title: Autophagy is Required for the Maintenance of Liver Progenitor Cell Functionality.
abstract: BACKGROUND
  Liver progenitor cells (LPCs) are bipotent stem cells existing in the adult liver, which could be activated upon massive liver injury and contribute to liver regeneration. However, mechanisms of maintenance of LPC functionality remain poorly understood. Previous studies found that autophagy was required for the self-renewal and differentiation of several tissue stem cells.
  
  
  METHODS
  The study compared the level of autophagic activity in LPCs and differentiated hepatocytes. Then, autophagic activity was inhibited in LPCs by lentivirus-mediated autophagy-related gene 5 or Beclin 1 knockdown. Clonogenic assay, cell viability assays, hepatic differentiation assay, and senescence analysis were conducted to assess the role of autophagy in regulating self-renewal, hepatic differentiation and senescence of LPCs.
  
  
  RESULTS
  We observed high autophagic activity in LPCs compared with differentiated hepatocytes. We found that inhibition of autophagy impaired the self-renewal, proliferation, and hepatic differentiation capability of LPCs under normal cultural condition, but had little impact on cell viability. Interestingly, while wild-type LPCs remained rarely affected by the toxin, etoposide, inhibition of autophagy induced the senescent phenotype of LPCs. Overexpression of Beclin 1 in Beclin 1-knockdown LPCs restored the functionality of stem cells.
  
  
  CONCLUSIONS
  Our findings indicate that autophagy may function as a critical regulator of LPC functionality under both physiological and pathological condition.
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yiji
authors.initials: Y
authors.lastname: Cheng
authors.forename: Bei
authors.initials: B
authors.lastname: Wang
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.forename: Shipeng
authors.initials: S
authors.lastname: Dang
authors.forename: Min
authors.initials: M
authors.lastname: Jin
authors.forename: Yufang
authors.initials: Y
authors.lastname: Shi
authors.forename: Li
authors.initials: L
authors.lastname: Hao
authors.forename: Zhenxi
authors.initials: Z
authors.lastname: Yang
authors.forename: Yanyun
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects / Q000235:genetics*; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology; D015870:Gene Expression; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008115:Liver Regeneration / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D005047:Etoposide