Temporal and Spatial Cellular and Molecular Pathological Alterations with Single-cell Resolution in the Adult Spinal Cord After Injury

Overview

Journal Signal Transduct Target Ther

Specialties Cell Biology
Pharmacology

Date 2022 Mar 2

PMID 35232960

Authors

Chen Li

Zhourui Wu

Liqiang Zhou

Jingliang Shao

Xiao Hu

Wei Xu

Yilong Ren

Xingfei Zhu

Weihong Ge

Kunshan Zhang

Jiping Liu

Runzhi Huang

Jing Yu

Dandan Luo

Xuejiao Yang

Wenmin Zhu

Rongrong Zhu

Changhong Zheng

Yi Eve Sun

Liming Cheng

Affiliations

Soon will be listed here.

Abstract

Spinal cord injury (SCI) involves diverse injury responses in different cell types in a temporally and spatially specific manner. Here, using single-cell transcriptomic analyses combined with classic anatomical, behavioral, electrophysiological analyses, we report, with single-cell resolution, temporal molecular and cellular changes in crush-injured adult mouse spinal cord. Data revealed pathological changes of 12 different major cell types, three of which infiltrated into the spinal cord at distinct times post-injury. We discovered novel microglia and astrocyte subtypes in the uninjured spinal cord, and their dynamic conversions into additional stage-specific subtypes/states. Most dynamic changes occur at 3-days post-injury and by day-14 the second wave of microglial activation emerged, accompanied with changes in various cell types including neurons, indicative of the second round of attacks. By day-38, major cell types are still substantially deviated from uninjured states, demonstrating prolonged alterations. This study provides a comprehensive mapping of cellular/molecular pathological changes along the temporal axis after SCI, which may facilitate the development of novel therapeutic strategies, including those targeting microglia.

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References

Osseward 2nd P, Pfaff S . Cell type and circuit modules in the spinal cord. Curr Opin Neurobiol. 2019; 56:175-184. PMC: 8559966. DOI: 10.1016/j.conb.2019.03.003. View

Thurgur H, Pinteaux E . Microglia in the Neurovascular Unit: Blood-Brain Barrier-microglia Interactions After Central Nervous System Disorders. Neuroscience. 2019; 405:55-67. DOI: 10.1016/j.neuroscience.2018.06.046. View

Duan H, Ge W, Zhang A, Xi Y, Chen Z, Luo D . Transcriptome analyses reveal molecular mechanisms underlying functional recovery after spinal cord injury. Proc Natl Acad Sci U S A. 2015; 112(43):13360-5. PMC: 4629389. DOI: 10.1073/pnas.1510176112. View

Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young J . Single-cell transcriptomic analysis of Alzheimer's disease. Nature. 2019; 570(7761):332-337. PMC: 6865822. DOI: 10.1038/s41586-019-1195-2. View

Pijuan-Sala B, Griffiths J, Guibentif C, Hiscock T, Jawaid W, Calero-Nieto F . A single-cell molecular map of mouse gastrulation and early organogenesis. Nature. 2019; 566(7745):490-495. PMC: 6522369. DOI: 10.1038/s41586-019-0933-9. View

Sathyamurthy A, Johnson K, Matson K, Dobrott C, Li L, Ryba A . Massively Parallel Single Nucleus Transcriptional Profiling Defines Spinal Cord Neurons and Their Activity during Behavior. Cell Rep. 2018; 22(8):2216-2225. PMC: 5849084. DOI: 10.1016/j.celrep.2018.02.003. View

McDonald J, Sadowsky C . Spinal-cord injury. Lancet. 2002; 359(9304):417-25. DOI: 10.1016/S0140-6736(02)07603-1. View

Herrmann J, Imura T, Song B, Qi J, Ao Y, Nguyen T . STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. J Neurosci. 2008; 28(28):7231-43. PMC: 2583788. DOI: 10.1523/JNEUROSCI.1709-08.2008. View

Edgerton V, Harkema S . Epidural stimulation of the spinal cord in spinal cord injury: current status and future challenges. Expert Rev Neurother. 2011; 11(10):1351-3. PMC: 3361963. DOI: 10.1586/ern.11.129. View

10.

Nardone R, Holler Y, Thomschewski A, Bathke A, Ellis A, Golaszewski S . Assessment of corticospinal excitability after traumatic spinal cord injury using MEP recruitment curves: a preliminary TMS study. Spinal Cord. 2015; 53(7):534-8. DOI: 10.1038/sc.2015.12. View

11.

Willis E, MacDonald K, Nguyen Q, Garrido A, Gillespie E, Harley S . Repopulating Microglia Promote Brain Repair in an IL-6-Dependent Manner. Cell. 2020; 180(5):833-846.e16. DOI: 10.1016/j.cell.2020.02.013. View

12.

Lee C, Zhou L, Liu J, Shi J, Geng Y, Liu M . Single-cell RNA-seq analysis revealed long-lasting adverse effects of tamoxifen on neurogenesis in prenatal and adult brains. Proc Natl Acad Sci U S A. 2020; 117(32):19578-19589. PMC: 7431037. DOI: 10.1073/pnas.1918883117. View

13.

Zeisel A, Munoz-Manchado A, Codeluppi S, Lonnerberg P, La Manno G, Jureus A . Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science. 2015; 347(6226):1138-42. DOI: 10.1126/science.aaa1934. View

14.

Fan B, Wei Z, Yao X, Shi G, Cheng X, Zhou X . Microenvironment Imbalance of Spinal Cord Injury. Cell Transplant. 2018; 27(6):853-866. PMC: 6050904. DOI: 10.1177/0963689718755778. View

15.

Luo D, Ge W, Hu X, Li C, Lee C, Zhou L . Unbiased transcriptomic analyses reveal distinct effects of immune deficiency in CNS function with and without injury. Protein Cell. 2018; 10(8):566-582. PMC: 6626597. DOI: 10.1007/s13238-018-0559-y. View

16.

Liddelow S, Guttenplan K, Clarke L, Bennett F, Bohlen C, Schirmer L . Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017; 541(7638):481-487. PMC: 5404890. DOI: 10.1038/nature21029. View

17.

Wang Z, Xiang J, Liu X, Yu S, Manfredsson F, Sandoval I . Deficiency in BDNF/TrkB Neurotrophic Activity Stimulates δ-Secretase by Upregulating C/EBPβ in Alzheimer's Disease. Cell Rep. 2019; 28(3):655-669.e5. PMC: 6684282. DOI: 10.1016/j.celrep.2019.06.054. View

18.

Ren Y, Ao Y, OShea T, Burda J, Bernstein A, Brumm A . Ependymal cell contribution to scar formation after spinal cord injury is minimal, local and dependent on direct ependymal injury. Sci Rep. 2017; 7:41122. PMC: 5259707. DOI: 10.1038/srep41122. View

19.

Zeisel A, Hochgerner H, Lonnerberg P, Johnsson A, Memic F, van der Zwan J . Molecular Architecture of the Mouse Nervous System. Cell. 2018; 174(4):999-1014.e22. PMC: 6086934. DOI: 10.1016/j.cell.2018.06.021. View

20.

Assinck P, Duncan G, Hilton B, Plemel J, Tetzlaff W . Cell transplantation therapy for spinal cord injury. Nat Neurosci. 2017; 20(5):637-647. DOI: 10.1038/nn.4541. View