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Cardiomyocytes fuse with surrounding noncardiomyocytes and reenter the cell cycle.

Matsuura K, Wada H, Nagai T, Iijima Y, Minamino T, Sano M, Akazawa H, Molkentin JD, Kasanuki H, Komuro I - J. Cell Biol. (2004)

Bottom Line: Furthermore, cardiomyocytes reentered the G2-M phase in the cell cycle after fusing with proliferative noncardiomyocytes.Transplanted endothelial cells or skeletal muscle-derived cells fused with adult cardiomyocytes in vivo.In the cryoinjured heart, there were Ki67-positive cells that expressed both cardiac and endothelial lineage marker proteins.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.

ABSTRACT
The concept of the plasticity or transdifferentiation of adult stem cells has been challenged by the phenomenon of cell fusion. In this work, we examined whether neonatal cardiomyocytes fuse with various somatic cells including endothelial cells, cardiac fibroblasts, bone marrow cells, and endothelial progenitor cells spontaneously in vitro. When cardiomyocytes were cocultured with endothelial cells or cardiac fibroblasts, they fused and showed phenotypes of cardiomyocytes. Furthermore, cardiomyocytes reentered the G2-M phase in the cell cycle after fusing with proliferative noncardiomyocytes. Transplanted endothelial cells or skeletal muscle-derived cells fused with adult cardiomyocytes in vivo. In the cryoinjured heart, there were Ki67-positive cells that expressed both cardiac and endothelial lineage marker proteins. These results suggest that cardiomyocytes fuse with other cells and enter the cell cycle by maintaining their phenotypes.

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Cardiac phenotype is dominated in fused cells. (A and B) Each bar represents the number of GFP+/RFP+ fused cells in 105 RFP+ HUVEC cocultured with GFP+ neonatal rat cardiomyocytes at different time in culture. The number of GFP+/RFP+ fused cells was increased with the time-dependent manner. The percentage of cTnT-positive cells and the percentage of vWF-positive cells in GFP+/RFP+ fused cells are presented by line graphs. The percentage of cTnT-positive cells in GFP+/RFP+ fused cells (A) increased and that of vWF-positive cells (B) decreased with the time-dependent manner. Data are mean ± SD of three independent experiments. *, P < 0.01 vs. 1 d; †, P < 0.01 vs. 4 d; ‡, P < 0.05 vs. 1 d. (C and D) Each bar represents the number of GFP+/RFP+ fused cells in 105 RFP+ cFB cocultured with GFP+ neonatal rat cardiomyocytes at different time in culture. The number of GFP+/RFP+ fused cells was increased with the time-dependent manner. The percentage of cTnT-positive cells and the percentage of vimentin-positive cells in GFP+/RFP+ fused cells are presented by line graphs. The percentage of cTnT-positive cells in GFP+/RFP+ fused cells (C) increased and that of vimentin-positive cells (D) decreased with the time-dependent manner. Data are mean ± SD of three independent experiments. *, P < 0.01 vs. 1 d; †, P < 0.01 vs. 4 d; ‡, P < 0.05 vs. 1 d.
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fig3: Cardiac phenotype is dominated in fused cells. (A and B) Each bar represents the number of GFP+/RFP+ fused cells in 105 RFP+ HUVEC cocultured with GFP+ neonatal rat cardiomyocytes at different time in culture. The number of GFP+/RFP+ fused cells was increased with the time-dependent manner. The percentage of cTnT-positive cells and the percentage of vWF-positive cells in GFP+/RFP+ fused cells are presented by line graphs. The percentage of cTnT-positive cells in GFP+/RFP+ fused cells (A) increased and that of vWF-positive cells (B) decreased with the time-dependent manner. Data are mean ± SD of three independent experiments. *, P < 0.01 vs. 1 d; †, P < 0.01 vs. 4 d; ‡, P < 0.05 vs. 1 d. (C and D) Each bar represents the number of GFP+/RFP+ fused cells in 105 RFP+ cFB cocultured with GFP+ neonatal rat cardiomyocytes at different time in culture. The number of GFP+/RFP+ fused cells was increased with the time-dependent manner. The percentage of cTnT-positive cells and the percentage of vimentin-positive cells in GFP+/RFP+ fused cells are presented by line graphs. The percentage of cTnT-positive cells in GFP+/RFP+ fused cells (C) increased and that of vimentin-positive cells (D) decreased with the time-dependent manner. Data are mean ± SD of three independent experiments. *, P < 0.01 vs. 1 d; †, P < 0.01 vs. 4 d; ‡, P < 0.05 vs. 1 d.

Mentions: The von Willebrand factor (vWF) and vimentin are phenotype-specific markers of endothelial cells and fibroblasts, respectively, and are never expressed in cardiomyocytes. When GFP+ cardiomyocytes were cocultured with RFP+ HUVEC or RFP+ cFB, some of GFP+/RFP+ fused cells expressed vWF (Fig. 2 B, e and f) and vimentin (Fig. 2 B, k and l), respectively. To elucidate the phenotype in fused cells, we quantified the percentage of cTnT-, vWF-, or vimentin-expressing cells in the GFP+/RFP+ fused cells. When GFP+ cardiomyocytes were cocultured with RFP+ HUVEC, the number of GFP+/RFP+ fused cells was increased with the time-dependent manner (Fig. 3, A and B, bar graphs; Table I). The percentage of cTnT-expressing cells in the total fused cells was also increased with the time-dependent manner (d 1, 58.6 ± 2.9%; d 4, 73.7 ± 3.9%; d 7, 76.2 ± 1.9%); on the other hand, the percentage of vWF-expressing cells in fused cells was decreased with the time-dependent manner (d 1, 41.3 ± 10.3%; d 4, 39.2 ± 3.7%; d 7, 27.7 ± 1.6%), suggesting that the cardiac phenotype becomes predominant in the cells formed by fusion between cardiomyocytes and endothelial cells (Fig. 3, A and B, line graphs; Table I). When GFP+ cardiomyocytes were cocultured with RFP+ cFB, the number of GFP+/RFP+ fused cells was gradually increased (Fig. 3, C and D, bar graphs; Table II). The percentage of cTnT-expressing cells in fused cells was also increased with the time-dependent manner (d 1, 54.2 ± 3.8%; d 4, 75.8 ± 5.6%; d 7, 83.5 ± 2.6%); on the other hand, the percentage of vimentin-expressing cells (Fig. 2 B, k and l) in fused cells was decreased progressively (d 1, 45.3 ± 9.3%; d 4, 25.9 ± 8.8%; d 7, 11.5 ± 1.6%), suggesting that cardiac phenotypes also dominate in fused cells between cardiomyocytes and cFB (Fig. 3, C and D, line graphs; Table II).


Cardiomyocytes fuse with surrounding noncardiomyocytes and reenter the cell cycle.

Matsuura K, Wada H, Nagai T, Iijima Y, Minamino T, Sano M, Akazawa H, Molkentin JD, Kasanuki H, Komuro I - J. Cell Biol. (2004)

Cardiac phenotype is dominated in fused cells. (A and B) Each bar represents the number of GFP+/RFP+ fused cells in 105 RFP+ HUVEC cocultured with GFP+ neonatal rat cardiomyocytes at different time in culture. The number of GFP+/RFP+ fused cells was increased with the time-dependent manner. The percentage of cTnT-positive cells and the percentage of vWF-positive cells in GFP+/RFP+ fused cells are presented by line graphs. The percentage of cTnT-positive cells in GFP+/RFP+ fused cells (A) increased and that of vWF-positive cells (B) decreased with the time-dependent manner. Data are mean ± SD of three independent experiments. *, P < 0.01 vs. 1 d; †, P < 0.01 vs. 4 d; ‡, P < 0.05 vs. 1 d. (C and D) Each bar represents the number of GFP+/RFP+ fused cells in 105 RFP+ cFB cocultured with GFP+ neonatal rat cardiomyocytes at different time in culture. The number of GFP+/RFP+ fused cells was increased with the time-dependent manner. The percentage of cTnT-positive cells and the percentage of vimentin-positive cells in GFP+/RFP+ fused cells are presented by line graphs. The percentage of cTnT-positive cells in GFP+/RFP+ fused cells (C) increased and that of vimentin-positive cells (D) decreased with the time-dependent manner. Data are mean ± SD of three independent experiments. *, P < 0.01 vs. 1 d; †, P < 0.01 vs. 4 d; ‡, P < 0.05 vs. 1 d.
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fig3: Cardiac phenotype is dominated in fused cells. (A and B) Each bar represents the number of GFP+/RFP+ fused cells in 105 RFP+ HUVEC cocultured with GFP+ neonatal rat cardiomyocytes at different time in culture. The number of GFP+/RFP+ fused cells was increased with the time-dependent manner. The percentage of cTnT-positive cells and the percentage of vWF-positive cells in GFP+/RFP+ fused cells are presented by line graphs. The percentage of cTnT-positive cells in GFP+/RFP+ fused cells (A) increased and that of vWF-positive cells (B) decreased with the time-dependent manner. Data are mean ± SD of three independent experiments. *, P < 0.01 vs. 1 d; †, P < 0.01 vs. 4 d; ‡, P < 0.05 vs. 1 d. (C and D) Each bar represents the number of GFP+/RFP+ fused cells in 105 RFP+ cFB cocultured with GFP+ neonatal rat cardiomyocytes at different time in culture. The number of GFP+/RFP+ fused cells was increased with the time-dependent manner. The percentage of cTnT-positive cells and the percentage of vimentin-positive cells in GFP+/RFP+ fused cells are presented by line graphs. The percentage of cTnT-positive cells in GFP+/RFP+ fused cells (C) increased and that of vimentin-positive cells (D) decreased with the time-dependent manner. Data are mean ± SD of three independent experiments. *, P < 0.01 vs. 1 d; †, P < 0.01 vs. 4 d; ‡, P < 0.05 vs. 1 d.
Mentions: The von Willebrand factor (vWF) and vimentin are phenotype-specific markers of endothelial cells and fibroblasts, respectively, and are never expressed in cardiomyocytes. When GFP+ cardiomyocytes were cocultured with RFP+ HUVEC or RFP+ cFB, some of GFP+/RFP+ fused cells expressed vWF (Fig. 2 B, e and f) and vimentin (Fig. 2 B, k and l), respectively. To elucidate the phenotype in fused cells, we quantified the percentage of cTnT-, vWF-, or vimentin-expressing cells in the GFP+/RFP+ fused cells. When GFP+ cardiomyocytes were cocultured with RFP+ HUVEC, the number of GFP+/RFP+ fused cells was increased with the time-dependent manner (Fig. 3, A and B, bar graphs; Table I). The percentage of cTnT-expressing cells in the total fused cells was also increased with the time-dependent manner (d 1, 58.6 ± 2.9%; d 4, 73.7 ± 3.9%; d 7, 76.2 ± 1.9%); on the other hand, the percentage of vWF-expressing cells in fused cells was decreased with the time-dependent manner (d 1, 41.3 ± 10.3%; d 4, 39.2 ± 3.7%; d 7, 27.7 ± 1.6%), suggesting that the cardiac phenotype becomes predominant in the cells formed by fusion between cardiomyocytes and endothelial cells (Fig. 3, A and B, line graphs; Table I). When GFP+ cardiomyocytes were cocultured with RFP+ cFB, the number of GFP+/RFP+ fused cells was gradually increased (Fig. 3, C and D, bar graphs; Table II). The percentage of cTnT-expressing cells in fused cells was also increased with the time-dependent manner (d 1, 54.2 ± 3.8%; d 4, 75.8 ± 5.6%; d 7, 83.5 ± 2.6%); on the other hand, the percentage of vimentin-expressing cells (Fig. 2 B, k and l) in fused cells was decreased progressively (d 1, 45.3 ± 9.3%; d 4, 25.9 ± 8.8%; d 7, 11.5 ± 1.6%), suggesting that cardiac phenotypes also dominate in fused cells between cardiomyocytes and cFB (Fig. 3, C and D, line graphs; Table II).

Bottom Line: Furthermore, cardiomyocytes reentered the G2-M phase in the cell cycle after fusing with proliferative noncardiomyocytes.Transplanted endothelial cells or skeletal muscle-derived cells fused with adult cardiomyocytes in vivo.In the cryoinjured heart, there were Ki67-positive cells that expressed both cardiac and endothelial lineage marker proteins.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.

ABSTRACT
The concept of the plasticity or transdifferentiation of adult stem cells has been challenged by the phenomenon of cell fusion. In this work, we examined whether neonatal cardiomyocytes fuse with various somatic cells including endothelial cells, cardiac fibroblasts, bone marrow cells, and endothelial progenitor cells spontaneously in vitro. When cardiomyocytes were cocultured with endothelial cells or cardiac fibroblasts, they fused and showed phenotypes of cardiomyocytes. Furthermore, cardiomyocytes reentered the G2-M phase in the cell cycle after fusing with proliferative noncardiomyocytes. Transplanted endothelial cells or skeletal muscle-derived cells fused with adult cardiomyocytes in vivo. In the cryoinjured heart, there were Ki67-positive cells that expressed both cardiac and endothelial lineage marker proteins. These results suggest that cardiomyocytes fuse with other cells and enter the cell cycle by maintaining their phenotypes.

Show MeSH
Related in: MedlinePlus