Use of p53-Silenced Endothelial Progenitor Cells to Treat Ischemia in Diabetic Peripheral Vascular Disease

Kundu N, etc
Journal of the American Heart Association, 2017


We transplanted p53 and p21KO mouse EPCs (mEPCs) into streptozotocin–induced diabetic (type 1 diabetes mellitus model) C57BL/6J and db/db (B6.BKS(D)-Leprdb/J) (type 2 model) post–femoral artery occlusion. Similarly, Ad-p53–silenced and Ad-p21–silenced human EPCs (CD34+) cells were transplanted into streptozotocin-induced diabetic NOD.CB17-Prkdcscid/J mice. We measured blood flow at 3, 7, and 10 days and hindlimb muscles were obtained postsacrifice for mRNA estimation and CD31 staining. Enhanced blood flow was noted with delivery of p53 and p21KO mEPCs in streptozotocin-induced diabetic C57BL/6J mice. Similar results were obtained when human Ad-p53shEPCs(CD34+) and Ad-p21shEPCs(CD34+) were transplanted into streptozotocin-induced nonobese diabetic severe combined immunodeficiency mice. Gene expression analysis of p53 and p21KO EPCs transplanted hindlimb muscles showed increased expression of endothelial markers such as endothelial nitric oxide synthase, vascular endothelial growth factor A, and platelet endothelial cell adhesion molecule 1. Similarly, quantitative reverse transcriptase polymerase chain reaction of human Ad-p53shEPCs (CD34+)– and Ad-p21shEPCs (CD34+)–transplanted hindlimb muscles also showed increased expression of endothelial markers such as vascular endothelial growth factor A, noted primarily in the p53-silenced EPCs group. However, such beneficial effect was not noted in the db/db type 2 diabetic mouse models.


Transient silencing of p53 using adenoviral vector in EPCs may have a therapeutic role in diabetic peripheral vascular disease.

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Journal
Journal of the American Heart Association
Year
2017
Page
doi: 10.1161/JAHA.116.005146
Institute
George Washington University