Autophagic death of adult hippocampal neural stem cells following insulin withdrawal

Seong Woon Yu, Seung Hoon Baek, Ryan T. Brennan, Christopher J. Bradley, Se Kyong Park, Yoon Sun Lee, Eun Jung Jun, Keith J. Lookingland, Eun Kyoung Kim, Heuiran Lee, John L. Goudreau, Seong Who Kim

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)2602-2610
Number of pages9
JournalStem Cells
Volume26
Issue number10
DOIs
StatePublished - Oct 2008
Externally publishedYes

Keywords

  • Adult neural stem cells
  • Autophagy
  • Bcl-2
  • Insulin withdrawal

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine

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