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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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Cardiomyocytes of neonatal rats reentered the cell cycle through cell fusion with HUVEC or cFB in vitro. (A and B) Quantitative analysis of the percentage of PH3-expressing cardiomyocytes fused with HUVEC or cFB. The percentage of PH3-expressing cardiomyocytes in all fused cells with HUVEC (A) and cFB (B) was significantly increased with the treatment with nocodazole, and was decreased after the withdrawal of nocodazole. Data are mean ± SD of four independent experiments. *, P < 0.05 vs. pretreatment. (C) Fluorescent images of GFP+ cardiomyocytes fused with RFP+ HUVEC (top and bottom rows, a–d and i–l) or RFP+ cFB (middle row, e–h) stained with Hoechst 33258 (blue). Typical prophase chromosome (c), metaphase chromosome (g), and anaphase chromosome (k) were visualized by Hoechst staining. Merged fluorescent images indicate that fused cells show mitotic figures. Bars, 50 μm.
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fig6: Cardiomyocytes of neonatal rats reentered the cell cycle through cell fusion with HUVEC or cFB in vitro. (A and B) Quantitative analysis of the percentage of PH3-expressing cardiomyocytes fused with HUVEC or cFB. The percentage of PH3-expressing cardiomyocytes in all fused cells with HUVEC (A) and cFB (B) was significantly increased with the treatment with nocodazole, and was decreased after the withdrawal of nocodazole. Data are mean ± SD of four independent experiments. *, P < 0.05 vs. pretreatment. (C) Fluorescent images of GFP+ cardiomyocytes fused with RFP+ HUVEC (top and bottom rows, a–d and i–l) or RFP+ cFB (middle row, e–h) stained with Hoechst 33258 (blue). Typical prophase chromosome (c), metaphase chromosome (g), and anaphase chromosome (k) were visualized by Hoechst staining. Merged fluorescent images indicate that fused cells show mitotic figures. Bars, 50 μm.

Mentions: To determine whether cardiomyocytes reenter the cell cycle after fusion, we examined the expression of the cell cycle marker proteins such as Ki67, phosphohistone H3 (PH3), and cyclinB1 in fused cells. First, we examined whether monocultured HUVEC, cFB, and neonatal cardiomyocytes expressed Ki67, PH3, and cyclinB1 (Fig. 4). Many of HUVEC and cFB in the growth medium expressed Ki67, PH3, and cyclinB1 in their nuclei. Some neonatal rat cardiomyocytes expressed Ki67, but not PH3 and cyclinB1, suggesting that some neonatal cardiomyocytes are in the G1-S stage, but not in the G2-M stage of the cell cycle. However, when fused with HUVEC and cFB some cardiomyocytes expressed PH3 (Fig. 5 b for HUVEC and Fig. 5 d for cFB) and cyclinB1 (Fig. 5 f for HUVEC and Fig. 5 h for cFB). Among cardiomyocytes fused with HUVEC, ∼9% of the cells expressed PH3 (Fig. 6 A). When treated for 6 h with nocodazole, an inhibitor of microtubule dynamics and cell cycle progression (Blajeski et al., 2002; Tamamori-Adachi et al., 2003), the number of PH3-expressing fused cells was increased up to ∼21% in fused cells. At 3 h after the withdrawal of nocodazole, this number was decreased to ∼15%. In cardiomyocytes fused with cFB (Fig. 6 B), ∼14% of the cells expressed PH3, and at 24 h after the nocodazole treatment the number of PH3-expressing fused cells was increased up to ∼29%. This number was decreased to ∼20% at 3 h after the withdrawal of nocodazole. These results suggest that some cardiomyocytes reenter the stage of mitosis after fusion with HUVEC and cFB. Mitosis of fused cardiomyocytes was confirmed by the existence of cells that showed visible chromosomes characteristic of the several distinct phases of mitosis (Fig. 6 C). In Fig. 6, GFP+ cardiomyocytes fused with RFP+ HUVEC (b and j) or RFP+ cFB (f) show prophase chromosomes (c), metaphase chromosomes (g), and anaphase chromosomes (k).


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)

Cardiomyocytes of neonatal rats reentered the cell cycle through cell fusion with HUVEC or cFB in vitro. (A and B) Quantitative analysis of the percentage of PH3-expressing cardiomyocytes fused with HUVEC or cFB. The percentage of PH3-expressing cardiomyocytes in all fused cells with HUVEC (A) and cFB (B) was significantly increased with the treatment with nocodazole, and was decreased after the withdrawal of nocodazole. Data are mean ± SD of four independent experiments. *, P < 0.05 vs. pretreatment. (C) Fluorescent images of GFP+ cardiomyocytes fused with RFP+ HUVEC (top and bottom rows, a–d and i–l) or RFP+ cFB (middle row, e–h) stained with Hoechst 33258 (blue). Typical prophase chromosome (c), metaphase chromosome (g), and anaphase chromosome (k) were visualized by Hoechst staining. Merged fluorescent images indicate that fused cells show mitotic figures. Bars, 50 μm.
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Related In: Results  -  Collection

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fig6: Cardiomyocytes of neonatal rats reentered the cell cycle through cell fusion with HUVEC or cFB in vitro. (A and B) Quantitative analysis of the percentage of PH3-expressing cardiomyocytes fused with HUVEC or cFB. The percentage of PH3-expressing cardiomyocytes in all fused cells with HUVEC (A) and cFB (B) was significantly increased with the treatment with nocodazole, and was decreased after the withdrawal of nocodazole. Data are mean ± SD of four independent experiments. *, P < 0.05 vs. pretreatment. (C) Fluorescent images of GFP+ cardiomyocytes fused with RFP+ HUVEC (top and bottom rows, a–d and i–l) or RFP+ cFB (middle row, e–h) stained with Hoechst 33258 (blue). Typical prophase chromosome (c), metaphase chromosome (g), and anaphase chromosome (k) were visualized by Hoechst staining. Merged fluorescent images indicate that fused cells show mitotic figures. Bars, 50 μm.
Mentions: To determine whether cardiomyocytes reenter the cell cycle after fusion, we examined the expression of the cell cycle marker proteins such as Ki67, phosphohistone H3 (PH3), and cyclinB1 in fused cells. First, we examined whether monocultured HUVEC, cFB, and neonatal cardiomyocytes expressed Ki67, PH3, and cyclinB1 (Fig. 4). Many of HUVEC and cFB in the growth medium expressed Ki67, PH3, and cyclinB1 in their nuclei. Some neonatal rat cardiomyocytes expressed Ki67, but not PH3 and cyclinB1, suggesting that some neonatal cardiomyocytes are in the G1-S stage, but not in the G2-M stage of the cell cycle. However, when fused with HUVEC and cFB some cardiomyocytes expressed PH3 (Fig. 5 b for HUVEC and Fig. 5 d for cFB) and cyclinB1 (Fig. 5 f for HUVEC and Fig. 5 h for cFB). Among cardiomyocytes fused with HUVEC, ∼9% of the cells expressed PH3 (Fig. 6 A). When treated for 6 h with nocodazole, an inhibitor of microtubule dynamics and cell cycle progression (Blajeski et al., 2002; Tamamori-Adachi et al., 2003), the number of PH3-expressing fused cells was increased up to ∼21% in fused cells. At 3 h after the withdrawal of nocodazole, this number was decreased to ∼15%. In cardiomyocytes fused with cFB (Fig. 6 B), ∼14% of the cells expressed PH3, and at 24 h after the nocodazole treatment the number of PH3-expressing fused cells was increased up to ∼29%. This number was decreased to ∼20% at 3 h after the withdrawal of nocodazole. These results suggest that some cardiomyocytes reenter the stage of mitosis after fusion with HUVEC and cFB. Mitosis of fused cardiomyocytes was confirmed by the existence of cells that showed visible chromosomes characteristic of the several distinct phases of mitosis (Fig. 6 C). In Fig. 6, GFP+ cardiomyocytes fused with RFP+ HUVEC (b and j) or RFP+ cFB (f) show prophase chromosomes (c), metaphase chromosomes (g), and anaphase chromosomes (k).

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