Impaired recruitment of HHT-1 mononuclear cells to the ischaemic heart is due to an altered CXCR4/CD26 balance

Simone Post, Anke M. Smits, Alexandra J. van den Broek, Joost P. G. Sluijter, Imo E. Hoefer, Ben J. Janssen, Repke J. Snijder, Johannes J. Mager, Gerard Pasterkamp, Christine L. Mummery, Pieter A. Doevendans, Marie-Jose Goumans*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

27 Citations (Web of Science)


Aims 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-1a (SDF-1 alpha) 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. Methods and results CXCR4 and CD26 expression on MNCs was determined by flow cytometry. Transwell migration to SDF-1 alpha 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-1 alpha 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. Conclusion We show that a decreased homing of HHT1-MNCs is caused by an impaired ability of the cells to respond to SDF-1 alpha. 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.
Original languageEnglish
Pages (from-to)494-502
JournalCardiovascular Research
Issue number3
Publication statusPublished - 1 Feb 2010


  • Mononuclear cells
  • Chemokines
  • Genetics
  • Myocardial infarction
  • Migration

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