Notch-RBP-J signaling regulates the mobilization and function of endothelial progenitor cells by dynamic modulation of CXCR4 expression in mice.
Bone marrow (BM)-derived endothelial progenitor cells (EPC) have therapeutic potentials in promoting tissue regeneration, but how these cells are modulated in vivo has been elusive. Here, we report that RBP-J, the critical transcription factor mediating Notch signaling, modulates EPC through CXCR4. In a mouse partial hepatectomy (PHx) model, RBP-J deficient EPC showed attenuated capacities of homing and facilitating liver regeneration. In resting mice, the conditional deletion of RBP-J led to a decrease of BM EPC, with a concomitant increase of EPC in the peripheral blood. This was accompanied by a down-regulation of CXCR4 on EPC in BM, although CXCR4 expression on EPC in the circulation was up-regulated in the absence of RBP-J. PHx in RBP-J deficient mice induced stronger EPC mobilization. In vitro, RBP-J deficient EPC showed lowered capacities of adhering, migrating, and forming vessel-like structures in three-dimensional cultures. Over-expression of CXCR4 could at least rescue the defects in vessel formation by the RBP-J deficient EPC. These data suggested that the RBP-J-mediated Notch signaling regulated EPC mobilization and function, at least partially through dynamic modulation of CXCR4 expression. Our findings not only provide new insights into the regulation of EPC, but also have implications for clinical therapies using EPC in diseases.
State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, China.
Lin
L
Wang
Yao-Chun
YC
Wang
Xing-Bin
XB
Hu
Bing-Fang
BF
Zhang
Guo-Rui
GR
Dou
Fei
F
He
Fang
F
Gao
Fan
F
Feng
Ying-Min
YM
Liang
Ke-Feng
KF
Dou
Hua
H
Han
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D017690:Cell Transplantation; D042783:Endothelial Cells / Q000166:cytology*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019718:Receptors, CXCR4 / Q000096:biosynthesis* / Q000737:chemistry; D051880:Receptors, Notch / Q000378:metabolism*; D012038:Regeneration; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*
C514936:CXCR4 protein, mouse; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497571:Rbpj protein, mouse; D019718:Receptors, CXCR4; D051880:Receptors, Notch