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Impaired skin wound healing in peroxisome proliferator-activated receptor (PPAR)alpha and PPARbeta mutant mice.

Michalik L, Desvergne B, Tan NS, Basu-Modak S, Escher P, Rieusset J, Peters JM, Kaya G, Gonzalez FJ, Zakany J, Metzger D, Chambon P, Duboule D, Wahli W - J. Cell Biol. (2001)

Bottom Line: Interestingly, PPARalpha and beta expression is reactivated in the adult epidermis after various stimuli, resulting in keratinocyte proliferation and differentiation such as tetradecanoylphorbol acetate topical application, hair plucking, or skin wound healing.PPARalpha is mainly involved in the early inflammation phase of the healing, whereas PPARbeta is implicated in the control of keratinocyte proliferation.In addition and very interestingly, PPARbeta mutant primary keratinocytes show impaired adhesion and migration properties.

View Article: PubMed Central - PubMed

Affiliation: Institut de Biologie Animale, Université de Lausanne, Bâtiment de Biologie, CH-1015 Lausanne, Switzerland.

ABSTRACT
We show here that the alpha, beta, and gamma isotypes of peroxisome proliferator-activated receptor (PPAR) are expressed in the mouse epidermis during fetal development and that they disappear progressively from the interfollicular epithelium after birth. Interestingly, PPARalpha and beta expression is reactivated in the adult epidermis after various stimuli, resulting in keratinocyte proliferation and differentiation such as tetradecanoylphorbol acetate topical application, hair plucking, or skin wound healing. Using PPARalpha, beta, and gamma mutant mice, we demonstrate that PPARalpha and beta are important for the rapid epithelialization of a skin wound and that each of them plays a specific role in this process. PPARalpha is mainly involved in the early inflammation phase of the healing, whereas PPARbeta is implicated in the control of keratinocyte proliferation. In addition and very interestingly, PPARbeta mutant primary keratinocytes show impaired adhesion and migration properties. Thus, the findings presented here reveal unpredicted roles for PPARalpha and beta in adult mouse epidermal repair.

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PPARβ expression is upregulated in SV129 adult mouse epidermis upon keratinocyte proliferation stimulation. TPA topical application. Vehicle- (a–f) or TPA-treated (g–l) dorsal skin. Hematoxilin/eosin (HE) staining (a and g); Keratin 6 (b and h) and Ki67 (c and i) immunolabeling; in situ hybridization with PPARα (d and j), PPARβ (e and k), and PPARγ (f and l) antisense probes (ASense); in situ hybridization of TPA-treated samples with sense control probes are shown (m–o). (B) Hair plucking. Unplucked (a–f) or plucked (g–l) dorsal skin. Hematoxilin/eosin (HE) staining (a and g); Keratin 6 (b and h) and Ki67 (c and i) immunolabeling; in situ hybridization with PPARα (d and j), PPARβ (e and k), and PPARγ (f and l) antisense probes (ASense); in situ hybridization of plucked samples with sense control probes are shown (m–o). Arrows indicate the epidermis/dermis interface. For both A and B, similar results were observed in six SV129 mice from independent litters. Bars, 80 μm.
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fig2: PPARβ expression is upregulated in SV129 adult mouse epidermis upon keratinocyte proliferation stimulation. TPA topical application. Vehicle- (a–f) or TPA-treated (g–l) dorsal skin. Hematoxilin/eosin (HE) staining (a and g); Keratin 6 (b and h) and Ki67 (c and i) immunolabeling; in situ hybridization with PPARα (d and j), PPARβ (e and k), and PPARγ (f and l) antisense probes (ASense); in situ hybridization of TPA-treated samples with sense control probes are shown (m–o). (B) Hair plucking. Unplucked (a–f) or plucked (g–l) dorsal skin. Hematoxilin/eosin (HE) staining (a and g); Keratin 6 (b and h) and Ki67 (c and i) immunolabeling; in situ hybridization with PPARα (d and j), PPARβ (e and k), and PPARγ (f and l) antisense probes (ASense); in situ hybridization of plucked samples with sense control probes are shown (m–o). Arrows indicate the epidermis/dermis interface. For both A and B, similar results were observed in six SV129 mice from independent litters. Bars, 80 μm.

Mentions: TPA applied on the dorsal skin of SV129 mice induced thickening of the epidermis within 48 h, whereas no change was observed on the vehicle-treated control samples. Histological staining of the TPA-treated skin showed a typical increase in keratinocyte stratification compared with the control (Fig. 2 A, and Table I). As markers for keratinocyte proliferation, we used the expression of both keratin 6 (K6) cytoskeletal protein (Navarro et al., 1995) and the Ki67 nuclear antigen. As shown in Fig. 2 A, K6 immunolabeling remained negative in the ethanol-treated control epidermis, whereas high levels were detected in the epidermis after TPA application, confirming that this agent induced the expected proliferation of the keratinocytes. Consistent with this, the number of Ki67-positive cells in the basal layer was also increased in the TPA-treated samples (Fig. 2 A, and Table I). In situ hybridization with PPARα-, β-, and γ-specific probes revealed that PPARβ expression was significantly upregulated in the TPA-treated epidermis, whereas only a faint signal was detected for PPARα and no signal for PPARγ (Fig. 2 A). Consistent with the results shown in Fig. 1 C, none of the three PPAR isotypes was detected in the interfollicular epidermis of the control sample.


Impaired skin wound healing in peroxisome proliferator-activated receptor (PPAR)alpha and PPARbeta mutant mice.

Michalik L, Desvergne B, Tan NS, Basu-Modak S, Escher P, Rieusset J, Peters JM, Kaya G, Gonzalez FJ, Zakany J, Metzger D, Chambon P, Duboule D, Wahli W - J. Cell Biol. (2001)

PPARβ expression is upregulated in SV129 adult mouse epidermis upon keratinocyte proliferation stimulation. TPA topical application. Vehicle- (a–f) or TPA-treated (g–l) dorsal skin. Hematoxilin/eosin (HE) staining (a and g); Keratin 6 (b and h) and Ki67 (c and i) immunolabeling; in situ hybridization with PPARα (d and j), PPARβ (e and k), and PPARγ (f and l) antisense probes (ASense); in situ hybridization of TPA-treated samples with sense control probes are shown (m–o). (B) Hair plucking. Unplucked (a–f) or plucked (g–l) dorsal skin. Hematoxilin/eosin (HE) staining (a and g); Keratin 6 (b and h) and Ki67 (c and i) immunolabeling; in situ hybridization with PPARα (d and j), PPARβ (e and k), and PPARγ (f and l) antisense probes (ASense); in situ hybridization of plucked samples with sense control probes are shown (m–o). Arrows indicate the epidermis/dermis interface. For both A and B, similar results were observed in six SV129 mice from independent litters. Bars, 80 μm.
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Related In: Results  -  Collection

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fig2: PPARβ expression is upregulated in SV129 adult mouse epidermis upon keratinocyte proliferation stimulation. TPA topical application. Vehicle- (a–f) or TPA-treated (g–l) dorsal skin. Hematoxilin/eosin (HE) staining (a and g); Keratin 6 (b and h) and Ki67 (c and i) immunolabeling; in situ hybridization with PPARα (d and j), PPARβ (e and k), and PPARγ (f and l) antisense probes (ASense); in situ hybridization of TPA-treated samples with sense control probes are shown (m–o). (B) Hair plucking. Unplucked (a–f) or plucked (g–l) dorsal skin. Hematoxilin/eosin (HE) staining (a and g); Keratin 6 (b and h) and Ki67 (c and i) immunolabeling; in situ hybridization with PPARα (d and j), PPARβ (e and k), and PPARγ (f and l) antisense probes (ASense); in situ hybridization of plucked samples with sense control probes are shown (m–o). Arrows indicate the epidermis/dermis interface. For both A and B, similar results were observed in six SV129 mice from independent litters. Bars, 80 μm.
Mentions: TPA applied on the dorsal skin of SV129 mice induced thickening of the epidermis within 48 h, whereas no change was observed on the vehicle-treated control samples. Histological staining of the TPA-treated skin showed a typical increase in keratinocyte stratification compared with the control (Fig. 2 A, and Table I). As markers for keratinocyte proliferation, we used the expression of both keratin 6 (K6) cytoskeletal protein (Navarro et al., 1995) and the Ki67 nuclear antigen. As shown in Fig. 2 A, K6 immunolabeling remained negative in the ethanol-treated control epidermis, whereas high levels were detected in the epidermis after TPA application, confirming that this agent induced the expected proliferation of the keratinocytes. Consistent with this, the number of Ki67-positive cells in the basal layer was also increased in the TPA-treated samples (Fig. 2 A, and Table I). In situ hybridization with PPARα-, β-, and γ-specific probes revealed that PPARβ expression was significantly upregulated in the TPA-treated epidermis, whereas only a faint signal was detected for PPARα and no signal for PPARγ (Fig. 2 A). Consistent with the results shown in Fig. 1 C, none of the three PPAR isotypes was detected in the interfollicular epidermis of the control sample.

Bottom Line: Interestingly, PPARalpha and beta expression is reactivated in the adult epidermis after various stimuli, resulting in keratinocyte proliferation and differentiation such as tetradecanoylphorbol acetate topical application, hair plucking, or skin wound healing.PPARalpha is mainly involved in the early inflammation phase of the healing, whereas PPARbeta is implicated in the control of keratinocyte proliferation.In addition and very interestingly, PPARbeta mutant primary keratinocytes show impaired adhesion and migration properties.

View Article: PubMed Central - PubMed

Affiliation: Institut de Biologie Animale, Université de Lausanne, Bâtiment de Biologie, CH-1015 Lausanne, Switzerland.

ABSTRACT
We show here that the alpha, beta, and gamma isotypes of peroxisome proliferator-activated receptor (PPAR) are expressed in the mouse epidermis during fetal development and that they disappear progressively from the interfollicular epithelium after birth. Interestingly, PPARalpha and beta expression is reactivated in the adult epidermis after various stimuli, resulting in keratinocyte proliferation and differentiation such as tetradecanoylphorbol acetate topical application, hair plucking, or skin wound healing. Using PPARalpha, beta, and gamma mutant mice, we demonstrate that PPARalpha and beta are important for the rapid epithelialization of a skin wound and that each of them plays a specific role in this process. PPARalpha is mainly involved in the early inflammation phase of the healing, whereas PPARbeta is implicated in the control of keratinocyte proliferation. In addition and very interestingly, PPARbeta mutant primary keratinocytes show impaired adhesion and migration properties. Thus, the findings presented here reveal unpredicted roles for PPARalpha and beta in adult mouse epidermal repair.

Show MeSH
Related in: MedlinePlus