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Autophagic death of adult hippocampal neural stem cells following insulin withdrawal. Stem Cells 2008 Oct;26(10):2602-10

Date

07/26/2008

Pubmed ID

18653772

DOI

10.1634/stemcells.2008-0153

Abstract

Novel therapeutic approaches using stem cell transplantation to treat neurodegenerative diseases have yielded promising results. However, survival of stem cells after transplantation has been very poor in animal models, and considerable efforts have been directed at increasing the viability of engrafted stem cells. Therefore, understanding the mechanisms that regulate survival and death of neural stem cells is critical to the development of stem cell-based therapies. Hippocampal neural (HCN) stem cells derived from the adult rat brain undergo cell death following insulin withdrawal, which is associated with downregulation of antiapoptotic Bcl-2 family members. To understand the type of cell death in HCN cells following insulin withdrawal, apoptosis markers were assessed. Of note, DNA fragmentation or caspase-3 activation was not observed, but rather dying cells displayed features of autophagy, including increased expression of Beclin 1 and the type II form of light chain 3. Electron micrographs showed the dramatically increased formation of autophagic vacuoles with cytoplasmic contents. Staurosporine induced robust activation of caspase-3 and nucleosomal DNA fragmentation, suggesting that the machinery of apoptosis is intact in HCN cells despite the apparent absence of apoptosis following insulin withdrawal. Autophagic cell death was suppressed by knockdown of autophagy-related gene 7, whereas promotion of autophagy by rapamycin increased cell death. Taken together, these data demonstrate that HCN cells undergo a caspase-independent, autophagic cell death following insulin withdrawal. Understanding the mechanisms governing autophagy of adult neural stem cells may provide novel strategies to improve the survival rate of transplanted stem cells for treatment of neurodegenerative diseases. Disclosure of potential conflicts of interest is found at the end of this article.

Author List

Yu SW, Baek SH, Brennan RT, Bradley CJ, Park SK, Lee YS, Jun EJ, Lookingland KJ, Kim EK, Lee H, Goudreau JL, Kim SW

Author

Ryan T. Brennan DO Assistant Professor in the Neurology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adult Stem Cells
Animals
Apoptosis
Autophagy
Cell Proliferation
Cells, Cultured
Down-Regulation
Hippocampus
Immunohistochemistry
Insulin
Intermediate Filament Proteins
Nerve Tissue Proteins
Nestin
Neurons
Rats
Stem Cells
Vacuoles
bcl-X Protein
jenkins-FCD Prod-480 9a4deaf152b0b06dd18151814fff2e18f6c05280