title: Downregulation of STRA6 expression in epidermal keratinocytes leads to hyperproliferation-associated differentiation in both in vitro and in vivo skin models.
abstract: Retinoids are known to affect skin cell proliferation and differentiation and are key molecules that target retinoid and retinoic acid receptors (RXRs and RARs), leading to physiological and pharmacologic effects. Our aim was to elucidate the role of the retinol-binding protein receptor STRA6, mediating cellular uptake of retinol, on skin structure and function. Our results indicate that STRA6 is constitutively expressed in human epidermal keratinocytes and dermal fibroblasts and is regulated via RAR/RXR-mediated pathways. HaCaT (Human adult low Calcium high Temperature) cells with stable STRA6 knockdown (STRA6KD) showed increased proliferation. Consistently, human organotypic 3D skin models using stable STRA6KD HaCaT cells showed a significantly thicker epidermis and enhanced expression of activation, differentiation, and proliferation markers. The effects were reversible after treatment with free retinol. Human skin reconstitution employing STRA6KD HaCaT cells leads to massive epithelial thickening under in vivo conditions in SCID mice. We propose that STRA6KD could lead to cellular vitamin A deficiency in keratinocytes. Consequently, STRA6 has a role for regulating retinoid homeostasis and in helping to program signaling that drives proliferation and differentiation of human skin cells. By its influence on hyperproliferation-associated differentiation, STRA6 could also have a role in skin regeneration and could be a target for pharmacological approaches to improve wound healing.
authors.affiliation: Department of Dermatology and Allergology, University Hospital, RWTH Aachen University, Aachen, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Skazik
authors.affiliation: Department of Dermatology and Allergology, University Hospital, RWTH Aachen University, Aachen, Germany.
authors.forename: Philipp M
authors.initials: PM
authors.lastname: Amann
authors.affiliation: Department of Dermatology and Allergology, University Hospital, RWTH Aachen University, Aachen, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Heise
authors.affiliation: Department of Dermatology and Allergology, University Hospital, RWTH Aachen University, Aachen, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Marquardt
authors.affiliation: Department of Dermatology and Allergology, University Hospital, RWTH Aachen University, Aachen, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Czaja
authors.affiliation: Department of Dermatology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Arianna
authors.initials: A
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary and.
authors.forename: Ralph
authors.initials: R
authors.lastname: Rühl
authors.affiliation: Department of Dermatology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kurschat
authors.affiliation: Department of Dermatology and Allergology, University Hospital, RWTH Aachen University, Aachen, Germany.
authors.forename: Hans F
authors.initials: HF
authors.lastname: Merk
authors.affiliation: Department of Dermatology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Bickers
authors.affiliation: Department of Dermatology and Allergology, University Hospital, RWTH Aachen University, Aachen, Germany.
authors.forename: Jens M
authors.initials: JM
authors.lastname: Baron
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D004817:Epidermis / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D012038:Regeneration; D012867:Skin / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism; D014801:Vitamin A / Q000494:pharmacology
chemical_list: D008024:Ligands; D008565:Membrane Proteins; D018168:Receptors, Retinoic Acid; C519685:STRA6 protein, human; C108001:Stra6 protein, mouse; D014801:Vitamin A; D014212:Tretinoin