Hyaluronan-CD44 interaction stimulates keratinocyte differentiation, lamellar body formation/secretion, and permeability barrier homeostasis.
In this study we investigated whether hyaluronan (HA)-CD44 interaction influences epidermal structure and function. Our data show that CD44 deficiency is accompanied by reduction in HA staining in CD44 knockout (k/o) mouse skin leading to a marked thinning of epidermis versus wild-type mouse skin. A significant delay in the early barrier recovery (following acute barrier disruption) occurs in CD44 k/o versus wild-type mouse skin. To assess the basis for these alterations in CD44 k/o mouse epidermis, we determined that differentiation markers are greatly reduced in the epidermis of CD44 k/o versus wild-type mice, while conversely HA binding to CD44 triggers differentiation in cultured human keratinocytes. CD44 downregulation (using CD44 small interfering RNAs) also inhibits HA-mediated keratinocyte differentiation. Slower barrier recovery in CD44 k/o mice could be further attributed to reduced lamellar body formation, loss of apical polarization of LB secretion, and downregulation of cholesterol synthesis. Accordingly, HA-CD44 binding stimulates both LB formation and secretion. Together, these observations demonstrate new roles for HA-CD44 interaction in regulating both epidermal differentiation and lipid synthesis/secretion, which in turn influence permeability barrier homeostasis. HA-CD44 signaling could comprise a novel approach to treat skin disorders characterized by abnormalities in differentiation, lipid synthesis, and/or barrier function.
Bourguignon
Lilly Y W
LY
Department of Medicine, University of California San Francisco and VA Medical Center, San Francisco, California, USA. lilly.bourguignon.ucsf.edu
Ramez
Mohamed
M
Gilad
Eli
E
Singleton
Patrick A
PA
Man
Mao-Qiang
MQ
Crumrine
Debra A
DA
Elias
Peter M
PM
Feingold
Kenneth R
KR
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D004817:Epidermis / Q000002:abnormalities* / Q000378:metabolism / Q000648:ultrastructure*; D006706:Homeostasis; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000378:metabolism*; D015603:Keratinocytes / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism; D008055:Lipids / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010539:Permeability
D018960:Hyaluronan Receptors; D008055:Lipids; D006820:Hyaluronic Acid