Efficient differentiation of human pluripotent stem cells into functional CD34+ progenitor cells by combined modulation of the MEK/ERK and BMP4 signaling pathways.
Differentiation of human pluripotent stem cells (hPSCs) into functional cell types is a crucial step in cell therapy. In the present study, we demonstrate that functional CD34(+) progenitor cells can be efficiently produced from human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) by combined modulation of 2 signaling pathways. A higher proportion of CD34(+) cells (∼ 20%) could be derived from hPSCs by inhibition of mitogen-activated protein kinase (MAPK) extracellular signal-regulated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling and activation of bone morphogenic protein-4 (BMP4) signaling. hPSC-derived CD34(+) progenitor cells further developed to endothelial and smooth muscle cells with functionality. Moreover, they contributed directly to neovasculogenesis in ischemic mouse hind limbs, thereby resulting in improved blood perfusion and limb salvage. Our results suggest that combined modulation of signaling pathways may be an efficient means of differentiating hPSCs into functional CD34(+) progenitor cells.
Park
Sang-Wook
SW
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
Jun Koh
Young
Y
Jeon
Jongwook
J
Cho
Yun-Hee
YH
Jang
Mi-Jin
MJ
Kang
Yujung
Y
Kim
Min-Jeong
MJ
Choi
Chulhee
C
Sook Cho
Yee
Y
Chung
Hyung-Min
HM
Koh
Gou Young
GY
Han
Yong-Mahn
YM
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism*; D015153:Blotting, Western; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D006614:Hindlimb / Q000098:blood supply / Q000378:metabolism; D007124:Immunoenzyme Techniques; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D007511:Ischemia / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D039904:Pluripotent Stem Cells / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D018952:Antigens, CD34; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D012333:RNA, Messenger; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases