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Abstract
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.
Highlights
Bone marrow (BM)-derived cells, such as the hematopoietic stem cells (HSC), the mesenchymal stem cells (MSC), and the endothelial progenitor cells (EPC), have shown promising potential in the treatment of various human disease [1,2]
The mice transfused with the RBP-J deficient bone marrow (BM) cells and the control BM cells were subjected to PHx, and the regeneration of SEC was evaluated on the third day after PHx, by immunofluorescent staining for Flk-1 and UEA-1
These data suggested that mice with RBP-J-deleted BM cells were less efficient in liver regeneration than mice with normal BM cells, probably due to abnormal Notch signaling in EPC
Summary
Bone marrow (BM)-derived cells, such as the hematopoietic stem cells (HSC), the mesenchymal stem cells (MSC), and the endothelial progenitor cells (EPC), have shown promising potential in the treatment of various human disease [1,2]. Several reports have documented evidence that the transfusion of BM cells might benefit patients suffering the end-stage liver diseases, including those caused by liver cirrhosis, hepatitis virus B and hepatitis virus C infections, and alcohol abuse [3,4,5,6,7,8]. EPC homed to the injury site can differentiate into endothelial cells (EC) to directly participate in vasculogenesis, and/or to produce angiogenic factors to contribute to vascular remodeling. These studies have prompted trials to use EPC to treat ischemic diseases [9] as well as to facilitate liver regeneration [6,7,8], signals regulating EPC mobilization and homing in vivo have been elusive. How SDF-1a-CXCR4 signaling is regulated in the mobilization and the recruitment of EPC to the injured tissues has been unclear
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