Type 2 Diabetic Mellitus Inhibits Skin Renewal through Inhibiting WNT-Dependent Lgr5+ Hair Follicle Stem Cell Activation in C57BL/6 Mice

Abstract

Background. Hair follicles are important accessory organs of the skin, and it is important for skin renewal and performs variety of important functions. Diabetes can cause several dermatoses; however, its effect on hair follicles is unclear. The purpose of this study was to investigate the effect of type II diabetes (T2DM) on the hair follicles of mice. Methods. Seven-week-old male C57BL/6 littermate mice were divided into two groups. The treatment group was injected with streptozotocin (STZ) to induce T2DM, and the control group was parallelly injected with the same dose of buffer. Seven days after injection, the back is depilated to observe the hair follicle regeneration. Hair follicle regeneration was observed by naked eyes and HE staining. The proliferation of the skin cells was observed by PCNA and K14 staining. The altered genes were screened by RNA sequencing and verified by qRT-PCR. In addition, Lgr5 + GFP/mTmG transgenic mice were used to observe the effect of T2DM on Lgr5 hair follicle stem cells (HFSC). And the expression of WNT4 and WNT8A were measured by Western Blot. Results. T2DM inhibited hair follicle regeneration. Compared to control mice, T2DM mice had smaller hair follicles, reduced skin thickness, and less expression of PCNA and K14. RNA sequencing showed that the two groups had significant differences in cell cycle and proliferation-related pathways. Compared with the control mice, the mRNA expression of Lgr4, Lgr5, Wnt4, and Wnt8a was decreased in the T2DM group. Moreover, T2DM inhibited the activation of Lgr5 HFSC and the expression of WNT4 and WNT8A. Conclusions. T2DM inhibited hair follicle regeneration and skin cells proliferation by inhibiting WNT-dependent Lgr5 HFSC activation. This may be an important reason for the reduction of skin renewal ability and the formation of chronic wounds caused by diabetes. It is important for the treatment of chronic diabetic wounds and the development of tissue engineering.

Tibetan Medicine Shi-Wei-Gan-Ning-San Alleviates Carbon Tetrachloride-Induced Chronic Liver Injury by Inhibiting TGF-β1 in Wistar Rats

“…Then, slides were stained with hematoxylin-eosin (H&E). Details are as described in the previous studies [ 16 , 17 ]. Histological changes were observed under a microscope (DM2500, Leica, Germany).…”

Wnt/β-catenin signaling activator restores hair regeneration suppressed by diabetes mellitus

“…Alopecia areata, one of the autoimmune diseases, shows reduced Wnt/β-catenin signaling that causes hair loss ( 16 ). Furthermore, there have been case studies of increased hair loss in diabetic patients ( 38 ) and reports of the hair growth inhibition by inactivated Wnt/β-catenin signaling in diabetes ( 8 ). Thus, our findings together with the importance of regulating the Wnt/β-catenin signaling pathway in several chronic diseases suggest that Wnt activators might be potential therapeutic agents for patients with several chronic diseases, including diabetic alopecia.…”

“…For instance, diabetic retinopathy is caused by up-regulation of Wnt/β-catenin signaling ( 5 ), whereas diabetic foot ulcer and diabetes-related Alzheimer’s diseases are caused by down-regulation of Wnt/β-catenin signaling ( 6 , 7 ). A recent study has shown that diabetes can inhibit hair regrowth by inhibiting Wnt/β-catenin signaling ( 8 ). However, this study was mainly focused on the effect of diabetes on hair follicle cycle transition, not on hair follicle neogenesis itself, using a hair depilation model.…”

Injury-induced interleukin-1 alpha promotes Lgr5 hair follicle stem cells de novo regeneration and proliferation via regulating regenerative microenvironment in mice

“…The hair follicle (HF), sebaceous gland and sweat gland, namely the appendage of the skin are derived from a single layer of multipotent progenitors during skin morphogenesis [ 1 ]. HFs are important cutaneous appendages that maintain skin function and self-renewal [ 2 ]. In postpartum humans, however, deep injuries to the skin heal with scar formation but do not regenerate, and the epidermal appendages lost at the injury site do not regenerate [ 3 ].…”

“…In the gut, Lgr5 cells are not necessary for gut homeostasis [ 18 ], but they are essential for intestinal regeneration after radiation [ 19 ]. Similarly, Lgr5 HFSCs are necessary for hair regeneration and wound healing but not for homeostasis [ 2 , 20 ]. Depletion of Lgr5 HFSCs inhibits hair regeneration; however, this phenomenon is reversible [ 21 ].…”