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Cytokinetic Failure-induced Tetraploidy Develops into Aneuploidy, Triggering Skin Aging in Phosphovimentin-deficient Mice.

Tanaka H, Goto H, Inoko A, Makihara H, Enomoto A, Horimoto K, Matsuyama M, Kurita K, Izawa I, Inagaki M - J. Biol. Chem. (2015)

Bottom Line: Early into wound healing, subcutaneous fibroblasts failed to undergo cytokinesis, resulting in binucleate tetraploidy.Thereafter, senescence-related markers were significantly elevated in VIM(SA/SA) mice.Because our tetraploidy-prone mouse model also exhibited subcutaneous fat loss at the age of 14 months, another premature aging phenotype, our data suggest that following cytokinetic failure, a subset of tetraploid cells enters a new cell cycle and develops into aneuploid cells in vivo, which promote premature aging.

View Article: PubMed Central - PubMed

Affiliation: From the Division of Biochemistry, Aichi Cancer Center Research Institute, Nagoya 464-8681.

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Formation of multinuclei, IF-bridge, and extra centrosomes in VIMSA/SA fibroblasts at early stage of wound healing.A and B, histological sections after wounding were stained with anti-vimentin (green) and DAPI (blue). An immunofluorescent micrograph of the VIMWT/WT mouse at day 7 after wounding is shown as a representative sample (A). White dot and yellow dashed lines are indicated as the borders between wound and unaffected (normal) areas and between epidermis and dermis, respectively (A). The position of wound edge is also marked by arrowhead (A). We calculated the ratio of anti-vimentin intensity at wound areas to at neighboring unaffected (normal) areas, using 10 sections per each wound (B). Data represent mean ± S.E. of three independent experiments (B). A 1:1 ratio is indicated as a green line in the graph (B). C–F, immunohistochemical (C) or immunofluorescent (D) images of affected areas at day 3 after wounding. Arrows or arrowheads in C indicate fibroblasts with IF-bridge (connecting two daughter cells) or two nuclei, respectively. Arrowheads in D indicate γ-tubulin spots in fibroblasts. We calculated the percentage of subcutaneous fibroblasts with bi-nuclei (E) or more than three γ-tubulin spots (centrosomes; F) at the indicated days, using more than 10 sections per each wound. Data represent mean ± S.E. of three independent experiments (E and F). Scale bars, 500 μm (A), 10 μm (C), and 5 μm (D). *, p < 0.05; **, p < 0.01; ***, p < 0.001.
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Figure 6: Formation of multinuclei, IF-bridge, and extra centrosomes in VIMSA/SA fibroblasts at early stage of wound healing.A and B, histological sections after wounding were stained with anti-vimentin (green) and DAPI (blue). An immunofluorescent micrograph of the VIMWT/WT mouse at day 7 after wounding is shown as a representative sample (A). White dot and yellow dashed lines are indicated as the borders between wound and unaffected (normal) areas and between epidermis and dermis, respectively (A). The position of wound edge is also marked by arrowhead (A). We calculated the ratio of anti-vimentin intensity at wound areas to at neighboring unaffected (normal) areas, using 10 sections per each wound (B). Data represent mean ± S.E. of three independent experiments (B). A 1:1 ratio is indicated as a green line in the graph (B). C–F, immunohistochemical (C) or immunofluorescent (D) images of affected areas at day 3 after wounding. Arrows or arrowheads in C indicate fibroblasts with IF-bridge (connecting two daughter cells) or two nuclei, respectively. Arrowheads in D indicate γ-tubulin spots in fibroblasts. We calculated the percentage of subcutaneous fibroblasts with bi-nuclei (E) or more than three γ-tubulin spots (centrosomes; F) at the indicated days, using more than 10 sections per each wound. Data represent mean ± S.E. of three independent experiments (E and F). Scale bars, 500 μm (A), 10 μm (C), and 5 μm (D). *, p < 0.05; **, p < 0.01; ***, p < 0.001.

Mentions: Antibody signals in a digital image of Figs. 5C and 6B were calculated as described previously (39). All data were shown as mean ± S.E. All p values (*, p < 0.05; **, p < 0.01; ***, p < 0.001) were determined by two-tailed Student's t test (Graph Pad software), compared with wild-type (VIMWT/WT) mice.


Cytokinetic Failure-induced Tetraploidy Develops into Aneuploidy, Triggering Skin Aging in Phosphovimentin-deficient Mice.

Tanaka H, Goto H, Inoko A, Makihara H, Enomoto A, Horimoto K, Matsuyama M, Kurita K, Izawa I, Inagaki M - J. Biol. Chem. (2015)

Formation of multinuclei, IF-bridge, and extra centrosomes in VIMSA/SA fibroblasts at early stage of wound healing.A and B, histological sections after wounding were stained with anti-vimentin (green) and DAPI (blue). An immunofluorescent micrograph of the VIMWT/WT mouse at day 7 after wounding is shown as a representative sample (A). White dot and yellow dashed lines are indicated as the borders between wound and unaffected (normal) areas and between epidermis and dermis, respectively (A). The position of wound edge is also marked by arrowhead (A). We calculated the ratio of anti-vimentin intensity at wound areas to at neighboring unaffected (normal) areas, using 10 sections per each wound (B). Data represent mean ± S.E. of three independent experiments (B). A 1:1 ratio is indicated as a green line in the graph (B). C–F, immunohistochemical (C) or immunofluorescent (D) images of affected areas at day 3 after wounding. Arrows or arrowheads in C indicate fibroblasts with IF-bridge (connecting two daughter cells) or two nuclei, respectively. Arrowheads in D indicate γ-tubulin spots in fibroblasts. We calculated the percentage of subcutaneous fibroblasts with bi-nuclei (E) or more than three γ-tubulin spots (centrosomes; F) at the indicated days, using more than 10 sections per each wound. Data represent mean ± S.E. of three independent experiments (E and F). Scale bars, 500 μm (A), 10 μm (C), and 5 μm (D). *, p < 0.05; **, p < 0.01; ***, p < 0.001.
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Figure 6: Formation of multinuclei, IF-bridge, and extra centrosomes in VIMSA/SA fibroblasts at early stage of wound healing.A and B, histological sections after wounding were stained with anti-vimentin (green) and DAPI (blue). An immunofluorescent micrograph of the VIMWT/WT mouse at day 7 after wounding is shown as a representative sample (A). White dot and yellow dashed lines are indicated as the borders between wound and unaffected (normal) areas and between epidermis and dermis, respectively (A). The position of wound edge is also marked by arrowhead (A). We calculated the ratio of anti-vimentin intensity at wound areas to at neighboring unaffected (normal) areas, using 10 sections per each wound (B). Data represent mean ± S.E. of three independent experiments (B). A 1:1 ratio is indicated as a green line in the graph (B). C–F, immunohistochemical (C) or immunofluorescent (D) images of affected areas at day 3 after wounding. Arrows or arrowheads in C indicate fibroblasts with IF-bridge (connecting two daughter cells) or two nuclei, respectively. Arrowheads in D indicate γ-tubulin spots in fibroblasts. We calculated the percentage of subcutaneous fibroblasts with bi-nuclei (E) or more than three γ-tubulin spots (centrosomes; F) at the indicated days, using more than 10 sections per each wound. Data represent mean ± S.E. of three independent experiments (E and F). Scale bars, 500 μm (A), 10 μm (C), and 5 μm (D). *, p < 0.05; **, p < 0.01; ***, p < 0.001.
Mentions: Antibody signals in a digital image of Figs. 5C and 6B were calculated as described previously (39). All data were shown as mean ± S.E. All p values (*, p < 0.05; **, p < 0.01; ***, p < 0.001) were determined by two-tailed Student's t test (Graph Pad software), compared with wild-type (VIMWT/WT) mice.

Bottom Line: Early into wound healing, subcutaneous fibroblasts failed to undergo cytokinesis, resulting in binucleate tetraploidy.Thereafter, senescence-related markers were significantly elevated in VIM(SA/SA) mice.Because our tetraploidy-prone mouse model also exhibited subcutaneous fat loss at the age of 14 months, another premature aging phenotype, our data suggest that following cytokinetic failure, a subset of tetraploid cells enters a new cell cycle and develops into aneuploid cells in vivo, which promote premature aging.

View Article: PubMed Central - PubMed

Affiliation: From the Division of Biochemistry, Aichi Cancer Center Research Institute, Nagoya 464-8681.

Show MeSH
Related in: MedlinePlus