Adventitial Sca1+ Cells Transduced with ETV2 Are Committed to the Endothelial Fate and Improve Vascular Remodeling after Injury

TY - JOUR

T1 - Adventitial Sca1+ Cells Transduced with ETV2 Are Committed to the Endothelial Fate and Improve Vascular Remodeling after Injury

AU - Le Bras, Alexandra

AU - Yu, Baoqi

AU - Issa Bhaloo, Shirin

AU - Hong, Xuechong

AU - Zhang, Zhongyi

AU - Hu, Yanhua

AU - Xu, Qingbo

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Objective - Vascular adventitial Sca1 + (stem cell antigen-1) progenitor cells preferentially differentiate into smooth muscle cells, which contribute to vascular remodeling and neointima formation in vessel grafts. Therefore, directing the differentiation of Sca1 + cells toward the endothelial lineage could represent a new therapeutic strategy against vascular disease. Approach and Results - We thus developed a fast, reproducible protocol based on the single-gene transfer of ETV2 (ETS variant 2) to differentiate Sca1 + cells toward the endothelial fate and studied the effect of cell conversion on vascular hyperplasia in a model of endothelial injury. After ETV2 transduction, Sca1 + adventitial cells presented a significant increase in the expression of early endothelial cell genes, including VE-cadherin, Flk-1, and Tie2 at the mRNA and protein levels. ETV2 overexpression also induced the downregulation of a panel of smooth muscle cell and mesenchymal genes through epigenetic regulations, by decreasing the expression of DNA-modifying enzymes ten-eleven translocation dioxygenases. Adventitial Sca1 + cells grafted on the adventitial side of wire-injured femoral arteries increased vascular wall hyperplasia compared with control arteries with no grafted cells. Arteries seeded with ETV2-transduced cells, on the contrary, showed reduced hyperplasia compared with control. Conclusions - These data give evidence that the genetic manipulation of vascular progenitors is a promising approach to improve vascular function after endothelial injury.

AB - Objective - Vascular adventitial Sca1 + (stem cell antigen-1) progenitor cells preferentially differentiate into smooth muscle cells, which contribute to vascular remodeling and neointima formation in vessel grafts. Therefore, directing the differentiation of Sca1 + cells toward the endothelial lineage could represent a new therapeutic strategy against vascular disease. Approach and Results - We thus developed a fast, reproducible protocol based on the single-gene transfer of ETV2 (ETS variant 2) to differentiate Sca1 + cells toward the endothelial fate and studied the effect of cell conversion on vascular hyperplasia in a model of endothelial injury. After ETV2 transduction, Sca1 + adventitial cells presented a significant increase in the expression of early endothelial cell genes, including VE-cadherin, Flk-1, and Tie2 at the mRNA and protein levels. ETV2 overexpression also induced the downregulation of a panel of smooth muscle cell and mesenchymal genes through epigenetic regulations, by decreasing the expression of DNA-modifying enzymes ten-eleven translocation dioxygenases. Adventitial Sca1 + cells grafted on the adventitial side of wire-injured femoral arteries increased vascular wall hyperplasia compared with control arteries with no grafted cells. Arteries seeded with ETV2-transduced cells, on the contrary, showed reduced hyperplasia compared with control. Conclusions - These data give evidence that the genetic manipulation of vascular progenitors is a promising approach to improve vascular function after endothelial injury.

KW - adventitia

KW - cell differentiation

KW - stem cells

KW - vascular diseases

KW - vascular remodeling

UR - http://www.scopus.com/inward/record.url?scp=85039444005&partnerID=8YFLogxK

U2 - 10.1161/ATVBAHA.117.309853

DO - 10.1161/ATVBAHA.117.309853

M3 - Article

AN - SCOPUS:85039444005

SN - 1079-5642

VL - 38

SP - 232

EP - 244

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

IS - 1

ER -