Oxygen glucose deprivation/reperfusion astrocytes promotes primary neural stem/progenitor cell proliferation by releasing high-mobility group box 1.
Cerebral ischemia/reperfusion is known to activate endogenous neural stem/progenitor cell (NS/PC) proliferation, but the mechanisms leading to NS/PC proliferation remain unknown. Astrocytes are vital components of the neurogenic niche and play a crucial role in regulating NS/PC proliferation and differentiation. After focal cerebral ischemia/reperfusion (I/R), astrocytes release a damage-associated molecular-pattern molecule called high-mobility group box 1 (HMGB1). Since HMGB1 is critical for NS/PC proliferation during brain development, we modeled I/R using glucose deprivation/reperfusion (OGD/R) in vitro and examined the effect of HMGB1 released by astrocytes on NS/PC proliferation. Further, we determined the role of the PI3K/Akt signaling pathway in this process. Using conditioned media from OGD/R astrocytes with or without RNA interference for HMGB1, as well as with anti-HMGB1 antibodies, we evaluated the effect of astrocyte-derived HMGB1 on NS/PC proliferation. Using the potent PI3K/Akt inhibitor, LY294002, we explored the likely mechanism of HMGB1-induced NS/PC proliferation. OGD/R astrocyte-conditioned media (ACM) increased NS/PC proliferation, and HMGB1 RNA interference prevented this effect. Using an HMGB1 neutralizing antibody in OGD/R ACM also abrogated NS/PC proliferation. LY294002 effectively reduced phospho-Akt levels and reduced NS/PC proliferation induced by HMGB1 in vitro. Our data demonstrate that HMGB1 released by OGD/R astrocytes promotes NS/PC proliferation through activation of the PI3K/Akt signaling pathway. Local HMGB1 release may induce endogenous NS/PC to proliferate following cerebral I/R and suggests that HMGB1 may play a pivotal role in brain tissue repair after an ischemic event.
Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 40016, China, limanneurosci@163.com.
Man
M
Li
Lin
L
Sun
Yuan
Y
Li
Chenchen
C
Xie
Dong
D
Wan
Yong
Y
Luo
D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D049109:Cell Proliferation / Q000502:physiology*; D002478:Cells, Cultured; D005947:Glucose / Q000172:deficiency*; D024243:HMGB1 Protein / Q000378:metabolism*; D058953:Neural Stem Cells / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D005947:Glucose; D010100:Oxygen