Monocyte chemotactic protein-3 is a myocardial mesenchymal stem cell homing factor.
MSCs have received attention for their therapeutic potential in a number of disease states, including bone formation, diabetes, stem cell engraftment after marrow transplantation, graft-versus-host disease, and heart failure. Despite this diverse interest, the molecular signals regulating MSC trafficking to sites of injury are unclear. MSCs are known to transiently home to the freshly infarcted myocardium. To identify MSC homing factors, we determined chemokine expression pattern as a function of time after myocardial infarction (MI). We merged these profiles with chemokine receptors expressed on MSCs but not cardiac fibroblasts, which do not home after MI. This analysis identified monocyte chemotactic protein-3 (MCP-3) as a potential MSC homing factor. Overexpression of MCP-3 1 month after MI restored MSC homing to the heart. After serial infusions of MSCs, cardiac function improved in MCP-3-expressing hearts (88.7%, p < .001) but not in control hearts (8.6%, p = .47). MSC engraftment was not associated with differentiation into cardiac myocytes. Rather, MSC engraftment appeared to result in recruitment of myofibroblasts and remodeling of the collagen matrix. These data indicate that MCP-3 is an MSC homing factor; local overexpression of MCP-3 recruits MSCs to sites of injured tissue and improves cardiac remodeling independent of cardiac myocyte regeneration.
Schenk
Soren
S
Departments of Biomedical Engineering, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Mal
Niladri
N
Finan
Amanda
A
Zhang
Ming
M
Kiedrowski
Matt
M
Popovic
Zoran
Z
McCarthy
Patrick M
PM
Penn
Marc S
MS
D000818:Animals; D002465:Cell Movement; D054410:Chemokine CCL7; D018925:Chemokines / Q000235:genetics / Q000502:physiology; D003094:Collagen / Q000378:metabolism; D003331:Coronary Vessels / Q000473:pathology*; D004452:Echocardiography; D006321:Heart / Q000502:physiology*; D045164:Mesenchymal Stem Cell Transplantation; D018613:Microscopy, Confocal; D023421:Models, Animal; D018945:Monocyte Chemoattractant Proteins / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D051381:Rats; D011917:Rats, Inbred Lew; D019707:Receptors, Chemokine / Q000235:genetics*
C515452:Ccl7 protein, rat; D054410:Chemokine CCL7; D018925:Chemokines; D018945:Monocyte Chemoattractant Proteins; D019707:Receptors, Chemokine; D003094:Collagen