Pre-Clinical Research
Direct Comparison of Different Stem Cell Types and Subpopulations Reveals Superior Paracrine Potency and Myocardial Repair Efficacy With Cardiosphere-Derived Cells

https://doi.org/10.1016/j.jacc.2011.11.029Get rights and content
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Objectives

The goal of this study was to conduct a direct head-to-head comparison of different stem cell types in vitro for various assays of potency and in vivo for functional myocardial repair in the same mouse model of myocardial infarction.

Background

Adult stem cells of diverse origins (e.g., bone marrow, fat, heart) and antigenic identity have been studied for repair of the damaged heart, but the relative utility of the various cell types remains unclear.

Methods

Human cardiosphere-derived cells (CDCs), bone marrow–derived mesenchymal stem cells, adipose tissue–derived mesenchymal stem cells, and bone marrow mononuclear cells were compared.

Results

CDCs revealed a distinctive phenotype with uniform expression of CD105, partial expression of c-kit and CD90, and negligible expression of hematopoietic markers. In vitro, CDCs showed the greatest myogenic differentiation potency, highest angiogenic potential, and relatively high production of various angiogenic and antiapoptotic-secreted factors. In vivo, injection of CDCs into the infarcted mouse hearts resulted in superior improvement of cardiac function, the highest cell engraftment and myogenic differentiation rates, and the least-abnormal heart morphology 3 weeks after treatment. CDC-treated hearts also exhibited the lowest number of apoptotic cells. The c-kit+ subpopulation purified from CDCs produced lower levels of paracrine factors and inferior functional benefit when compared with unsorted CDCs. To validate the comparison of cells from various human donors, selected results were confirmed in cells of different types derived from individual rats.

Conclusions

CDCs exhibited a balanced profile of paracrine factor production and, among various comparator cell types/subpopulations, provided the greatest functional benefit in experimental myocardial infarction.

Key Words

cardiac stem cells
mesenchymal stem cells
myocardial regeneration
paracrine effects

Abbreviations and Acronyms

α-SA
α-sarcomeric actin
AD-MSCs
adipose tissue–derived mesenchymal stem cells
bFGF
basic fibroblast growth factor
BM-MNCs
bone marrow mononuclear cells
BM-MSCs
bone marrow–derived mesenchymal stem cells
CDCs
cardiosphere-derived cells
ELISA
enzyme-linked immunoadsorbent assay
HGF
hepatocyte growth factor
HNA
human nuclear antigen
IGF
insulin-like growth factor
IMDM
Iscove's modified Dulbecco's medium
LV
left ventricular
LVEF
left ventricular ejection fraction
PCR
polymerase chain reaction
SCID
severe combined immunodeficiency
SDF
stromal cell–derived factor
TUNEL
terminal deoxynucleotidyl transferase dUTP nick end labeling
VEGF
vascular endothelial growth factor

Cited by (0)

This study was supported by the National Institutes of Health (HL095203) to Capricor, Inc., by the National Institutes of Health (U54 HL081028) to Dr. E. Marbán, and by the Cedars-Sinai Board of Governors Heart Stem Cell Center. Dr. E. Marbán is the Mark S. Siegel Family Professor of the Cedars-Sinai Medical Center. Dr. E. Marbán and Dr. L. Marbán hold founders' equity in Capricor, Inc. Drs. Smith, Blusztajn, Terrovitis, and L. Marbán are employed by Capricor, Inc. Drs. Malliaras and Terrovitis are consultants of Capricor, Inc.

All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Li, Cheng, and Malliaras contributed equally to this work.