|
Title
|
|
|
|
CD26/DPP-4 inhibition recruits regenerative stem cells via stromal cell-derived factor-1 and beneficially influences ischaemia-reperfusion injury in mouse lung transplantation
| |
|
Author
|
|
|
|
| |
|
Abstract
|
|
|
|
| OBJECTIVES The CD26 antigen is a transmembrane glycoprotein that is constitutively expressed on activated lymphocytes and in pulmonary parenchyma. This molecule is also identified as dipeptidyl peptidase-4 (DPP-4) that cleaves a host of biologically active peptides. Here, we aimed to identify an important substrate of CD26/DPP-4stromal cell-derived factor-1 (SDF-1/CXCL12)as a key modulator for stem-cell homing together with its receptor CXCR4 in response to ischaemic injury of the lung. METHODS Orthotopic single lung transplantation (Tx) was performed between syngeneic C57BL/6 mice. Inhibition of CD26/DPP-4 activity in recipients was achieved using vildagliptin (10 mg/kg, every 12 h) subcutaneously, and 6 h ischaemia time was applied prior to implantation. Forty-eight hours after Tx, lung histology, SDF-1 levels (enzyme-linked immunosorbent assay) in lung, spleen and plasma, and expression of the SDF-1 receptor CXCR4 in blood and lung were assessed. Homing of regenerative progenitor cells to the transplanted lung was evaluated using fluorescent-activated cell sorting. RESULTS Compared with untreated lung transplanted mice, systemic DPP-4 inhibition of Tx recipients resulted in an increase in protein concentration of SDF-1 in plasma, spleen and lung. Concordantly, the frequency of cells bearing the SDF-1 receptor CXCR4 rose significantly in the circulation and also in the lungs of DPP-4-inhibited recipients. We found co-expression of CXCR4/CD34 in the grafts of animals treated with vildagliptin, and the stem-cell markers Flt-3 and c-kit were present on a significantly increased number of cells. The morphology of grafts from DPP-4 inhibitor-treated recipients revealed less alveolar oedema when compared with untreated recipients. CONCLUSIONS Targeting the SDF-1CXCR4 axis through CD26/DPP-4 inhibition increased the intragraft number of progenitor cells contributing to the recovery from ischaemia-reperfusion lung injury. Stabilization of endogenous SDF-1 is achievable and may be a promising strategy to intensify sequestration of regenerative stem cells and thus emerges as a novel therapeutic concept. |
| |
|
Language
|
|
|
|
English
| |
|
Source (journal)
|
|
|
|
European journal of cardiothoracic surgery. - Berlin
| |
|
Publication
|
|
|
|
Berlin
:
2012
| |
|
ISSN
|
|
|
|
1010-7940
| |
|
DOI
|
|
|
|
10.1093/EJCTS/EZR180
| |
|
Volume/pages
|
|
|
|
41
:5
(2012)
, p. 1166-1173
| |
|
ISI
|
|
|
|
000303161800050
| |
|
Full text (Publisher's DOI)
|
|
|
|
| |
|
Full text (publisher's version - intranet only)
|
|
|
|
| |
|