Efficient homing of multipotent adult mesenchymal stem cells depends on FROUNT-mediated clustering of CCR2.
Circulating stem cells of different origin have been demonstrated to improve repair of various organs both after systemic and local application, although the mechanisms that cause these effects are still not fully understood. We have used a combination of DNA microarray analysis and in vitro migration assays to screen for molecules that mediate homing of long-term renewing adult bone marrow-derived multipotent mesenchymal stem cells (BM-MASCs). We show that the cytokine receptor CCR2 is necessary for organ-specific homing of bone marrow-derived MASCs to the heart in a transgenic mouse model and into hearts damaged by ischemia/reperfusion. Homing and migration of stem cells was dependent on the intracellular adaptor molecule FROUNT, which interacts with CCR2. FROUNT was required for polarization of MASCs, resulting in clustering of CCR2 and reorganization of the cytoskeleton. Recruited MASCs summoned by the CCR2 ligand MCP-1/CCL2 expressed SDF1, which might trap additional bone marrow-derived circulating cells to contribute to the complex process of homing and retention of circulating stem and progenitor cells to remodel diseased organs.
Max-Planck-Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany.
Fikru
F
Belema-Bedada
Shizuka
S
Uchida
Alessandra
A
Martire
Sawa
S
Kostin
Thomas
T
Braun
D008841:Actin Cytoskeleton / Q000235:genetics / Q000378:metabolism; D053687:Adult Stem Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D033922:Clathrin Heavy Chains / Q000235:genetics / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D011940:Receptor Aggregation; D054390:Receptors, CCR2 / Q000378:metabolism*; D015427:Reperfusion Injury / Q000473:pathology; D014162:Transfection; D019076:Transgenes
C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; C503215:FROUNT protein, mouse; D054390:Receptors, CCR2; D033922:Clathrin Heavy Chains