Cell therapy enhances function of remote non-infarcted myocardium.
Cell transplantation improves cardiac function after myocardial infarction; however, the underlying mechanisms are not well-understood. Therefore, the goals of this study were to determine if neonatal rat cardiomyocytes transplanted into adult rat hearts 1 week after infarction would, after 8-10 weeks: 1) improve global myocardial function, 2) contract in a Ca2+ dependent manner, 3) influence mechanical properties of remote uninjured myocardium and 4) alter passive mechanical properties of infarct regions. The cardiomyocytes formed small grafts of ultrastructurally maturing myocardium that enhanced fractional shortening compared to non-treated infarcted hearts. Chemically demembranated tissue strips of cardiomyocyte grafts produced force when activated by Ca2+, whereas scar tissue did not. Furthermore, the Ca2+ sensitivity of force was greater in cardiomyocyte grafts compared to control myocardium. Surprisingly, cardiomyocytes grafts isolated in the infarct zone increased Ca2+ sensitivity of remote uninjured myocardium to levels greater than either remote myocardium from non-treated infarcted hearts or sham-operated controls. Enhanced calcium sensitivity was associated with decreased phosphorylation of cTnT, tropomyosin and MLC2, but not changes in myosin or troponin isoforms. Passive compliance of grafts resembled normal myocardium, while infarct tissue distant from grafts had compliance typical of scar. Thus, cardiomyocyte grafts are contractile, improve local tissue compliance and enhance calcium sensitivity of remote myocardium. Because the volume of remote myocardium greatly exceeds that of the grafts, this enhanced calcium sensitivity may be a major contributor to global improvements in ventricular function after cell transplantation.
Moreno-Gonzalez
Alicia
A
Department of Bioengineering, University of Washington, Seattle, WA 98195-7962, USA.
Korte
F Steven
FS
Dai
Jin
J
Chen
Kent
K
Ho
Bryan
B
Reinecke
Hans
H
Murry
Charles E
CE
Regnier
Michael
M
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D024722:Cardiac Myosins / Q000378:metabolism; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D002478:Cells, Cultured; D004452:Echocardiography; D004591:Electrophoresis, Polyacrylamide Gel; D066298:In Vitro Techniques; D046529:Microscopy, Electron, Transmission; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000637:transplantation*; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D014335:Tropomyosin / Q000378:metabolism
D018994:Myosin Light Chains; D014335:Tropomyosin; C107184:myosin light chain 2; D024722:Cardiac Myosins
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