gene expression patterns among protoplasmic and fibrous astrocytes in human samples. Protoplasmic astrocytes are distributed relatively uniformly within cortical gray matter, whereas fibrous astrocytes are organized along white matter tracts. The findings also suggested that protoplasmic astrocytes acquired their identity before fibrous ones.

According to the authors, sampling at earlier timepoints could also help determine the relationship between some of the cell types. "How these astrocytes are generated during development or if they are derived from a common progenitor remains unknown," they noted.

Meanwhile, the researchers compared the diversification of motor neurons into alpha and gamma cells and found marked differences between mice and humans. "Our analysis suggests that diversification of motor neurons into alpha and gamma takes place in early fetal development, while the earliest evidence of this diversification in the mouse has been described at embryonic day 17.5," the authors wrote.

The authors integrated their findings with previously published datasets on human developing spinal cord spanning 22 weeks of gestation to validate their findings. "This dataset represents a comprehensive resource for exploring the biology of the human spinal cord over time," they wrote.

For the other study, also published in Nature Neuroscience on Monday, researchers from the Karolinska Institute and Stockholm University in Sweden, along with their collaborators, conducted single-cell RNA sequencing and spatial transcriptomics analyses on 16 prenatal human spinal cord samples, ranging from week five to 15 of gestation.

Using this data, the researchers created a comprehensive map of all cell types and states in the human developing spinal cord, revealing their locations and specific gene expression.

"In the long run, this discovery will help the development of new therapies for different diseases and pediatric tumors in the human spinal cord," said co-corresponding author Xiaofei Li, an assistant professor in the stem cell biology department at the Karolinska Institute, in an email.

The study also found remarkable differences between the development of mice and human spinal cords.

While previous mice studies had shown that neural stem and progenitor cells (NPCs) proliferate highly during fetal development, the researchers found that many human NPCs did not proliferate even at the early embryonic stage. "The proliferative NPCs lose their proliferation during the first trimester in humans, much earlier than in rodents," the authors wrote, adding that this loss of active NPCs after fetal development limits regeneration in the mammalian adult spinal cord — for example, after spinal cord injury.

The researchers also found other differences between mice and human spinal cord development. One of them was that unlike rodent astrocytes, which migrate horizontally during development to the mantle zone and the future lateral white matter, human astrocytes were first restricted to the dorsal region of the spinal cord.

The authors also noted that many regulons — groups of genes that are regulated as a unit — were only present in human but not mouse spinal cords, suggesting that neurodevelopment is regulated differently between the two species.

Next, the researchers used their developmental atlas of the human spinal cord to investigate gene expression in childhood spinal ependymomas, a cancer type with high recurrence rate, probably due to the proliferation of drug-resistant pediatric spinal cancer stem cells (CSCs). The authors studied differences in gene expression between CSCs and normal stem cells and discovered potential targets for ependymoma diagnosis and treatment.

"Our database will not only serve as a developmental cell atlas resource but also provide important information for research on human neurodevelopmental disorders as well as regenerative strategies and cancer treatments," the authors concluded.

According to Li, due to the limited samples, the study only focused on first trimester development. In the future, he said his team plans to include human spinal cord samples from postnatal timepoints.