Hyaluronan–CD44 Interaction Stimulates Keratinocyte Differentiation, Lamellar Body Formation/Secretion, and Permeability Barrier Homeostasis Lilly Y.W.

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Hyaluronan–CD44 Interaction Stimulates Keratinocyte Differentiation, Lamellar Body Formation/Secretion, and Permeability Barrier Homeostasis Lilly Y.W. Bourguignon, Mohamed Ramez, Eli Gilad, Patrick A. Singleton, Mao-Qiang Man, Debra A. Crumrine, Peter M. Elias, Kenneth R. Feingold Journal of Investigative Dermatology Volume 126, Issue 6, Pages 1356-1365 (June 2006) DOI: 10.1038/sj.jid.5700260 Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Immunohistochemical and ultrastructural analyses of wild-type (CD44+/+) and CD44 k/o (CD44−/−) mouse epidermis. Skin biopsies were obtained from the back of the mice. (a–f) Light microscopic analyses of the wild-type (CD44+/+) (a) versus CD44 k/o (b) mouse epidermis using hematoxylin and eosin staining; Detection of CD44 staining in the wild-type (CD44+/+) (c) versus CD44 k/o (CD44−/−) (d) mouse epidermis using anti-CD44-mediated immunoperoxidase staining; and detection of HA staining in the wild-type (CD44+/+) (e) versus CD44 k/o (CD44−/−) (f) mouse epidermis using HA-binding protein-mediated immunoperoxidase staining (bars: 20μm). (g and h) Electron microscopic analyses of the wild-type (CD44+/+) (g) versus CD44 k/o (CD44−/−) (h) mouse epidermis. (Note epidermal attenuation, loss of rete ridges, and thin SC in CD44 k/o mice. SC: stratum corneum; SG: stratum granulosum; BM: basement membranes (white arrows); OsO4 post-fixation; bars: 1.0μm). (i and j) Detection of a proliferation marker in wild-type (CD44+/+) (i) and CD44 k/o (CD44−/−) (j) mouse epidermis using anti-PCNA-mediated immunoperoxidase staining (bars: 20μm). Journal of Investigative Dermatology 2006 126, 1356-1365DOI: (10.1038/sj.jid.5700260) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Analyses of barrier recovery (a and b) in wild-type (CD44+/+) and CD44 k/o (CD44−/−) mouse epidermis. (a and b) TEWL in wild-type (CD44+/+) and CD44 k/o (CD44−/−) mouse epidermis was measured after 1, 3, and 6hours after tape stripping (a) and acetone treatment (b). The degree to which recovery of the barrier after these two treatments in wild-type (CD44+/+) versus CD44 k/o (CD44−/−) mouse epidermis is achieved at these time points is recorded (The error bars enclosed mean±SD). Journal of Investigative Dermatology 2006 126, 1356-1365DOI: (10.1038/sj.jid.5700260) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Analyses of differentiation marker expression in mouse epidermis (a–f) and CHK (g, h, and i). (a–f) Detection of differentiation markers in wild-type (CD44+/+) and CD44 k/o (CD44−/−) mouse epidermis (using the skin biopsies obtained from the back of the mice). (a and b) Anti-involucrin-mediated immunoperoxidase staining of the wild-type (CD44+/+) (a) versus CD44 k/o (CD44−/−) and (b) mouse epidermis; (c and d) Antiprofilaggrin-mediated immunoperoxidase staining of the wild-type (CD44+/+) (c) versus CD44 k/o (CD44−/−) and (d) mouse epidermis; (e and f): Anti-K-10-mediated immunoperoxidase staining of the wild-type (CD44+/+) (e) versus CD44 k/o (CD44−/−) and (f) mouse epidermis (Bars: 20μm). (g) Expression of differentiation markers (involucrin, profilaggrin, and K-10) in CHK. Keratinocytes (untreated or pretreated with rat anti-CD44 IgG or normal rat IgG) were incubated with HA (50μg/ml) at 37°C for 36hours. Subsequently, cells were solubilized by 1% Nonidet P-40 (NP-40) buffer. Cell lysates (isolated from keratinocytes treated with no HA (lane 1) or with HA (lane 2); or pretreated with rat anti-CD44 IgG plus HA (lane 3) or pretreated with normal rat IgG plus HA (lane 4)) were then used for immunoblotting using anti-involucrin antibody (a) or antiprofilaggrin antibody (b) or anti-K-10 antibody (c) or antiactin antibody (as a loading control) (d), respectively. (h and i) Expression of differentiation markers (involucrin, profilaggrin, and K-10) in CHK treated with CD44siRNA or scrambled sequences: (h): Keratinocytes (transfected with CD44siRNA-scrambled sequences (lane 1) or CD44siRNA (lane 2) were solubilized by 1% Nonidet P-40 buffer and immunoblotted with anti-CD44 antibody (a) or antiactin antibody (b); (i): Keratinocytes (transfected with CD44siRNA-scrambled sequences (lanes 1 and 2) or CD44siRNA (lanes 3 and 4)) were incubated with no HA (lanes 1 and 3) or with HA (lanes 2 and 4) at 37°C for 36hours. These cells were then solubilized by 1% Nonidet P-40 buffer and immunoblotted with anti-involucrin (a) or antiprofilaggrin (b) or anti-K-10 (c) or antiactin (as a loading control) (d). Journal of Investigative Dermatology 2006 126, 1356-1365DOI: (10.1038/sj.jid.5700260) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Measurement of lipid and/or cholesterol synthesis. (a) Analyses of lipid synthesis in wild-type (CD44+/+) and CD44 k/o (CD44−/−) mouse epidermis. Detection of the level of cholesterol synthesis (a); Non-saponifiable lipid synthesis (b); and fatty acid synthesis (c) in the epidermis of wild-type (CD44+/+) versus CD44 k/o (CD44−/−). (b) Analyses of cholesterol synthesis in CHK-transfected with either CD44siRNA-scrambled sequences (a and b) (followed by no HA treatment (a) or HA treatment (b)) or CD44siRNA (followed by HA treatment (c)). Journal of Investigative Dermatology 2006 126, 1356-1365DOI: (10.1038/sj.jid.5700260) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Electron microscopic and ultrastructural cytochemical analyses of LB formation and secretion in wild-type (CD44+/+) versus CD44 k/o (CD44−/−) mouse epidermis. Note high density of LB (white arrows) in the cytosol of the SG of untreated wild-type (CD44+/+) mouse epidermis (a) versus a reduced number of LB (white arrows) in untreated CD44 k/o (CD44−/−) mouse epidermis (b); Note increased LB secretion and dispersion of secreted lamellar material (white arrows) in the wild-type (CD44+/+) mouse epidermis (1hour after acute barrier disruption by tape stripping) (c); and note both reduced LB secretion (white arrows) at SG–SC interface and failure of newly secreted lamellar material to disperse (asterisks) in CD44 k/o (CD44−/−) mouse epidermis (1hour after acute barrier disruption by tape stripping) (d); (e and f) Detection of the LB content marker (acid hydrolase) in the wild-type and CD44 k/o mice. Note secretion of acid lipase activity restricted to the apex (black arrows) (very little in the baso-lateral (white arrow heads)) of wild-type (CD44+/+) mouse epidermis (1hour after acute barrier disruption by tape stripping) (e). In contrast, note aberrant polarity of secreted, acid lipase activity toward the baso-lateral (white arrow heads), plus apical surface (black arrows) of the mid- to outer cell layers of the SG in the CD44 k/o (CD44−/−) mouse epidermis (1hour after acute barrier disruption by tape stripping) (f). (SC: stratum corneum; SG: stratum granulosum; (a–f) OsO4 postfixation. Bars=(a, c, and d) 0.50μm upper 0.20μm lower and (b) 0.50μm. Journal of Investigative Dermatology 2006 126, 1356-1365DOI: (10.1038/sj.jid.5700260) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Electron microscopic analyses of LB formation and secretion in human keratinocytes grown in organotypic cultures. Human keratinocytes were grown in a collagen-basement membrane in Transwell dishes according to MatTek organotypic tissue culture conditions as described in the Materials and Methods. (a and b): (a) LB formation (white arrows) in cells treated with no HA; (b) LB formation (white arrows) in cells treated with HA; (c) LB formation (white arrows) in cells pretreated with rat anti-CD44 plus HA; (d) LB formation (white arrows) in cells pretreated with normal rat IgG plus HA; (e) Minimal LB secretory processes detected in cells treated with no HA; (f) LB secretory processes (dark arrows) detected in cells treated with HA. (a–f: OsO4 post-fixation; SC: stratum corneum; SG: stratum granulosum. Bars=(a–d) 0.50μm and (e and f) 0.25μm. Journal of Investigative Dermatology 2006 126, 1356-1365DOI: (10.1038/sj.jid.5700260) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 7 A proposed model for illustrating HA–CD44 interaction in regulating epidermal structure and function. In epidermis, HA interaction with CD44 promotes proliferation, differentiation and cholesterol synthesis. In particular, these parallel arms of proliferation and differentiation promote corneocyte formation; and stimulate both keratinocyte differentiation and LB formation/secretion (perhaps driven by prior changes in cholesterol synthesis), which all are required for normal epidermal permeability barrier function. (CD44 deficiency in k/o mice results in abnormal epidermal structure and function.) Journal of Investigative Dermatology 2006 126, 1356-1365DOI: (10.1038/sj.jid.5700260) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions