Impaired recruitment of HHT-1 mononuclear cells to the ischaemic heart is due to an altered CXCR4/CD26 balance.
OBJECTIVE
Mononuclear cells (MNCs) from patients with hereditary haemorrhagic telangiectasia type 1 (HHT1), a genetic disorder caused by mutations in endoglin, show a reduced ability to home to infarcted mouse myocardium. Stromal cell-derived factor-1alpha (SDF-1alpha) and the chemokine receptor CXCR4 are crucial for homing and negatively influenced by CD26. The aim of this study was to gain insight into the impaired homing of HHT1-MNCs.


RESULTS
CXCR4 and CD26 expression on MNCs was determined by flow cytometry. Transwell migration to SDF-1alpha was used to analyse in vitro migration. Experimentally induced myocardial infarction in mice, followed by tail vein injection of MNCs, was applied to study homing in vivo. HHT1-MNCs expressed elevated levels of CXCR4, but this was counterbalanced by high levels of CD26, resulting in decreased migration towards an SDF-1alpha gradient in vitro. Migration was enhanced by inhibiting CD26 with Diprotin-A. While MNCs from healthy controls responded to transforming growth factor-beta stimulation by increasing CXCR4 and lowering CD26 expression levels, HHT1-MNCs did not react as efficiently: in particular, CD26 expression remained high. Inhibiting CD26 on MNCs increased the homing of human cells into the infarcted mouse heart. Interestingly, the defect in homing of HHT1-MNCs was restored by pre-incubating the HHT1-MNCs with Diprotin-A before injection into the tail vein.


CONCLUSIONS
We show that a decreased homing of HHT1-MNCs is caused by an impaired ability of the cells to respond to SDF-1alpha. Our results suggest that modulating CD26 levels using inhibitors like Diprotin-A can restore homing in cases where increased expression of CD26 contributes to the underlying pathological mechanism.
Post
Simone
S
Department of Cardiology, Division Heart & Lung, UMCU, Utrecht, The Netherlands.
Smits
Anke M
AM
van den Broek
Alexandra J
AJ
Sluijter
Joost P G
JP
Hoefer
Imo E
IE
Janssen
Ben J
BJ
Snijder
Repke J
RJ
Mager
Johannes J
JJ
Pasterkamp
Gerard
G
Mummery
Christine L
CL
Doevendans
Pieter A
PA
Goumans
Marie-José
MJ
D000818:Animals; D002465:Cell Movement; D018819:Dipeptidyl Peptidase 4 / Q000502:physiology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009203:Myocardial Infarction / Q000473:pathology*; D019718:Receptors, CXCR4 / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D019718:Receptors, CXCR4; D016212:Transforming Growth Factor beta; D018819:Dipeptidyl Peptidase 4