Transplantation of cardiac progenitor cells ameliorates cardiac dysfunction after myocardial infarction in mice
Katsuhisa Matsuura, … , Nobuhisa Hagiwara, Issei Komuro
Katsuhisa Matsuura, … , Nobuhisa Hagiwara, Issei Komuro
Published July 13, 2009
Citation Information: J Clin Invest. 2009;119(8):2204-2217. https://doi.org/10.1172/JCI37456.
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Research Article Cardiology

Transplantation of cardiac progenitor cells ameliorates cardiac dysfunction after myocardial infarction in mice

Abstract

Cardiac progenitor cells are a potential source of cell therapy for heart failure. Although recent studies have shown that transplantation of cardiac stem/progenitor cells improves function of infarcted hearts, the precise mechanisms of the improvement in function remain poorly understood. The present study demonstrates that transplantation of sheets of clonally expanded stem cell antigen 1–positive (Sca-1–positive) cells (CPCs) ameliorates cardiac dysfunction after myocardial infarction in mice. CPC efficiently differentiated into cardiomyocytes and secreted various cytokines, including soluble VCAM-1 (sVCAM-1). Secreted sVCAM-1 induced migration of endothelial cells and CPCs and prevented cardiomyocyte death from oxidative stress through activation of Akt, ERK, and p38 MAPK. Treatment with antibodies specific for very late antigen-4 (VLA-4), a receptor of sVCAM-1, abolished the effects of CPC-derived conditioned medium on cardiomyocytes and CPCs in vitro and inhibited angiogenesis, CPC migration, and survival in vivo, which led to attenuation of improved cardiac function following transplantation of CPC sheets. These results suggest that CPC transplantation improves cardiac function after myocardial infarction through cardiomyocyte differentiation and paracrine mechanisms mediated via the sVCAM-1/VLA-4 signaling pathway.

Authors

Katsuhisa Matsuura, Atsushi Honda, Toshio Nagai, Noritoshi Fukushima, Koji Iwanaga, Masakuni Tokunaga, Tatsuya Shimizu, Teruo Okano, Hiroshi Kasanuki, Nobuhisa Hagiwara, Issei Komuro

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Figure 7

The roles of VLA-4 signaling on CPC sheet transplantation-mediated improved cardiac function.

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The roles of VLA-4 signaling on CPC sheet transplantation-mediated impro...
Analysis of cardiac function by echocardiography (A, n = 5) and catheterization (B, n = 5). Anti–VLA-4 Ab treatment inhibited the reduction of LVDd, LVDs, and LVEDP and the improvement of FS and +dp/dt by CPC sheet transplantation. Isotype Ab was used as a control. †P < 0.05 versus anti–VLA-4 Abs (n = 5 per group). ‡P < 0.01 versus anti–VLA-4 Abs (n = 5 per group). (C) Masson trichrome staining. The fibrotic area 4 weeks after transplantation was calculated and is shown in the graph (n = 5). Anti–VLA-4 Ab treatment inhibited the reduction of fibrotic area following CPC sheet transplantation. Lower panels show representative images. Scale bars: 1 mm. (D) vWF staining. The number of vWF-positive vessels in the border area was counted and is shown in the graph (n = 5). Anti–VLA-4 Ab treatment inhibited the increased number of vessels in the border area following CPC sheet transplantation. Lower panels show representative images. Scale bars: 100 μm. Nuclei were stained with hematoxylin. (E) RFP staining. The number of RFP-positive cells (brown) was counted and is shown in the graph (n = 5). Anti–VLA-4 Ab treatment decreased the number of RFP+ cells in the infarcted area following CPC sheet transplantation. Lower panels show representative images. Nuclei were stained with hematoxylin. Scale bars: 100 μm. Data are shown as mean + SEM.