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Cardiovascular Research Advance Access first published online on May 9, 2009
This version [Corrected Proof] published online on June 25, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp146
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Human cardiomyocyte progenitor cell transplantation preserves long-term function of the infarcted mouse myocardium

Anke M. Smits1,3,{dagger}, Linda W. van Laake1,2,{dagger}, Krista den Ouden1, Chantal Schreurs2, Károly Szuhai3, Cees J. van Echteld1,4, Christine L. Mummery2,4,{ddagger}, Pieter A. Doevendans1,4 and Marie-José Goumans1,3,*

1 Department of Cardiology, University Medical Center, Utrecht, The Netherlands
2 Hubrecht Institute (Developmental Biology and Stem Cell Research), Utrecht, The Netherlands
3 Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands
4 Interuniversity Cardiology Institute of the Netherlands (ICIN), Utrecht, The Netherlands

* Corresponding author: Laboratory of Molecular Cell Biology, Postal zone S1-P, PO Box 9600, 2300 RC Leiden, The Netherlands. Tel: +31 71 526 9277; fax: +31 71 526 8270. E-mail address: m.j.goumans{at}lumc.nl

Aims: 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.

Methods and 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.

Conclusion: 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.

KEYWORDS cardiomyocyte progenitor cell; stem cell; cell differentiation; ventricular function; infarction

Time for primary review: 31 days

{dagger} Both authors contributed equally to this manuscript.

{ddagger} Present address. Laboratory of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands


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