Harnessing the Power of Regenerative Therapy for Vitiligo and Alopecia Areata.

Vitiligo and alopecia areata (AA) are common autoimmune conditions characterized by white spots on the skin (vitiligo) and bald spots on the scalp (AA), which significantly impact patients' lives by damaging their appearance and function. Melanocytes are the target of immune destruction in vitiligo and are hypothesized to be the site of immune attack in AA. This inflammatory process can be partially reversed by immunosuppressive drugs. Both conditions demonstrate regenerative components that are just now being identified. In this review, we focus on the regenerative medicine aspects of vitiligo and AA, using experimental data from human, mouse, and in vitro models, summarizing the key pathways involved in repopulation of the epidermis with melanocytes in vitiligo and in regrowth of hair follicles in AA. We also discuss treatments that may activate these pathways. Of the regenerative treatments, JAK inhibitors and bimatoprost stimulate repopulation of depleted cells in both diseases, intralesional injections of autologous concentrated platelet-rich plasma and minoxidil showed some benefit in AA, and phototherapy with narrowband UVB was shown to be effective especially in vitiligo. Finally, we discuss future treatments based on the mobilization of stem cells to regenerate anagen hair follicles in AA and intraepidermal melanocytes in vitiligo.

Yin-yang 1 negatively regulates the differentiation-specific transcription of mouse loricrin gene in undifferentiated keratinocytes.

Loricrin is a major component of the epidermal cornified cell envelope, and is expressed only in terminally differentiated keratinocytes. This cell differentiation-specific expression pattern suggests specific suppression of loricrin gene expression in undifferentiated keratinocytes as well as its activation in differentiated keratinocytes. We identified a negative regulatory sequence element in the first intron of the mouse loricrin gene involved in suppression of loricrin gene expression in undifferentiated keratinocytes. A database search indicated that this sequence contained the putative inverted Yin-Yang 1 (YY1)-binding motif. Constructs with point mutations in the putative YY1-binding motif showed increased reporter activity, indicating that YY1 negatively regulates loricrin gene transcription. Co-transfection experiments using a YY1 expression vector revealed that YY1 represses loricrin promoter activity. Western blotting and immunohistochemical analyses indicated that YY1 is more abundant in undifferentiated than in differentiated keratinocytes. These findings suggest that YY1 contributes to specific loricrin gene expression in differentiated keratinocytes by suppression of its transcription in undifferentiated keratinocytes. Furthermore, we demonstrated that forced expression of YY1 in differentiated keratinocytes results in specific downregulation of expression of other early and late differentiation markers.

Transcriptional regulation of bcl-2 mediated by the sonic hedgehog signaling pathway through gli-1.

Basal cell carcinomas (BCCs) express high levels of the antiapoptotic proto-oncogene, bcl-2, and we have shown that bcl-2 contributes to the malignant phenotype in a transgenic mouse model. The basis of bcl-2 transcriptional regulation in keratinocytes is unknown. The sonic hedgehog (SHH) signaling pathway is frequently altered in BCCs. Mediators of shh signaling include the downstream transactivator, gli-1, and transrepressor, gli-3. Seven candidate gli binding sites were identified in the bcl-2 promoter. Cotransfection of increasing amounts of gli-1 in keratinoycytes resulted in a corresponding dose-dependent increase in bcl-2 promoter luciferase activity. Gli-1 was also able to up-regulate endogenous bcl-2. Gli-3 cotransfection resulted in no significant changes in bcl-2 promoter activity compared with control. Gli-3 has been demonstrated to be proteolytically processed into an N-terminal repressive form that can inhibit downstream transactivation by gli-1. Gli-3 mutants possessing only the N-terminal region or the C-terminal region were made and used in luciferase assays. The N terminus of gli-3 inhibited gli-1 transactivation of the bcl-2 promoter. Gel shift analysis and luciferase assays demonstrated that gli binding site 4 (-428 to -420), is important for gli transcriptional regulation. Skin samples from transgenic mice expressing an RU486 gli-1 transgene exhibited significantly higher levels of endogenous bcl-2 protein in epidermal keratinocytes as assessed by immunoblotting and immunohistochemistry. Together, these findings provide consistent evidence that gli proteins can transcriptionally regulate the bcl-2 promoter and that gli-3 can inhibit transactivation by gli-1. These studies further suggest that one consequence of the deregulation of shh signaling in BCC is the up-regulation of bcl-2.