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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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Enhanced keratinocyte proliferative response in PPARβ1/− upon stimulation. (A) TPA topical application. (a–f) PPARβ+/+ vehicle (a–c) or TPA-treated (d–f) dorsal epidermis, hematoxilin/eosin staining (HE) (a and d), and after keratin 6 (b and e) or Ki67 (c and f) immunostaining. (g–l) PPARβ+/− vehicle– (g–i) or TPA-treated (j–l) dorsal epidermis, hematoxilin/eosin staining (HE) (g and j), and after keratin 6 (h and k) or Ki67 (i and l) immunostaining. (B) Hair plucking. (a–f) PPARβ+/+ unplucked (a–c) or plucked (d–f) dorsal epidermis, hematoxilin/eosin staining (HE) (a and d), and after keratin 6 (b and e) or Ki67 (c and f) immunostaining. (g–l) PPARβ+/− unplucked (g–i) or plucked (j–l) dorsal epidermis, hematoxilin/eosin staining (HE) (g and j), and after keratin 6 (h and k) or Ki67 (i and l) immunostaining. Arrows indicate the epidermis/dermis interface. Bars, 80 μm.
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fig3: Enhanced keratinocyte proliferative response in PPARβ1/− upon stimulation. (A) TPA topical application. (a–f) PPARβ+/+ vehicle (a–c) or TPA-treated (d–f) dorsal epidermis, hematoxilin/eosin staining (HE) (a and d), and after keratin 6 (b and e) or Ki67 (c and f) immunostaining. (g–l) PPARβ+/− vehicle– (g–i) or TPA-treated (j–l) dorsal epidermis, hematoxilin/eosin staining (HE) (g and j), and after keratin 6 (h and k) or Ki67 (i and l) immunostaining. (B) Hair plucking. (a–f) PPARβ+/+ unplucked (a–c) or plucked (d–f) dorsal epidermis, hematoxilin/eosin staining (HE) (a and d), and after keratin 6 (b and e) or Ki67 (c and f) immunostaining. (g–l) PPARβ+/− unplucked (g–i) or plucked (j–l) dorsal epidermis, hematoxilin/eosin staining (HE) (g and j), and after keratin 6 (h and k) or Ki67 (i and l) immunostaining. Arrows indicate the epidermis/dermis interface. Bars, 80 μm.

Mentions: To test the hypothesis of a PPARβ implication in the control of keratinocyte proliferation, we used the above mentioned PPARβ+/− mutant mice. As shown in Fig. 3 A, these heterozygous mice showed a normal skin architecture upon histological staining. However, a careful examination of the epidermal thickness and of the keratinocyte proliferation rate indicate a slight but significant increase of both parameters in the PPARβ+/− mice compared with the wild-type control animals (Table I). Thus, if PPARβ and keratinocyte proliferation are linked, the latter might be affected in the mutant heterozygous animals after proliferation stimuli. Therefore, we performed a TPA stimulation on the dorsal epidermis of PPARβ+/− and control wild-type mice. As shown in Fig. 3 A, a hyperplasia of the TPA-treated epidermis occurred as expected in control mice. Compared with the wild-type control, the PPARβ+/− mice showed a more pronounced stratification of the epidermis. Confirming the morphological observation, the K6 and Ki67 induction in the epidermis was higher in the PPARβ mutant mice than in the wild-type animals (Fig. 3 A, and Table I). The higher proliferative response of the keratinocytes in the epidermis of the PPARβ+/− mice was also observed after hair plucking of the dorsal skin (Fig. 3 B, and Table I). Thus, in both assays, the proliferative response of the keratinocytes was significantly higher in the heterozygous mice compared with the wild-type control (Table I). These data provide further evidence for PPARβ involvement in the control of keratinocyte proliferation. PPARα, on the contrary, does not seem to be involved in this mechanism, as the TPA stimulation on dorsal skin induced identical epidermis hyperplasia in both PPARα wild-type control and PPARα−/− mice (data not shown).


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)

Enhanced keratinocyte proliferative response in PPARβ1/− upon stimulation. (A) TPA topical application. (a–f) PPARβ+/+ vehicle (a–c) or TPA-treated (d–f) dorsal epidermis, hematoxilin/eosin staining (HE) (a and d), and after keratin 6 (b and e) or Ki67 (c and f) immunostaining. (g–l) PPARβ+/− vehicle– (g–i) or TPA-treated (j–l) dorsal epidermis, hematoxilin/eosin staining (HE) (g and j), and after keratin 6 (h and k) or Ki67 (i and l) immunostaining. (B) Hair plucking. (a–f) PPARβ+/+ unplucked (a–c) or plucked (d–f) dorsal epidermis, hematoxilin/eosin staining (HE) (a and d), and after keratin 6 (b and e) or Ki67 (c and f) immunostaining. (g–l) PPARβ+/− unplucked (g–i) or plucked (j–l) dorsal epidermis, hematoxilin/eosin staining (HE) (g and j), and after keratin 6 (h and k) or Ki67 (i and l) immunostaining. Arrows indicate the epidermis/dermis interface. Bars, 80 μm.
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fig3: Enhanced keratinocyte proliferative response in PPARβ1/− upon stimulation. (A) TPA topical application. (a–f) PPARβ+/+ vehicle (a–c) or TPA-treated (d–f) dorsal epidermis, hematoxilin/eosin staining (HE) (a and d), and after keratin 6 (b and e) or Ki67 (c and f) immunostaining. (g–l) PPARβ+/− vehicle– (g–i) or TPA-treated (j–l) dorsal epidermis, hematoxilin/eosin staining (HE) (g and j), and after keratin 6 (h and k) or Ki67 (i and l) immunostaining. (B) Hair plucking. (a–f) PPARβ+/+ unplucked (a–c) or plucked (d–f) dorsal epidermis, hematoxilin/eosin staining (HE) (a and d), and after keratin 6 (b and e) or Ki67 (c and f) immunostaining. (g–l) PPARβ+/− unplucked (g–i) or plucked (j–l) dorsal epidermis, hematoxilin/eosin staining (HE) (g and j), and after keratin 6 (h and k) or Ki67 (i and l) immunostaining. Arrows indicate the epidermis/dermis interface. Bars, 80 μm.
Mentions: To test the hypothesis of a PPARβ implication in the control of keratinocyte proliferation, we used the above mentioned PPARβ+/− mutant mice. As shown in Fig. 3 A, these heterozygous mice showed a normal skin architecture upon histological staining. However, a careful examination of the epidermal thickness and of the keratinocyte proliferation rate indicate a slight but significant increase of both parameters in the PPARβ+/− mice compared with the wild-type control animals (Table I). Thus, if PPARβ and keratinocyte proliferation are linked, the latter might be affected in the mutant heterozygous animals after proliferation stimuli. Therefore, we performed a TPA stimulation on the dorsal epidermis of PPARβ+/− and control wild-type mice. As shown in Fig. 3 A, a hyperplasia of the TPA-treated epidermis occurred as expected in control mice. Compared with the wild-type control, the PPARβ+/− mice showed a more pronounced stratification of the epidermis. Confirming the morphological observation, the K6 and Ki67 induction in the epidermis was higher in the PPARβ mutant mice than in the wild-type animals (Fig. 3 A, and Table I). The higher proliferative response of the keratinocytes in the epidermis of the PPARβ+/− mice was also observed after hair plucking of the dorsal skin (Fig. 3 B, and Table I). Thus, in both assays, the proliferative response of the keratinocytes was significantly higher in the heterozygous mice compared with the wild-type control (Table I). These data provide further evidence for PPARβ involvement in the control of keratinocyte proliferation. PPARα, on the contrary, does not seem to be involved in this mechanism, as the TPA stimulation on dorsal skin induced identical epidermis hyperplasia in both PPARα wild-type control and PPARα−/− mice (data not shown).

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