Ex vivo acidic preconditioning enhances bone marrow ckit+ cell therapeutic potential via increased CXCR4 expression

Chiara Cencioni, Roberta Melchionna, Stefania Straino, Marta Romani, Claudia Cappuzzello, Valentina Annese, Joseph C. Wu, Giulio Pompilio, Angela Santoni, Carlo Gaetano, Monica Napolitano, Maurizio C. Capogrossi

Research output: Contribution to journalArticlepeer-review


Aims The chemokine receptor CXCR4 modulates endothelial progenitor cell migration, homing, and differentiation, and plays a key role in cardiovascular regeneration. Here we examined the effect of ex vivo acidic preconditioning (AP) on CXCR4 expression and on the regenerative potential of mouse bone marrow (BM) ckit+ cells. Methods and results Acidic preconditioning was achieved by exposing BM ckit+ cells to hypercarbic acidosis (pH 7.0) for 24 h; control cells were kept at pH 7.4. Acidic preconditioning enhanced CXCR4 and stromal cell-derived factor 1 (SDF-1) mRNA levels, as well as CXCR4 phosphorylation. Acidic preconditioning ability to modulate CXCR4 expression depended on cytosolic calcium [Ca2+]i mobilization and on nitric oxide (NO), as determined by [Ca2+]i buffering with BAPTA, and by treatment with the NO donor (DETA/NO) and the NO synthase inhibitor (L-NAME). Further, AP increased SDF-1-driven chemotaxis, transendothelial migration, and differentiation toward the endothelial lineage in vitro. In a mouse model of hindlimb ischaemia, control and AP ckit+ cells were transplanted into the ischaemic muscle; AP cells accelerated blood flow recovery, increased capillary, and arteriole number as well as the number of regenerating muscle fibres vs. control. These effects were abolished by treating AP cells with L-NAME. Conclusion Acidic preconditioning represents a novel strategy to enhance BM ckit+ cell therapeutic potential via NO-dependent increase in CXCR4 expression.

Original languageEnglish
Pages (from-to)2007-2016
Number of pages10
JournalEuropean Heart Journal
Issue number26
Publication statusPublished - 2013


  • Cell migration
  • Cell therapy
  • Chemokines
  • Hindlimb ischaemia
  • Preconditioning

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Medicine(all)


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