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. 2011 Feb 10;6(2):e15652.
doi: 10.1371/journal.pone.0015652.

Cell origin of human mesenchymal stem cells determines a different healing performance in cardiac regeneration

Ralf Gaebel  1 , Dario Furlani, Heiko Sorg, Bianca Polchow, Johannes Frank, Karen Bieback, Weiwei Wang, Christian Klopsch, Lee-Lee Ong, Wenzhong Li, Nan Ma, Gustav Steinhoff
Affiliations

Cell origin of human mesenchymal stem cells determines a different healing performance in cardiac regeneration

Ralf Gaebel et al. PLoS One. .

Abstract

The possible different therapeutic efficacy of human mesenchymal stem cells (hMSC) derived from umbilical cord blood (CB), adipose tissue (AT) or bone marrow (BM) for the treatment of myocardial infarction (MI) remains unexplored. This study was to assess the regenerative potential of hMSC from different origins and to evaluate the role of CD105 in cardiac regeneration. Male SCID mice underwent LAD-ligation and received the respective cell type (400.000/per animal) intramyocardially. Six weeks post infarction, cardiac catheterization showed significant preservation of left ventricular functions in BM and CD105(+)-CB treated groups compared to CB and nontreated MI group (MI-C). Cell survival analyzed by quantitative real time PCR for human GAPDH and capillary density measured by immunostaining showed consistent results. Furthermore, cardiac remodeling can be significantly attenuated by BM-hMSC compared to MI-C. Under hypoxic conditions in vitro, remarkably increased extracellular acidification and apoptosis has been detected from CB-hMSC compared to BM and CD105 purified CB-derived hMSC. Our findings suggests that hMSC originating from different sources showed a different healing performance in cardiac regeneration and CD105(+) hMSC exhibited a favorable survival pattern in infarcted hearts, which translates into a more robust preservation of cardiac function.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Phenotypic characterization of hMSC from different sources.
A. FACS analysis showed that the cells were negative for CD45 expression and positive for CD29, CD44, CD73 and CD105, which are phenotypes currently known to be characteristic of hMSC. The gray line indicates the control of the CD marker isotypes. B. In vitro differentiation capacity of transplanted hMSC. hMSC from bone marrow were cultured in adipogenic and chondrogenic medium. Chondrogenic differentiation (left). Immunostaining for aggrecan (red). Nuclei were counterstained with DAPI (blue). Adipogenic differentiation (right). Immunostaining with fatty acid binding protein-4 (brown).
Figure 2
Figure 2. Heart functions 6 weeks after MI.
A. Recovery of cardiac performance shows improvement for hearts with implanted human BM- and CD105-purified CB-hMSC compared to MI-CB hearts. B. Left ventricular functions at both baseline and stress condition assessed by catheterization.
Figure 3
Figure 3. Infarction size 6 weeks after MI.
A. Representative ventricular cross sections of heart level c. B. Ratio of infarction size to entire LV is significantly decreased in MI-BM and MI-CB105+ compared to MIC.
Figure 4
Figure 4. Capillary density 6 weeks after MI.
A. Representative endothelial CD31 staining at the infarction border zone of level c sections. B. Capillary density in both the RA and the BZ of the LV is significantly higher in MI-AT, MI-BM and MI-CB105+ compared to MIC.
Figure 5
Figure 5. Fibrosis 6 weeks after MI.
A. Representative Fast Green FCF (myocytes)/Sirius Red (fibrosis) stainings at the BZ. B. Significantly decrease of collagen deposition has been shown in both the RA and the BZ in MI-CB105+ compared to MI-CB and MI-C.
Figure 6
Figure 6. Late cardiomyocytes apoptosis.
A. Representative immunostaining for TUNEL (green) and cardiac troponin (red) at the BZ 6 weeks after MI. B. Cardiomyocytes apoptosis was significantly reduced in the BZ in MI-BM and MI-CB105+ compared to MI-C.
Figure 7
Figure 7. Identification of transplanted hMSC in infracted myocardium.
6 weeks after MI: A–C. Representative immunofluorescent micrographs of hearts transplanted with hMSC. A transplanted hMSC could be identified in infarcted myocardium B. A number of hMSC (Arrows, human nuclei in green) were co-localized with CD31 positive cells (red). C. Occasionally hMSC (Arrow, human nuclei in green) co-localized with cardiac troponin positive cell (red). (Confocal image, original magnification 630×) D. Quantitative real-time PCR analysis for human GAPDH expression level at different infarction sections: MI-BM and MI-CB105+ hearts show significantly higher localisation of human cells in the middle and apex section.
Figure 8
Figure 8. Real time acidification rate as a live cell parameter.
CB derived hMSC show significant increased metabolic activity under hypoxic situation compared to BM- and CD105-purified CB-derived hMSC.
Figure 9
Figure 9. CD105 cell isolated from BM hMSC were transiently transfected with GFP, antisense-Oligodesoxynukleotide (ODN-CD105), scramble ODN.
A. Transfection efficiency is shown on the upper picture (GFP) B. Silencing of CD105 blocks BM-hMSC tube formation compared to nature and scrambled group. The BM-hMSC were embedded in Matrigel and incubated in EGM-2 seven days after transfection and then imaged. C. Cell proliferation was analyzed at 24, 48 and 96 h after the ODN-CD105 and scramble ODN transfection by MTT assay.
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