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C3a and C5a Are Chemotactic Factors for Human Mesenchymal Stem Cells, Which Cause Prolonged ERK1/2 Phosphorylation¹

Torrey Pines Institute for Molecular Studies, San Diego, CA 92121

Mesenchymal stem cells (MSCs) have a great potential for tissue repair, especially if they can be delivered efficiently to sites of tissue injury. Since complement activation occurs whenever there is tissue damage, the effects of the complement activation products C3a and C5a on MSCs were examined. Both C3a and C5a were chemoattractants for human bone marrow-derived MSCs, which expressed both the C3a receptor (C3aR) and the C5a receptor (C5aR; CD88) on the cell surface. Specific C3aR and C5aR inhibitors blocked the chemotactic response, as did pertussis toxin, indicating that the response was mediated by the known anaphylatoxin receptors in a G_i activation-dependent fashion. While C5a causes strong and prolonged activation of various signaling pathways in many different cell types, the response observed with C3a is generally transient and weak. However, we show herein that in MSCs both C3a and C5a caused prolonged and robust ERK1/2 and Akt phosphorylation. Phospho-ERK1/2 was translocated to the nucleus in both C3a and C5a-stimulated MSCs, which was associated with subsequent phosphorylation of the transcription factor Elk, which could not be detected in other cell types stimulated with C3a. More surprisingly, the C3aR itself was translocated to the nucleus in C3a-stimulated MSCs, especially at low cell densities. Since nuclear activation/translocation of G protein-coupled receptors has been shown to induce long-term effects, this novel observation implies that C3a exerts far-reaching consequences on MSC biology. These results suggest that the anaphylatoxins C3a and C5a present in injured tissues contribute to the recruitment of MSCs and regulation of their behavior.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was funded by grants (Tobacco-Related Disease Research Program (TRDRP) 13RT-0083) to I.U.S. and (TRDRP 16RT-0134) to S.K.K.

² Address correspondence and reprint requests to Dr. Ingrid U. Schraufstatter, Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, San Diego, CA 92121. E-mail address: ischraufstatter{at}tpims.org

³ Current address: The Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037.

⁴ Abbreviations used in this paper: MSC, mesenchymal stem cell; bFGF, basic fibroblast growth factor; C3aR, C3a receptor; C5aR, C5a receptor (CD88); DAPI, 4',6-diamidino-2-phenylindole; EGF, epidermal growth factor; GPCR, G protein-coupled receptor; LPA, lysophosphatidic acid; SDF-1, stromal cell-derived factor 1.