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Interaction of reactive astrocytes with type I collagen induces astrocytic scar formation through the integrin–N-cadherin pathway after spinal cord injury

Nature Medicine volume 23, pages 818–828 (2017)Cite this article

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Abstract

Central nervous system (CNS) injury transforms naive astrocytes into reactive astrocytes, which eventually become scar-forming astrocytes that can impair axonal regeneration and functional recovery. This sequential phenotypic change, known as reactive astrogliosis, has long been considered unidirectional and irreversible. However, we report here that reactive astrocytes isolated from injured spinal cord reverted in retrograde to naive astrocytes when transplanted into a naive spinal cord, whereas they formed astrocytic scars when transplanted into injured spinal cord, indicating the environment-dependent plasticity of reactive astrogliosis. We also found that type I collagen was highly expressed in the spinal cord during the scar-forming phase and induced astrocytic scar formation via the integrin–N-cadherin pathway. In a mouse model of spinal cord injury, pharmacological blockade of reactive astrocyte–type I collagen interaction prevented astrocytic scar formation, thereby leading to improved axonal regrowth and better functional outcomes. Our findings reveal environmental cues regulating astrocytic fate decisions, thereby providing a potential therapeutic target for CNS injury.

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Figure 1: Selective in situ isolation and gene expression analysis of astrocytes from naive and injured spinal cords.
Figure 2: Environment-dependent morphological changes in NAs transplanted into naive or injured spinal cords.
Figure 3: Environment-dependent transcriptional profiles of NAs transplanted into naive or injured spinal cord.
Figure 4: The plasticity of reactive astrogliosis depends on the surrounding spinal cord environment.
Figure 5: RNA–seq analysis reveals the role of Col I in the induction of N-cadherin-dependent adhesion in RAs.
Figure 6: Inhibition of integrin-mediated RA–Col I interaction prevents astrocytic scar formation and promotes functional recovery after SCI.

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Acknowledgements

We thank T. Tachibana (Osaka City University) for the gift of anti-nestin antibody. This study was supported by a Grant-in-Aid for Young Scientist (A) (25713053) (S.O.); Challenging Exploratory Research from the Ministry of Education, Science, and Sports (16K15668) (S.O.); a Grant-in-Aid for Young Scientist (B) (16K20059) (K. Kobayakawa); Scientific Research on Innovative Areas (Comprehensive Brain Science Network and Foundation of Synapse Neurocircuit Pathology) (K. Kobayakawa); and research foundations from the general insurance association of Japan (M.H.).

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Authors and Affiliations

  1. Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Masamitsu Hara, Takeyuki Saito, Ken Kijima, Shingo Yoshizaki & Seiji Okada

  2. Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Masamitsu Hara, Kazu Kobayakawa, Hiromi Kumamaru, Kazuya Yokota, Takeyuki Saito, Ken Kijima, Shingo Yoshizaki, Katsumi Harimaya, Yasuharu Nakashima & Seiji Okada

  3. Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

    Yasuyuki Ohkawa

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Contributions

M.H. designed and performed most of the experiments with technical help from H.K., T.S., and S.Y. Y.O. performed the RNA–seq analysis. K.Y. and K. Kijima analyzed the data from LMD. K. Kobayakawa, K.H., and Y.N. designed the studies and supervised the overall project. S.O. designed the studies, supervised the overall project, and performed the final manuscript preparation.

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Correspondence to Seiji Okada.

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Hara, M., Kobayakawa, K., Ohkawa, Y. et al. Interaction of reactive astrocytes with type I collagen induces astrocytic scar formation through the integrin–N-cadherin pathway after spinal cord injury. Nat Med 23, 818–828 (2017). https://doi.org/10.1038/nm.4354

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