Matrix Hyaluronan-Activated CD44 Signaling Promotes Keratinocyte Activities and Improves Abnormal Epidermal Functions

Hyaluronan (HA), a major component of the extracellular matrix, is enriched in skin tissues, particularly the epidermis. HA binds to a ubiquitous, abundant, and functionally important family of cell surface receptors, CD44. This article reviews the current evidence for HA/CD44-mediated activation of RhoGTPase signaling and calcium mobilization, leading to the regulation of keratinocyte activities and various epidermal functions. It further discusses the role of HA-mediated CD44 interactions with unique downstream effectors, such as RhoGTPases (RhoA and Rac1), Rho-kinase, protein kinase-Nγ, and phosphoinositide-specific phospholipases (phospholipases Cε and Cγ1) in coordinating certain intracellular signaling pathways, such as calcium mobilization, phosphatidylinositol 3-kinase–AKT activation, cortactin-actin binding, and actin-associated cytoskeleton reorganization; generating the onset of important keratinocyte activities, such as cell adhesion, proliferation, migration, and differentiation; and performing epidermal functions. Topical application of selective HA fragments (large versus small HA) to the skin of wild-type mice (but not CD44 knockout mice) improves keratinocyte-associated epidermal functions and accelerates permeability barrier recovery and skin wound healing. Consequently, specific HA fragment (large versus small HA)–mediated signaling events (through the CD44 receptor) are required for keratinocyte activities, which offer new HA-based therapeutic options for patients experiencing epidermal dysfunction and skin damage as well as aging-related skin diseases, such as epidermal thinning (atrophy), permeability barrier dysfunction, and chronic nonhealing wounds. Hyaluronan (HA), a major component of the extracellular matrix, is enriched in skin tissues, particularly the epidermis. HA binds to a ubiquitous, abundant, and functionally important family of cell surface receptors, CD44. This article reviews the current evidence for HA/CD44-mediated activation of RhoGTPase signaling and calcium mobilization, leading to the regulation of keratinocyte activities and various epidermal functions. It further discusses the role of HA-mediated CD44 interactions with unique downstream effectors, such as RhoGTPases (RhoA and Rac1), Rho-kinase, protein kinase-Nγ, and phosphoinositide-specific phospholipases (phospholipases Cε and Cγ1) in coordinating certain intracellular signaling pathways, such as calcium mobilization, phosphatidylinositol 3-kinase–AKT activation, cortactin-actin binding, and actin-associated cytoskeleton reorganization; generating the onset of important keratinocyte activities, such as cell adhesion, proliferation, migration, and differentiation; and performing epidermal functions. Topical application of selective HA fragments (large versus small HA) to the skin of wild-type mice (but not CD44 knockout mice) improves keratinocyte-associated epidermal functions and accelerates permeability barrier recovery and skin wound healing. Consequently, specific HA fragment (large versus small HA)–mediated signaling events (through the CD44 receptor) are required for keratinocyte activities, which offer new HA-based therapeutic options for patients experiencing epidermal dysfunction and skin damage as well as aging-related skin diseases, such as epidermal thinning (atrophy), permeability barrier dysfunction, and chronic nonhealing wounds. CME Accreditation Statement: This activity (“ASIP 2014 AJP CME Program in Pathogenesis”) has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians.The ASCP designates this journal-based CME activity (“ASIP 2014 AJP CME Program in Pathogenesis”) for a maximum of 48 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose. CME Accreditation Statement: This activity (“ASIP 2014 AJP CME Program in Pathogenesis”) has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians. The ASCP designates this journal-based CME activity (“ASIP 2014 AJP CME Program in Pathogenesis”) for a maximum of 48 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity. CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose. In the epidermis, extracellular matrix (ECM) components form an integral part of the hemidesmosomes and mediate keratinocyte attachment to the underlying basement membrane. Matrix hyaluronan (HA) is the major glycosaminoglycan in the ECM of most mammalian tissues, including epidermis and dermis,1Tammi R. Ripellino J.A. Margolis R.U. Tammi M. Localization of epidermal hyaluronic acid using the hyaluronate binding region of cartilage proteoglycan as a specific probe.J Invest Dermatol. 1988; 90: 412-414Crossref PubMed Scopus (186) Google Scholar, 2Tammi R. MacCallum D. Hascall V.C. Pienimaki J.P. Hyttinen M. Tammi M. Hyaluronan bound to CD44 on keratinocytes is displaced by hyaluronan decasaccharides and not hexasaccharides.J Biol Chem. 1998; 273: 28878-28888Crossref PubMed Scopus (122) Google Scholar and HA has been implicated in several skin epidermal functions.1Tammi R. Ripellino J.A. Margolis R.U. Tammi M. Localization of epidermal hyaluronic acid using the hyaluronate binding region of cartilage proteoglycan as a specific probe.J Invest Dermatol. 1988; 90: 412-414Crossref PubMed Scopus (186) Google Scholar, 2Tammi R. MacCallum D. Hascall V.C. Pienimaki J.P. Hyttinen M. Tammi M. Hyaluronan bound to CD44 on keratinocytes is displaced by hyaluronan decasaccharides and not hexasaccharides.J Biol Chem. 1998; 273: 28878-28888Crossref PubMed Scopus (122) Google Scholar However, the cellular and molecular mechanism by which keratinocytes respond to HA is not fully understood. The predominant receptor for HA on the cell surface of keratinocytes is CD44.3Underhill C. CD44: the hyaluronan receptor.J Cell Sci. 1992; 103: 293-298Crossref PubMed Google Scholar CD44 is encoded by a single gene that contains 19 exons.4Screaton G.R. Bell M.V. Jackson D.G. Cornelis F.B. Gerth U. Bell J.I. Genomic structure of DNA encoding the lymphocyte homing receptor CD44 reveals at least 12 alternatively spliced exons.Proc Natl Acad Sci U S A. 1992; 89: 12160-12164Crossref PubMed Scopus (974) Google Scholar The most common form, CD44 standard form, contains exons 1 to 5 (N-terminal 150 amino acids), exons 15 and 16 (membrane proximal 85 amino acids), exon 17 (transmembrane domain), and a portion of exons 17 and 19 (cytoplasmic tail, 70 amino acids).4Screaton G.R. Bell M.V. Jackson D.G. Cornelis F.B. Gerth U. Bell J.I. Genomic structure of DNA encoding the lymphocyte homing receptor CD44 reveals at least 12 alternatively spliced exons.Proc Natl Acad Sci U S A. 1992; 89: 12160-12164Crossref PubMed Scopus (974) Google Scholar Of the 19 exons, 12 can be alternatively spliced.4Screaton G.R. Bell M.V. Jackson D.G. Cornelis F.B. Gerth U. Bell J.I. Genomic structure of DNA encoding the lymphocyte homing receptor CD44 reveals at least 12 alternatively spliced exons.Proc Natl Acad Sci U S A. 1992; 89: 12160-12164Crossref PubMed Scopus (974) Google Scholar Most often, the alternative splicing occurs between exons 5 and 15, leading to an insertion in tandem of one or more variant exons (exon 6 to exon 14; v1 to v10) within the membrane proximal region of the extracellular domain.4Screaton G.R. Bell M.V. Jackson D.G. Cornelis F.B. Gerth U. Bell J.I. Genomic structure of DNA encoding the lymphocyte homing receptor CD44 reveals at least 12 alternatively spliced exons.Proc Natl Acad Sci U S A. 1992; 89: 12160-12164Crossref PubMed Scopus (974) Google Scholar For example, keratinocytes contain the additional exons v3 to v10 inserted into the CD44 standard form transcripts.5Haggerty J.G. Bretton R.H. Milstone L.M. Identification and characterization of a cell surface proteoglycan on keratinocytes.J Invest Dermatol. 1992; 99: 374-380Crossref PubMed Scopus (47) Google Scholar This isoform has been designated as CD44v3-10 (or Epican).5Haggerty J.G. Bretton R.H. Milstone L.M. Identification and characterization of a cell surface proteoglycan on keratinocytes.J Invest Dermatol. 1992; 99: 374-380Crossref PubMed Scopus (47) Google Scholar Several lines of evidence indicate that the HA-CD44 interaction selects unique downstream effectors and coordinates intracellular signaling pathways that initiate a concomitant onset of multiple cellular functions.6Turley E.A. Nobel P.W. Bourguignon of hyaluronan Biol Chem. PubMed Scopus Google Scholar mice an to CD44 in their skin or CD44 knockout mice a in HA on the keratinocyte cell surface and the of certain keratinocyte M. D. interaction keratinocyte and epidermal barrier Invest Dermatol. PubMed Scopus Google Scholar CD44 and HA are in the epidermal keratinocytes of CD44 wild-type M. D. interaction keratinocyte and epidermal barrier Invest Dermatol. PubMed Scopus Google Scholar CD44 and HA can be in the epidermal keratinocytes of CD44 or CD44 knockout M. D. interaction keratinocyte and epidermal barrier Invest Dermatol. 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