|
|
Blood, 1 March 2008, Vol. 111, No. 5, pp. 2640-2646.
Prepublished online as a Blood First Edition Paper on November 21, 2007; DOI 10.1182/blood-2007-04-086231.
 Previous Article | Next Article 
Submitted April 19, 2007
Accepted October 27, 2007
Activation of Epac stimulates integrin-dependent homing of progenitor cells
Guillaume Carmona, Emmanouil Chavakis*, Ulrike Koehl, Andreas M. Zeiher, and Stefanie Dimmeler
Molecular Cardiology, Dept of Internal Medicine III, J.W. Goethe University Frankfurt, Frankfurt, Germany
Pediatric Hematology & Oncology, Dept of Pediatrics III, J.W. Goethe University Frankfurt, Frankfurt, Germany
* Corresponding author; email: chavakis{at}em.uni-frankfurt.de.
Cell therapy is a novel promising option for treatment of patients with ischemic diseases. Administered endothelial progenitor cells (EPC) are recruited to ischemic regions and improve neovascularization. However, the number of cells, which home to ischemic tissues, is restricted. The small GTPase Rap1 plays an important role in the regulation of leukocyte adhesion, polarization, and chemotaxis. Here we investigated, whether pharmacological activation of Epac1, a nucleotide exchange protein for Rap1, which is directly activated by cAMP, can improve the adhesive and migratory capacity of distinct progenitor cell populations. Stimulation of Epac by a cAMP-analog, increased Rap1 activity and stimulated the adhesion of ex vivo expanded human EPC, CD34+ hematopoietic progenitor cells and mesenchymal stem cells (MSC). Specifically, short-term stimulation with a specific Epac activator increased the  2-integrin-dependent adhesion of EPC to mature endothelial cell monolayers, and of EPC and CD34+ hematopoietic progenitor cells to ICAM-1. Furthermore, the Epac activator enhanced the 1-integrin-dependent adhesion of EPC and MSC to the matrix protein fibronectin. In addition, Epac1 activation induced the 1- and 2-integrin- dependent migration of EPC on fibronectin and fibrinogen, respectively. Interestingly, activation of Epac rapidly increased lateral mobility of 1- and 2-integrins, thereby, inducing integrin polarization and stimulated 1-integrin affinity, while the 2-integrin affinity was not increased. Furthermore, prestimulation of EPC with the Epac activator increased homing to ischemic muscles and neovascularization-promoting capacity of intravenously injected EPC in the murine model of hind limb ischemia. Taken together, these data demonstrate that activation of Epac1 increases integrin activity and integrin-dependent homing functions of progenitor cells and enhance their in vivo therapeutical potential. These results may provide a platform for the development of novel therapeutical approaches to improve progenitor cell homing.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
Related Article in Blood Online:
-
Epac1 activation and progenitor-cell homing
- Domenico Ribatti
Blood 2008 111: 2501.
[Full Text]
[PDF]
This article has been cited by other articles:
|
|
|
|
 
S. Dimmeler and A. Leri
Aging and Disease as Modifiers of Efficacy of Cell Therapy
Circ. Res.,
June 6, 2008;
102(11):
1319 - 1330.
[Abstract]
[Full Text]
[PDF]
|
|
|
| |
