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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
原, 正光
http://hdl.handle.net/2324/1931776
出版情報：九州大学, 2017, 博士（医学）, 課程博士
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Interaction of reactive astrocytes with collagen type I induces astrocytic scar formation 2
through the integrin/N-cadherin pathway after spinal cord injury 3
4
5
6
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8
Authors: 9
Masamitsu Hara
1,2
, Kazu Kobayakawa
2
, Yasuyuki Ohkawa
3
, Hiromi Kumamaru
2
, Kazuya 10
Yokota
2
, Takeyuki Saito
1,2
, Ken Kijima
1,2
, Shingo Yoshizaki
1,2
, Katsumi Harimaya
2
, Yasuharu 11
Nakashima
2
and Seiji Okada
1,2
12
13
Affiliations: 14
1
Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu 15
University, Fukuoka, Japan 16
2
Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 17
Fukuoka, Japan 18
3
Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 19
Japan 20
Correspondence should be addressed to S.O. (seokada@ortho.med.kyushu-u.ac.jp) 21
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Abstract 1
Central nervous system (CNS) injury activates naïve astrocytes into reactive astrocytes, which 2
eventually transform into scar-forming astrocytes that can impair axonal regeneration and 3
functional recovery. This sequential phenotypic change, known as reactive astrogliosis, has 4
long been considered unidirectional and irreversible. However, we report here that reactive 5
astrocytes isolated from injured spinal cords retrogradely reverted to naïve astrocytes when 6
transplanted into a naïve spinal cord, whereas they formed astrocytic scars when transplanted 7
into an injured spinal cord, indicating the environment-dependent reversibility of reactive 8
astrogliosis. We also found that collagen type I was highly expressed during the scar-forming 9
phase and induced astrocytic scar formation via the integrin/N-cadherin pathway. 10
Pharmacological blockade of reactive astrocyte-collagen type I interaction prevented astrocytic 11
scar formation, thereby leading to improved axonal regrowth and better functional outcomes 12
in a mouse model of spinal cord injury. Our findings reveal environmental cues regulating 13
astrocytic fate decisions, thereby providing a potential therapeutic target for CNS injury. 14
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Introduction 1
Spinal cord injury (SCI) is a devastating trauma that causes persistent severe motor/sensory 2
dysfunction
1,2
. After SCI, astrocytes, the most abundant resident cells in the central nervous 3
system (CNS), play a crucial role in the SCI pathology through a phenotypic change known as 4
reactive astrogliosis. In this process, naïve astrocytes (NAs) sequentially exhibit opposite 5
phenotypes: first as reactive astrocytes (RAs) and then as scar-forming astrocytes (SAs). In the 6
subacute phase of SCI (4-14 days post-injury (dpi) in the mouse), RAs migrate to the lesion 7
epicenter and seclude inflammatory cells, leading to tissue repair and functional improvement 8
after SCI
2
. However, RAs gradually transform into SAs that form astrocytic scars, the main 9
impediment for CNS axonal regeneration, resulting in a limited functional recovery in the 10
chronic phase of SCI
3,4
(more than 14 dpi in the mouse). Astrocytic scars have been shown to 11
be irreversible and permanently inhibit axonal regrowth in both rodents and humans with SCI
4-
12
6
, although there is a different opinion that attenuating astrocytic scar formation failed to 13
promote axonal regeneration after SCI
7,8
. As such, clarifying the mechanism of astrocytic scar 14
formation and regulating this scar formation may be a potential therapeutic strategy for SCI. 15
Astrocytic scars have been studied for more than half a century
9,10
, and their formation has 16
been suggested to be regulated by complex and combinatorial inter- and intra-cellular signaling 17
mechanisms
3,5,11
. However, despite the large number of studies examining these astrocytic 18
changes
5,11,12
, the mechanism underlying astrocytic scar formation remains unclear. One factor 19
limiting basic research in this area is the lack of clear definitions of NAs, RAs, and SAs. A 20
conventional method for distinguishing between these cells is a histological analysis, but this 21
method is neither objective nor quantitative. 22
In this study, we established a clear distinction between NAs, RAs, and SAs based on marker 23
gene expression and investigated the regulatory mechanism underlying astrocytic scar 24
4
formation after SCI. 1