Single-cell transcriptomic landscape of the developing human spinal cord

doi:10.1038/s41593-023-01311-w

. 2023 May;26(5):902-914.

doi: 10.1038/s41593-023-01311-w. Epub 2023 Apr 24.

Single-cell transcriptomic landscape of the developing human spinal cord

Jimena Andersen^#^{1

2

3}, Nicholas Thom^#^{1

2}, Jennifer L Shadrach⁴, Xiaoyu Chen^{1

2}, Massimo Mario Onesto^{1

2

5}, Neal D Amin^{1

2}, Se-Jin Yoon^{1

2}, Li Li³, William J Greenleaf^{6

7}, Fabian Müller^{6

8}, Anca M Pașca⁹, Julia A Kaltschmidt⁴, Sergiu P Pașca^{10

11}

Affiliations

¹ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
² Stanford Brain Organogenesis, Wu Tsai Neurosciences Institute, Stanford, CA, USA.
³ Department of Human Genetics, Emory University, Atlanta, GA, USA.
⁴ Department of Neurosurgery, Stanford University, Stanford, CA, USA.
⁵ Neurosciences Graduate Program, Stanford University, Stanford, CA, USA.
⁶ Department of Genetics, Stanford University, Stanford, CA, USA.
⁷ Department of Applied Physics, Stanford University, Stanford, CA, USA.
⁸ Center for Bioinformatics, Saarland University, Saarbrücken, Germany.
⁹ Department of Pediatrics, Division of Neonatology, Stanford University, Stanford, CA, USA.
¹⁰ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA. spasca@stanford.edu.
¹¹ Stanford Brain Organogenesis, Wu Tsai Neurosciences Institute, Stanford, CA, USA. spasca@stanford.edu.

^# Contributed equally.

PMID: 37095394
DOI: 10.1038/s41593-023-01311-w

Single-cell transcriptomic landscape of the developing human spinal cord

Jimena Andersen et al. Nat Neurosci. 2023 May.

. 2023 May;26(5):902-914.

doi: 10.1038/s41593-023-01311-w. Epub 2023 Apr 24.

Authors

Affiliations

¹ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
² Stanford Brain Organogenesis, Wu Tsai Neurosciences Institute, Stanford, CA, USA.
³ Department of Human Genetics, Emory University, Atlanta, GA, USA.
⁴ Department of Neurosurgery, Stanford University, Stanford, CA, USA.
⁵ Neurosciences Graduate Program, Stanford University, Stanford, CA, USA.
⁶ Department of Genetics, Stanford University, Stanford, CA, USA.
⁷ Department of Applied Physics, Stanford University, Stanford, CA, USA.
⁸ Center for Bioinformatics, Saarland University, Saarbrücken, Germany.
⁹ Department of Pediatrics, Division of Neonatology, Stanford University, Stanford, CA, USA.
¹⁰ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA. spasca@stanford.edu.
¹¹ Stanford Brain Organogenesis, Wu Tsai Neurosciences Institute, Stanford, CA, USA. spasca@stanford.edu.

^# Contributed equally.

PMID: 37095394
DOI: 10.1038/s41593-023-01311-w

Abstract

Understanding spinal cord assembly is essential to elucidate how motor behavior is controlled and how disorders arise. The human spinal cord is exquisitely organized, and this complex organization contributes to the diversity and intricacy of motor behavior and sensory processing. But how this complexity arises at the cellular level in the human spinal cord remains unknown. Here we transcriptomically profiled the midgestation human spinal cord with single-cell resolution and discovered remarkable heterogeneity across and within cell types. Glia displayed diversity related to positional identity along the dorso-ventral and rostro-caudal axes, while astrocytes with specialized transcriptional programs mapped into white and gray matter subtypes. Motor neurons clustered at this stage into groups suggestive of alpha and gamma neurons. We also integrated our data with multiple existing datasets of the developing human spinal cord spanning 22 weeks of gestation to investigate the cell diversity over time. Together with mapping of disease-related genes, this transcriptomic mapping of the developing human spinal cord opens new avenues for interrogating the cellular basis of motor control in humans and guides human stem cell-based models of disease.

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References

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[1] Jessell, T. M. Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nat. Rev. Genet. 1, 20–29 (2000). - PubMed - DOI

[2] Jessell, T. M. Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nat. Rev. Genet. 1, 20–29 (2000). - PubMed - DOI

[3] Haim, L. B. & Rowitch, D. H. Functional diversity of astrocytes in neural circuit regulation. Nat. Rev. Neurosci. 18, 31–41 (2017). - PubMed - DOI

[4] Haim, L. B. & Rowitch, D. H. Functional diversity of astrocytes in neural circuit regulation. Nat. Rev. Neurosci. 18, 31–41 (2017). - PubMed - DOI

[5] Monani, U. R. Spinal muscular atrophy: a deficiency in a ubiquitous protein; a motor neuron-specific disease. Neuron 48, 885–896 (2005). - PubMed - DOI

[6] Monani, U. R. Spinal muscular atrophy: a deficiency in a ubiquitous protein; a motor neuron-specific disease. Neuron 48, 885–896 (2005). - PubMed - DOI

[7] Swash, M., Leader, M., Brown, A. & Swettenham, K. W. Focal loss of anterior horn cells in the cervical cord in motor neuron disease. Brain 109, 939–952 (1986). - PubMed - DOI

[8] Swash, M., Leader, M., Brown, A. & Swettenham, K. W. Focal loss of anterior horn cells in the cervical cord in motor neuron disease. Brain 109, 939–952 (1986). - PubMed - DOI

[9] Bergen, V., Lange, M., Peidli, S., Wolf, F. A. & Theis, F. J. Generalizing RNA velocity to transient cell states through dynamical modeling. Nat. Biotechnol. 38, 1408–1414 (2020). - PubMed - DOI

[10] Bergen, V., Lange, M., Peidli, S., Wolf, F. A. & Theis, F. J. Generalizing RNA velocity to transient cell states through dynamical modeling. Nat. Biotechnol. 38, 1408–1414 (2020). - PubMed - DOI

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Single-cell transcriptomic landscape of the developing human spinal cord

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Single-cell transcriptomic landscape of the developing human spinal cord

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