The bispecific SDF1-GPVI fusion protein preserves myocardial function after transient ischemia in mice.
BACKGROUND
CXCR4-positive bone marrow cells (BMCs) are critically involved in cardiac repair mechanisms contributing to preserved cardiac function. Stromal cell-derived factor-1 (SDF-1) is the most prominent BMC homing factor known to augment BMC engraftment, which is a limiting step of stem cell-based therapy. After myocardial infarction, SDF-1 expression is rapidly upregulated and promotes myocardial repair.


RESULTS
We have established a bifunctional protein consisting of an SDF-1 domain and a glycoprotein VI (GPVI) domain with high binding affinity to the SDF-1 receptor CXCR4 and extracellular matrix proteins that become exposed after tissue injury. SDF1-GPVI triggers chemotaxis of CXCR4-positive cells, preserves cell survival, enhances endothelial differentiation of BMCs in vitro, and reveals proangiogenic effects in ovo. In a mouse model of myocardial infarction, administration of the bifunctional protein leads to enhanced recruitment of BMCs, increases capillary density, reduces infarct size, and preserves cardiac function.


CONCLUSIONS
These results indicate that administration of SDF1-GPVI may be a promising strategy to treat myocardial infarction to promote myocardial repair and to preserve cardiac function.
Innere Medizin III, Eberhard Karls Universität, Tübingen, Otfried-Müller-Strasse 10, Tübingen, Germany.
Melanie
M
Ziegler
Margitta
M
Elvers
Yvonne
Y
Baumer
Christoph
C
Leder
Carmen
C
Ochmann
Tanja
T
Schönberger
Tobias
T
Jürgens
Tobias
T
Geisler
Burkhard
B
Schlosshauer
Oleg
O
Lunov
Stefan
S
Engelhardt
Thomas
T
Simmet
Meinrad
M
Gawaz
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D064987:Cell- and Tissue-Based Therapy; D054377:Chemokine CXCL12 / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D003094:Collagen / Q000378:metabolism; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology*; D002546:Ischemic Attack, Transient / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011485:Protein Binding; D019718:Receptors, CXCR4 / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D016896:Treatment Outcome
C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D010980:Platelet Membrane Glycoproteins; D019718:Receptors, CXCR4; D011993:Recombinant Fusion Proteins; C098341:platelet membrane glycoprotein VI; D003094:Collagen