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Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction

Abstract

Mesenchymal stem cells are multipotent cells that can differentiate into cardiomyocytes and vascular endothelial cells. Here we show, using cell sheet technology, that monolayered mesenchymal stem cells have multipotent and self-propagating properties after transplantation into infarcted rat hearts. We cultured adipose tissue–derived mesenchymal stem cells characterized by flow cytometry using temperature-responsive culture dishes. Four weeks after coronary ligation, we transplanted the monolayered mesenchymal stem cells onto the scarred myocardium. After transplantation, the engrafted sheet gradually grew to form a thick stratum that included newly formed vessels, undifferentiated cells and few cardiomyocytes. The mesenchymal stem cell sheet also acted through paracrine pathways to trigger angiogenesis. Unlike a fibroblast cell sheet, the monolayered mesenchymal stem cells reversed wall thinning in the scar area and improved cardiac function in rats with myocardial infarction. Thus, transplantation of monolayered mesenchymal stem cells may be a new therapeutic strategy for cardiac tissue regeneration.

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Figure 1: Preparation of monolayered MSCs.
Figure 2: Characteristics of monolayered MSCs.
Figure 3: Engraftment, survival and growth of monolayered MSCs.
Figure 4: Differentiation of MSCs within the MSC tissue after growth in situ.
Figure 5: Cardiac structure and function after transplantation of monolayered MSCs.

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Acknowledgements

We thank J.I. Hoffman for his statistical advice. We thank T. Iwase, T. Ito, S. Murakami, N. Sakata and Y. Isono for their technical support. We thank Y. Tsuboi and H. Sonoda for their assistance with microscopic analysis of monolayered cell grafts. We also thank Y. Sawa for his suggestions on this study. This work was supported by research grants for Cardiovascular Disease (16C-6) and Human Genome Tissue Engineering 005 and 009 from the Japanese Ministry of Health, Labor and Welfare, and the Program for Promotion of Fundamental Studies in Health Science of the Japanese National Institute of Biomedical Innovation.

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Correspondence to Noritoshi Nagaya or Hidezo Mori.

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Competing interests

Teruo Okano is an investor in Cell Seed, Ltd., Tokyo, Japan, and an inventor/developer designated on the patent for temperature-responsive culture surface.

Supplementary information

Supplementary Fig. 1

Comparison of cell surface markers between adipose tissue-derived MSCs and bone marrow-derived MSCs. (PDF 133 kb)

Supplementary Table 1

Characteristics of animals. (PDF 23 kb)

Supplementary Table 2

Quantitative counts of XY-chromosomes by FISH. (PDF 17 kb)

Supplementary Table 3

Echocardiographic data. (PDF 22 kb)

Supplementary Methods (PDF 50 kb)

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Miyahara, Y., Nagaya, N., Kataoka, M. et al. Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction. Nat Med 12, 459–465 (2006). https://doi.org/10.1038/nm1391

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