title: Sonic hedgehog released from scratch-injured astrocytes is a key signal necessary but not sufficient for the astrocyte de-differentiation.
abstract: Recent studies demonstrated that mature atrocytes have the capacity for de-differentiating into neural stem/progenitor cells (NSPCs) in vitro and in vivo. However, it is still unknown what signals endow astroglial cells with a de-differentiation potential. Furthermore, the signaling molecules and underlying mechanism that confer astrocytes with the competence of NSPC phenotypes have not been completely elucidated. Here, we found that sonic hedgehog (Shh) production in astrocytes following mechanical injury was significantly elevated, and that incubation of astrocyes with the injured astrocyte conditioned medium (ACM) causes astrocytes to gradually lose their immunophenotypical profiles, and acquire NSPC characteristics, as demonstrated by down-regulation of typical astrocytic markers (GFAP and S100) and up-regulation of markers that are generally expressed in NSCs, (nestin, Sox2, and CD133). ACM treated astrocytes exhibit self-renewal capacity and multipotency similar to NSPCs. Concomitantly, in addition to Ptc, there was a significant up-regulation of the Shh downstream signal components Gli2 and Cyclin D1 which are involved in cell proliferation, dramatic changes in cell morphology, and the disruption of cell-cycle G1 arrest. Conversely, the depletion of Shh by administration of its neutralizing antibody (Shh n-Ab) effectively inhibited the de-differentiation process. Strikingly, Shh alone had little effect on astrocyte de-differentiation to NSPCs. These data above suggest that Shh is a key instructive molecule while other molecules secreted from insulted astrocytes may synergistically promote the de-differentiation event.
authors: Institute of Neurosciences, The Fourth Military Medical University, Xi'an, China. yanghao71_99@yahoo.com
authors: Hao
authors: H
authors: Yang
authors: Guo-Dong
authors: GD
authors: Feng
authors: Cathy
authors: C
authors: Olivera
authors: Xi-Ying
authors: XY
authors: Jiao
authors: Angela
authors: A
authors: Vitale
authors: Ju
authors: J
authors: Gong
authors: Si-Wei
authors: SW
authors: You
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D015415:Biomarkers / Q000378:metabolism; D054337:Cell Dedifferentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D019938:Cyclin D1 / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000072079:Patched Receptors; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013314:Stress, Mechanical; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D000075746:Zinc Finger Protein Gli2
chemical_list: D015415:Biomarkers; D017077:Culture Media, Conditioned; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; C546888:Shh protein, rat; D000075746:Zinc Finger Protein Gli2; D019938:Cyclin D1