title: Prolyl hydroxylase domain protein 2 silencing enhances the survival and paracrine function of transplanted adipose-derived stem cells in infarcted myocardium.
abstract: BACKGROUND
  Transplantation of stem cells into damaged hearts has had modest success as a treatment for ischemic heart disease. One of the limitations is the poor stem cell survival in the diseased microenvironment. Prolyl hydroxylase domain protein 2 (PHD2) is a cellular oxygen sensor that regulates 2 key transcription factors involved in cell survival and inflammation: hypoxia-inducible factor and nuclear factor-κB.
  
  
  OBJECTIVE
  We studied whether and how PHD2 silencing in human adipose-derived stem cells (ADSCs) enhances their cardioprotective effects after transplantation into infarcted hearts.
  
  
  RESULTS
  ADSCs were transduced with lentiviral short hairpin RNA against prolyl hydroxylase domain protein 2 (shPHD2) to silence PHD2. ADSCs, with or without shPHD2, were transplanted after myocardial infarction in mice. ADSCs reduced cardiomyocyte apoptosis, fibrosis, and infarct size and improved cardiac function. shPHD2-ADSCs exerted significantly more protection. PHD2 silencing induced greater ADSC survival, which was abolished by short hairpin RNA against hypoxia-inducible factor-1α. Conditioned medium from shPHD2-ADSCs decreased cardiomyocyte apoptosis. Insulin-like growth factor-1 (IGF-1) levels were significantly higher in the conditioned medium of shPHD2-ADSCs versus ADSCs, and depletion of IGF-1 attenuated the cardioprotective effects of shPHD2-ADSC-conditioned medium. Nuclear factor-κB activation was induced by shPHD2 to induce IGF-1 secretion via binding to IGF-1 gene promoter.
  
  
  CONCLUSIONS
  PHD2 silencing promotes ADSCs survival in infarcted hearts and enhances their paracrine function to protect cardiomyocytes. The prosurvival effect of shPHD2 on ADSCs is hypoxia-inducible factor-1α dependent, and the enhanced paracrine function of shPHD2-ADSCs is associated with nuclear factor-κB-mediated IGF-1 upregulation. PHD2 silencing in stem cells may be a novel strategy for enhancing the effectiveness of stem cell therapy after myocardial infarction.
authors.affiliation: Department of Cardiology, Daping Hospital.
authors.forename: Wei Eric
authors.initials: WE
authors.lastname: Wang
authors.forename: Dezhong
authors.initials: D
authors.lastname: Yang
authors.forename: Liangpeng
authors.initials: L
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Yulan
authors.initials: Y
authors.lastname: Peng
authors.forename: Caiyu
authors.initials: C
authors.lastname: Chen
authors.forename: Peng
authors.initials: P
authors.lastname: Chen
authors.forename: Xuewei
authors.initials: X
authors.lastname: Xia
authors.forename: Hongyong
authors.initials: H
authors.lastname: Wang
authors.forename: Jiahui
authors.initials: J
authors.lastname: Jiang
authors.forename: Qiao
authors.initials: Q
authors.lastname: Liao
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Ganfeng
authors.initials: G
authors.lastname: Xie
authors.forename: Haiyun
authors.initials: H
authors.lastname: Huang
authors.forename: Yanli
authors.initials: Y
authors.lastname: Guo
authors.forename: Linda
authors.initials: L
authors.lastname: Ye
authors.forename: Dayue Darrel
authors.initials: DD
authors.lastname: Duan
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Chen
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
authors.forename: Chunyu
authors.initials: C
authors.lastname: Zeng
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D020868:Gene Silencing / Q000502:physiology*; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics* / Q000601:surgery*; D019899:Paracrine Communication / Q000235:genetics*; D011393:Procollagen-Proline Dioxygenase / Q000096:biosynthesis* / Q000235:genetics; D034741:RNA, Small Interfering / Q000096:biosynthesis / Q000235:genetics; D033581:Stem Cell Transplantation / Q000379:methods
chemical_list: D034741:RNA, Small Interfering; C490190:EGLN1 protein, human; D011393:Procollagen-Proline Dioxygenase; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases
keywords: myocardial infarction; myocytes, cardiac; paracrine effect; stem cells; survival