title: 1α,25-dihydroxyvitamin D3 modulates the hair-inductive capacity of dermal papilla cells: therapeutic potential for hair regeneration.
abstract: Dermal papilla cells (DPCs) have the potential to induce differentiation of epithelial stem cells into hair, and Wnt signaling is deeply involved in the initiation process. The functional limitation of expanded adult DPCs has been a difficult challenge for cell-based hair regrowth therapy. We previously reported that 1α,25-dihydroxyvitamin D(3) (VD(3)) upregulates expression of transforming growth factor (TGF)-β2 and alkaline phosphatase (ALP) activity, both features of hair-inducing human DPCs (hDPCs). In this study, we further examined the effects and signaling pathways associated with VD(3) actions on DPCs. VD(3) suppressed hDPC proliferation in a dose-dependent, noncytotoxic manner. Among the Wnt-related genes investigated, Wnt10b expression was significantly upregulated by VD(3) in hDPCs. Wnt10b upregulation, as well as upregulation of ALPL (ALP, liver/bone/kidney) and TGF-β2, by VD(3) was specific in hDPCs and not detected in human dermal fibroblasts. Screening of paracrine or endocrine factors in the skin indicated that all-trans retinoic acid (atRA) upregulated Wnt10b gene expression, although synergistic upregulation (combined atRA and VD(3)) was not seen. RNA interference with vitamin D receptor (VDR) revealed that VD(3) upregulation of Wnt10b, ALPL, and TGF-β2 was mediated through the genomic VDR pathway. In a rat model of de novo hair regeneration by murine DPC transplantation, pretreatment with VD(3) significantly enhanced hair folliculogenesis. Specifically, a greater number of outgrowing hair shafts and higher maturation of regenerated follicles were observed. Together, these data suggest that VD(3) may promote functional differentiation of DPCs and be useful in preserving the hair follicle-inductive capacity of cultured DPCs for hair regeneration therapies.
authors.affiliation: Department of Plastic Surgery, University of Tokyo, Tokyo, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Aoi
authors.forename: Keita
authors.initials: K
authors.lastname: Inoue
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Chikanishi
authors.forename: Ryoji
authors.initials: R
authors.lastname: Fujiki
authors.forename: Hanako
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Harunosuke
authors.initials: H
authors.lastname: Kato
authors.forename: Hitomi
authors.initials: H
authors.lastname: Eto
authors.forename: Kentaro
authors.initials: K
authors.lastname: Doi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Itami
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
authors.forename: Kotaro
authors.initials: K
authors.lastname: Yoshimura
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D020405:Dermis / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D018859:Hair Follicle / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D007641:Keratolytic Agents / Q000494:pharmacology; D008297:Male; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D060888:Real-Time Polymerase Chain Reaction; D012038:Regeneration / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D007641:Keratolytic Agents; D012333:RNA, Messenger; D051153:Wnt Proteins; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D014212:Tretinoin; D000469:Alkaline Phosphatase