An Intrinsic Oscillation of Gene Networks Inside Hair Follicle Stem Cells: An Additional Layer That Can Modulate Hair Stem Cell Activities

Abstract

This article explores and summarizes recent progress in and the characterization of main players in the regulation and cyclic regeneration of hair follicles. The review discusses current views and discoveries on the molecular mechanisms that allow hair follicle stem cells (hfSCs) to synergistically integrate homeostasis during quiescence and activation. Discussion elaborates on a model that shows how different populations of skin stem cells coalesce intrinsic and extrinsic mechanisms, resulting in the maintenance of stemness and hair regenerative potential during an organism's lifespan. Primarily, we focus on the question of how the intrinsic oscillation of gene networks in hfSCs sense and respond to the surrounding niche environment. The review also investigates the existence of a cell-autonomous mechanism and the reciprocal interactions between molecular signaling axes in hfSCs and niche components, which demonstrates its critical driving force in either the activation of whole mini-organ regeneration or quiescent homeostasis maintenance. These exciting novel discoveries in skin stem cells and the surrounding niche components propose a model of the intrinsic stem cell oscillator which is potentially instructive for translational regenerative medicine. Further studies, deciphering of the distribution of molecular signals coupled with the nature of their oscillation within the stem cells and niche environments, may impact the speed and efficiency of various approaches that could stimulate the development of self-renewal and cell-based therapies for hair follicle stem cell regeneration.

Keywords: BMP signaling; WNT signaling; dermal papilla; hair follicle stem cells (hfSCs); niche.

FIGURE 1

Skin and appendages. (A) Schematic, illustrating a section through the skin including hair follicle along with the sebaceous gland as well as the sweat gland protruding into the dermis with fibroblasts and adipocytes and underlying hypodermis. (B) Graphic representation of skin epidermis: basal layer with the expression of Keratin 5 (K5) and Keratin 14 (K14) above, spinous layer positive for Keratin 1 (K1) and Keratin 10 (K10) and on the top granular and cornified layers marked accordingly with Filaggrin and Loricrin. (C) Illustration of the junctional connection between keratinocytes of basal layer and fibroblasts of the papillary dermis, firmed by hemidesmosomes, which are composed of integrin subunits α and β attached to the basement membrane and bridged by plectin to keratin cytoskeleton filaments. The docking filaments of the basement membrane: laminin, collagen, and elastic fibers form part of the extracellular matrix (ECM) produced by keratinocytes and dermal fibroblasts. Tight adhesion of keratinocytes in the epidermis is created by tight junctions and the formation of desmosomes. The papillary dermis is primarily composed of fibroblasts, arranged in loose networks and elastic fibers of the ECM. DP, dermal papillae.

FIGURE 2

Development and cyclic regeneration of hair follicle. (A) Graphic stages of hair follicle (HF) morphogenesis: hair placode (initiation of HFs pattern formation), immature hair germ, hair peg, and fully developed and differentiated anagen hair by the end of first postnatal resting phase of telogen. Mature HF is built of a reservoir of hair follicle Stem Cells (hfSCs) which is connected above to an associated sebaceous gland (SG), located below the responsive hair germ (HG) with underlying dermal papilla (DP). During the cyclic hair growth, each HF undergoes phases of telogen (quiescence, resting), anagen (activation, regrowth), and catagen (degeneration). (B) During the growth phase, the hair bulb cells comprise actively proliferative matrix cells which undergo final differentiation creating an inner root sheath (IRS) and hair shaft (HS, protruding out of the skin surface, visible part of HF) layers of the HF mini-organ. HS, hair shaft is composed of Ch, the cuticle of the hair shaft; Co, cortex of hair shaft; Me, medulla; DP, dermal papilla; IRS, inner root sheath contains; He, Henle’s layer; Hu, Huxley’s layer; Ci, cuticle; Cp, companion layer; ORS, outer root sheath.

FIGURE 3

Intrinsic signaling oscillation in hair follicle stem cells. (A) Graphic depiction of stemness genes expressed in quiescent telogen including bulge with hfSCs along with upper bulge and infundibulum of HF, hair germ, suprabasal bulge layer (SBL) layer, and DP. (B) Model of proposed intrinsic oscillation in hfSCs represents intrinsic dynamic competitive oscillation along BMP signaling axis of activators and inhibitors and its reciprocal interaction between BMP and WNT pathways in SCs (stem cells) homeostasis regulation.

FIGURE 4

Intrinsic oscillator in hfSCs consolidates with extrinsic signaling in niche environment during hair cycle regeneration. (A) Proposed model of the molecular oscillation in hfSCs and its cross-talk during the quiescent-telogen and onset of HF activation during early anagen. The model also depicts intrinsic dynamic oscillation in hfSCs through observed rearrangements in ligand-receptor dependency and cross-talk between the main players of BMP and WNT signaling in SCs, and niche synchronized regulation. (B) Model of intrinsic oscillation in hfSCs between BMP and WNT signaling pathways, which sense and respond in an autocrine way to intra bulge hfSCs and in a paracrine way to the surrounding niche environment, including signaling center DP (intrinsic synergistic oscillation vs. intrinsic competitive oscillation with an accumulation of activators and/or inhibitors). (C) Model of internal feedback regulatory loop in DP between BMP and WNT signaling pathways, which sense and reciprocally respond to the hfSCs and the surrounding niche environment, especially bulge hfSCs in a paracrine way (synergistic vs. competitive accumulation of activators and/or inhibitors). (D) Model of wave interference in opposed phases between either hfSCs with repressive BMP and DP with stimulating WNT or in the reverse situation of hfSCs with activation of WNT and DP with inhibitory BMP signaling. The model of wave interference in opposed phases proposes attenuation with the inhibitory (OFF) effect of signals coming from either the intrinsic hfSCs oscillator or from the internal feedback regulatory loop of DP regardless of whether they are predominantly in BMP or WNT signaling. It results in reducing and flattening the wave amplitude, of BMP or WNT signaling either in hfSCs or DP (a dotted black sinusoid lines), creating a weaker resultant wave than individual waves before, and the mutual influence of these waves causes destructive interference. (E) Model of constructive interference with wave interference in the same stages (or in the same phases) of the repeating pattern waves between hfSCs and DP, with either repressive BMP resulting in quiescence (OFF) effect or stimulatory WNT leading to activation (ON) effect. The model of waves interference in the same phases proposes either inhibitory (OFF, a dotted red sinusoid line) effect or activatory (ON, a dotted green sinusoid line) effect of signals coming from either intrinsic hfSCs oscillator or internal feedback regulatory loop of DP and the phases depend on whether synchronization happens in BMP or WNT signaling for both hfSCs and DP. It creates a stronger resultant wave with a higher amplitude of either BMP (stronger inhibition) or WNT (stronger activation) signaling in both hfSCs and DP. (F) Model of the intrinsic oscillator in hfSCs which consolidates with extrinsic signaling in surrounding niche environment during hair cycle regeneration. MSCs, melanocyte stem cells.