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Cardiovasc Res. 2014 Jul 1;103(1):121-30. doi: 10.1093/cvr/cvu104. Epub 2014 Apr 17.

Sphingosine kinase 1 expressed by endothelial colony-forming cells has a critical role in their revascularization activity.

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Aix-Marseille Université, Vascular Research Center of Marseille (VRCM), INSERM UMR-S 1076, Faculté de Pharmacie, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France.
Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Université de Toulouse III, 1 Av Jean Poulhès, BP 84225,  31432 Toulouse Cedex 4, France.
Centre de Recherche en Cancérologie, INSERM UMR-1037, Université de Toulouse III, BP 84225, CHU Rangueil, 31432 Toulouse Cedex 4, France.
EA 4553: Individualisation des Traitements des Cancers Ovariens et ORL, Institut Claudius Regaud, 20-24 rue du Pont St Pierre, 31052 Toulouse Cedex 4, France.
Aix-Marseille Université, Vascular Research Center of Marseille (VRCM), INSERM UMR-S 1076, Faculté de Pharmacie, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France



Cell therapy based on endothelial colony-forming cells (ECFCs) is a promising option for ischaemic cardiovascular diseases. A better understanding of the mechanisms by which these cells promote revascularization remains a critical challenge to improving their therapeutic potential. We aimed to identify the critical mechanisms involved in the revascularization activity of ECFCs by using the paracrine properties of mesenchymal stem cells (MSC).


Conditioned medium from human bone marrow-derived MSCs (MSC-CM) increased the angiogenic activity of cord blood ECFCs in vitro (proliferation, migration, and pseudo-tube formation), the survival of ECFCs in mice (Matrigel Plug assay), and the capacity of ECFCs to promote the recovery of blood perfusion in mice with hindlimb ischaemia. Furthermore, the capillary density in ischaemic gastrocnemius muscle was significantly increased in mice transplanted with the ECFCs pre-treated with the MSC-CM. The enhancement of ECFCs activity involved the up-regulation of sphingosine kinase 1 (SphK1) expression and activity. The inhibition of SphK1 in ECFCs by using an inhibitor or a siRNA knockdown of SphK1 prevented the stimulation of the ECFCs induced by the MSC-CM. The improvement of ECFC activity by MSC-CM also involved the up-regulation of sphingosine-1-phosphate receptor 1 (S1P1) and a S1P/S1P1/3-dependent mechanism. Finally, we showed that the stimulation of ECFCs with exogenous S1P increased angiogenesis and promoted blood perfusion in hindlimb ischaemia.


The up-regulation of SphK1 and S1P-dependent pathways is critical for the angiogenic/vasculogenic activity of ECFCs. The identification of this pathway provides attractive targets to optimize cell-based therapy for revascularization in ischaemic diseases.


Cell therapy; Endothelial progenitor cells; Ischaemia; Mesenchymal stem cells; Sphingosine kinase 1

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