Published online before print January 2, 2009, doi: 10.1161/ATVBAHA.108.182006
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© 2009 American Heart Association, Inc.
Cell Biology/Signaling |
Caspase-8 Is Involved in Neovascularization-Promoting Progenitor Cell Functions
From the Molecular Cardiology, Department of Internal Medicine III (D.S., L.R., G.C., E.C., C.U., A.F., A.M.Z., S.D.), University of Frankfurt, Germany; Biological Chemistry (T.-B.K., D.W.), Weizmann Institute of Science, Rehovot, Israel; Experimental Immunology Branch (Y.J.C.), National Cancer Institute, National Institutes of Health, Bethesda, Md; and Biochemistry (Y.L.D., I.D.), University of Frankfurt, Germany.
Correspondence to Stefanie Dimmeler, PhD, Molecular Cardiology, the Department of Internal Medicine III, University of Frankfurt, Theodor Stern-Kai 7, 60590 Frankfurt, Germany. E-mail dimmeler{at}em.uni-frankfurt.de
Objective— Endothelial progenitor cells (EPCs) comprise a heterogeneous population of cells, which improve therapeutic neovascularization after ischemia. The neovascularization-promoting potential of progenitor cells depends on survival and retention of the infused cells to the tissue. Caspases mediate apoptosis but are also involved in other critical biological processes. Therefore, we aimed to address the role of caspases in proangiogenic cells.
Methods and Results— The caspase-8 inhibitor zIETD abrogated the ex vivo formation of EPCs, inhibited EPC adhesion and migration, and reduced their capacity to improve neovascularization in vivo. Consistently, cells isolated from caspase-8-deficient mice exhibited a reduced capacity for enhancing neovascularization when transplanted into mice after hindlimb ischemia. Because inhibition of Caspase-8 reduced the adhesion and homing functions of EPCs, we further determined the surface expression of integrins and receptors involved in cell recruitment to ischemic tissues. Pharmacological inhibition of caspase-8 and genetic depletion of caspase-8 reduced the expression of the fibronectin receptor subunits 
5 and β1 and the SDF-1 receptor CXCR4. Moreover, we identified the E3 ubiquitin ligase Cbl-b, which negatively regulates integrin and receptor-mediated signaling, as a potential Caspase-8 substrate.
Conclusion— In summary, our data demonstrate a novel apoptosis-unrelated role of caspase-8 in proangiogenic cells.
The neovascularization-promoting potential of progenitor cells depends on survival and retention of the infused cells to the tissue. Here we provide evidence that caspase-8 is essential for progenitor cell adhesion, migration, and in vivo homing demonstrating a novel apoptosis-unrelated role of caspase-8 in proangiogenic cells.
Key Words: progenitor cells • homing • integrin • angiogenesis • cell therapy
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Arterioscler Thromb Vasc Biol 2009 29: 444-446.
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  Q. Xiao and Q. Xu Caspase-8, a Double-Edged Sword for EPC Functioning Arterioscler Thromb Vasc Biol, April 1, 2009; 29(4): 444 - 446. [Full Text] [PDF]
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