Association of fibrosis in the bulge portion with hair follicle miniaturization in androgenetic alopecia

To the Editor: Androgenetic alopecia (AGA) is the most common hair loss disorder characterized by progressive hair miniaturization (in which large terminal hairs are gradual replaced by thin vellus hairs). Currently, the pathologic mechanism of AGA remains unclear. Growing evidence suggests that the bulge portion of hair follicles (HFs) plays an important role in the pathogenesis of AGA. The bulge area is located between the opening of the sebaceous gland and the attachment site of the arrector pili muscle (Supplemental Fig 1; available via Mendeley at https://doi.org/10.17632/w2xry2zp8y.1) and is a niche of multipotent stem cells that are necessary for regeneration of HFs, sebaceous glands, and epidermis.1Myung P. Ito M. Dissecting the bulge in hair regeneration.J Clin Invest. 2012; 122: 448-454Crossref PubMed Scopus (57) Google Scholar It has been proven that the failure of conversion from bulge stem cells to progenitor cells participates in AGA development.2Garza L.A. Yang C.-C. Zhao T. et al.Bald scalp in men with androgenetic alopecia retains hair follicle stem cells but lacks CD200-rich and CD34-positive hair follicle progenitor cells.J Clin Invest. 2011; 121: 613-622Crossref PubMed Scopus (200) Google Scholar In our previous study, we discovered that fibrosis-related genes were overexpressed in the bugle portion of AGA-affected HFs,3Miao Y. Qu Q. Jiang W. et al.Identification of functional patterns of androgenetic alopecia using transcriptome profiling in distinct locations of hair follicles.J Invest Dermatol. 2018; 138: 972-975Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar implying that fibrosis participates in the disturbance of bulge stem cell conversion and leads to HF miniaturization. Hair diameter is an indicator of the miniaturization stage of HFs during AGA development. The average diameter of scalp terminal hair is approximately 80 μm, and 60 μm is a sensitive index to evaluate the progression of AGA.4Ishino A. Takahashi T. Suzuki J. Nakazawa Y. Iwabuchi T. Tajima M. Contribution of hair density and hair diameter to the appearance and progression of androgenetic alopecia in Japanese men.Br J Dermatol. 2014; 171: 1052-1059Crossref PubMed Scopus (17) Google Scholar In this study, we collected 300 follicular units from 10 Chinese men (8 patients with AGA and 2 healthy individuals, 23-41 years old; 30 follicular units/patient). The frontal HFs from patients with AGA were divided into 3 groups according to their diameters: early miniaturized HFs (EMHFs) of 80 to 100 μm, mediate miniaturized HFs (MMHFs) of 60 to 80 μm, and advanced miniaturized HFs (AMHFs) of 0 to 60 μm. The healthy occipital HFs (HOHFs) of patients with AGA and healthy frontal HFs (HFHFs) of healthy individuals were taken as control groups. All experiments were endorsed by the Ethics Committee of Southern Medical University and complied with the Declaration of Helsinki. All patients gave written informed consent before participation in this study. Hematoxylin-eosin staining showed that most of HFs in the MMHF group (85.6%) and AMHF group (93.5%) had some spindled cells with myofibroblast-like appearance in the bugle region, whereas few spindled cells were found in the EMHF (12.4%), HFHF (4.5%), and HOHF groups (5.6%) (Fig 1). Transmission electron microscopy was performed to confirm the presence of fibroblastoid cells within MMHF and AMHF bulge epithelium. As expected, collagen filaments were found within the cytoplasm of bulge keratinocytes (Supplemental Fig 2; available via Mendeley at https://doi.org/10.17632/w2xry2zp8y.1), indicating that fibrosis occurs within the bugle region of the MMHF and AMHF groups. The messenger RNA expression of fibrosis markers within the bulge region was analyzed in the 5 groups. Compared with HFHF and HOHF groups, expression of fibrosis markers (vimentin, fibronectin, Hsp47, and S100A4) were gradually upregulated in the EMHF, MMHF, and AMHF groups (Fig 2), suggesting that fibrosis of the bulge potion is positively correlated with the miniaturization of AGA-affected HFs. Our study shows that fibrosis occurs in the bulge region of AGA-affected HFs and is correlated with their miniaturization stage. The mechanism probably is that fibrosis of the bulge portion causes dysfunction of stem cells and inhibition of hair growth, finally leading to HF miniaturization. In conclusion, to our knowledge, our study puts forward a novel insight of AGA pathogenesis with a pathologic framework of “fibrosis–hair miniaturization,” suggesting that drugs inhibiting fibrosis are potential therapy to reverse hair miniaturization during AGA development. None disclosed.