Human cardiomyocyte progenitor cell transplantation preserves long-term function of the infarcted mouse myocardium.
OBJECTIVE
Recent clinical studies revealed that positive results of cell transplantation on cardiac function are limited to the short- and mid-term restoration phase following myocardial infarction (MI), emphasizing the need for long-term follow-up. These transient effects may depend on the transplanted cell-type or its differentiation state. We have identified a population of cardiomyocyte progenitor cells (CMPCs) capable of differentiating efficiently into beating cardiomyocytes, endothelial cells, and smooth muscle cells in vitro. We investigated whether CMPCs or pre-differentiated CMPC-derived cardiomyocytes (CMPC-CM) are able to restore the injured myocardium after MI in mice.


RESULTS
MI was induced in immunodeficient mice and was followed by intra-myocardial injection of CMPCs, CMPC-CM, or vehicle. Cardiac function was measured longitudinally up to 3 months post-MI using 9.4 Tesla magnetic resonance imaging. The fate of the human cells was determined by immunohistochemistry. Transplantation of CMPCs or CMPC-CM resulted in a higher ejection fraction and reduced the extent of left ventricular remodelling up to 3 months after MI when compared with vehicle-injected animals. CMPCs and CMPC-CM generated new cardiac tissue consisting of human cardiomyocytes and blood vessels. Fusion of human nuclei with murine nuclei was not observed.


CONCLUSIONS
CMPCs differentiated into the same cell types in situ as can be obtained in vitro. This excludes the need for in vitro pre-differentiation, making CMPCs a promising source for (autologous) cell-based therapy.
Smits
Anke M
AM
Department of Cardiology, University Medical Center, Utrecht, The Netherlands.
van Laake
Linda W
LW
den Ouden
Krista
K
Schreurs
Chantal
C
Szuhai
Károly
K
van Echteld
Cees J
CJ
Mummery
Christine L
CL
Doevendans
Pieter A
PA
Goumans
Marie-José
MJ
D000818:Animals; D002454:Cell Differentiation; D002459:Cell Fusion; D002470:Cell Survival; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000473:pathology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000473:pathology / Q000637:transplantation; D005318:Fetal Heart / Q000166:cytology; D006801:Humans; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D032383:Myocytes, Cardiac / Q000473:pathology / Q000637:transplantation*; D032389:Myocytes, Smooth Muscle / Q000473:pathology / Q000637:transplantation; D020127:Recovery of Function; D012038:Regeneration; D033581:Stem Cell Transplantation; D013318:Stroke Volume; D013997:Time Factors; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling