PHD2 Silencing Enhances the Survival and Paracrine Function of Transplanted Adipose-Derived Stem Cells in Infarcted Myocardium
Rationale: 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 two key transcription factors involved in cell survival and inflammation, hypoxia-inducible factor (HIF) and nuclear factor-κB (NF-κB).
Objective: We studied if and how PHD2 silencing in human adipose-derived stem cells (ADSCs) enhances their cardioprotective effects after transplantation into infarcted hearts.
Methods and Results: ADSCs were transduced with lentiviral shPHD2 to silence PHD2. ADSCs with or without shPHD2 were transplanted after myocardial infarction (MI) in mice. ADSCs reduced cardiomyocyte apoptosis, fibrosis and infarct size and improved cardiac function. shPHD2-ADSCs exerted significantly more protection. PHD2 silencing induced greater ADSCs survival, which was abolished by shHIF-1α Conditioned medium (CM) from shPHD2-ADSCs decreased cardiomyocyte apoptosis. Insulin-like growth factor 1 (IGF-1) levels were significantly higher in the CM of shPHD2-ADSCs versus ADSCs, and depletion of IGF-1 attenuated the cardioprotective effects of shPHD2-ADSCs-CM. NF-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 MI hearts and enhances their paracrine function to protect cardiomyocytes. The pro-survival effect of shPHD2 on ADSCs is HIF-1α dependent and the enhanced paracrine function of shPHD2-ADSCs is associated with NF-κB-mediated IGF-1 up-regulation. PHD2 silencing instem cells may be a novel strategy for enhancing the effectiveness of stem cell therapy after MI.
