TY - JOUR
T1 - Enhanced hemangioblast generation and improved vascular repair and regeneration from embryonic stem cells by defined transcription factors
AU - Liu, Fang
AU - Bhang, Suk Ho
AU - Arentson, Elizabeth
AU - Sawada, Atsushi
AU - Kim, Chan Kyu
AU - Kang, Inyoung
AU - Yu, Jinsheng
AU - Sakurai, Nagisa
AU - Kim, Suk Hyung
AU - Yoo, Judy Ji Woon
AU - Kim, Paul
AU - Pahng, Seong Ho
AU - Xia, Younan
AU - Solnica-Krezel, Lilianna
AU - Choi, Kyunghee
N1 - Funding Information:
We thank the Cell Sorter Cores of the Alvin J. Siteman Cancer Center (supported in part by an NCI Cancer Centre Support Grant No. P30 CA91842) and the Department of Pathology and Immunology at the Washington University School of Medicine. This work was supported by grants from American Heart Association Postdoctoral Fellowship 10POST4570022 (to F.L.) and National Institutes of Health grants HL63736 and HL55337 (to K.C.).
PY - 2013
Y1 - 2013
N2 - The fetal liver kinase 1 (FLK-1)+ hemangioblast can generate hematopoietic, endothelial, and smooth muscle cells (SMCs). ER71/ETV2, GATA2, and SCL form a core transcriptional network in hemangioblast development. Transient coexpression of these three factors during mesoderm formation stage in mouse embryonic stem cells (ESCs) robustly enhanced hemangioblast generation by activating bone morphogenetic protein (BMP) and FLK-1 signaling while inhibiting phosphatidylinositol 3-kinase, WNT signaling, and cardiac output. Moreover, etsrp, gata2, and scl inhibition converted hematopoietic field of the zebrafish anterior lateral plate mesoderm to cardiac. FLK-1+ hemangioblasts generated by transient coexpression of the three factors (ER71-GATA2-SCL [EGS]-induced FLK-1+) effectively produced hematopoietic, endothelial, and SMCs in culture and in vivo. Importantly, EGS-induced FLK-1+ hemangioblasts, when codelivered with mesenchymal stem cells as spheroids, were protected from apoptosis and generated functional endothelial cells and SMCs in ischemic mouse hindlimbs, resulting in improved blood perfusion and limb salvage. ESC-derived, EGS-induced FLK-1+ hemangioblasts could provide an attractive cell source for future hematopoietic and vascular repair and regeneration.
AB - The fetal liver kinase 1 (FLK-1)+ hemangioblast can generate hematopoietic, endothelial, and smooth muscle cells (SMCs). ER71/ETV2, GATA2, and SCL form a core transcriptional network in hemangioblast development. Transient coexpression of these three factors during mesoderm formation stage in mouse embryonic stem cells (ESCs) robustly enhanced hemangioblast generation by activating bone morphogenetic protein (BMP) and FLK-1 signaling while inhibiting phosphatidylinositol 3-kinase, WNT signaling, and cardiac output. Moreover, etsrp, gata2, and scl inhibition converted hematopoietic field of the zebrafish anterior lateral plate mesoderm to cardiac. FLK-1+ hemangioblasts generated by transient coexpression of the three factors (ER71-GATA2-SCL [EGS]-induced FLK-1+) effectively produced hematopoietic, endothelial, and SMCs in culture and in vivo. Importantly, EGS-induced FLK-1+ hemangioblasts, when codelivered with mesenchymal stem cells as spheroids, were protected from apoptosis and generated functional endothelial cells and SMCs in ischemic mouse hindlimbs, resulting in improved blood perfusion and limb salvage. ESC-derived, EGS-induced FLK-1+ hemangioblasts could provide an attractive cell source for future hematopoietic and vascular repair and regeneration.
UR - http://www.scopus.com/inward/record.url?scp=84881323407&partnerID=8YFLogxK
U2 - 10.1016/j.stemcr.2013.06.005
DO - 10.1016/j.stemcr.2013.06.005
M3 - Article
C2 - 24052951
AN - SCOPUS:84881323407
SN - 2213-6711
VL - 1
SP - 166
EP - 182
JO - Stem Cell Reports
JF - Stem Cell Reports
IS - 2
ER -