CD26/DPP-4 inhibition recruits regenerative stem cells via stromal cell-derived factor-1 and beneficially influences ischaemia-reperfusion injury in mouse lung transplantation.
OBJECTIVE
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-4-stromal 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-1-CXCR4 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.
Division of Thoracic Surgery, University Hospital, Zurich, Switzerland. wolfgang.jungraithmayr@usz.ch
Wolfgang
W
Jungraithmayr
Ingrid
I
De Meester
Veerle
V
Matheeussen
Lesley
L
Baerts
Stephan
S
Arni
Walter
W
Weder
D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000502:physiology*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism / Q000502:physiology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000502:physiology; D007279:Injections, Subcutaneous; D008168:Lung / Q000378:metabolism; D016040:Lung Transplantation / Q000009:adverse effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009570:Nitriles / Q000008:administration & dosage / Q000627:therapeutic use; D011759:Pyrrolidines / Q000008:administration & dosage / Q000627:therapeutic use; D019718:Receptors, CXCR4 / Q000378:metabolism; D015427:Reperfusion Injury / Q000209:etiology / Q000517:prevention & control*; D000077597:Vildagliptin
D018952:Antigens, CD34; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D054873:Dipeptidyl-Peptidase IV Inhibitors; D009570:Nitriles; D011759:Pyrrolidines; D019718:Receptors, CXCR4; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse; D000077597:Vildagliptin; D000218:Adamantane