Functional complexity of hair follicle stem cell niche and therapeutic targeting of niche dysfunction for hair regeneration

Abstract

Stem cell activity is subject to non-cell-autonomous regulation from the local microenvironment, or niche. In adaption to varying physiological conditions and the ever-changing external environment, the stem cell niche has evolved with multifunctionality that enables stem cells to detect these changes and to communicate with remote cells/tissues to tailor their activity for organismal needs. The cyclic growth of hair follicles is powered by hair follicle stem cells (HFSCs). Using HFSCs as a model, we categorize niche cells into 3 functional modules, including signaling, sensing and message-relaying. Signaling modules, such as dermal papilla cells, immune cells and adipocytes, regulate HFSC activity through short-range cell-cell contact or paracrine effects. Macrophages capacitate the HFSC niche to sense tissue injury and mechanical cues and adipocytes seem to modulate HFSC activity in response to systemic nutritional states. Sympathetic nerves implement the message-relaying function by transmitting external light signals through an ipRGC-SCN-sympathetic circuit to facilitate hair regeneration. Hair growth can be disrupted by niche pathology, e.g. dysfunction of dermal papilla cells in androgenetic alopecia and influx of auto-reacting T cells in alopecia areata and lichen planopilaris. Understanding the functions and pathological changes of the HFSC niche can provide new insight for the treatment of hair loss.

Keywords: Alopecia; Alopecia areata; Androgenetic alopecia; Function; Hair follicle stem cell; Lichen planopilaris; Niche; Therapy.

Fig. 1

Hair follicle structure, hair follicle stem cell and hair cycle. Quiescent HFSCs reside in the bulge region and primed HFSCs are located in the secondary hair germ. They are transiently activated in early anagen, giving rise to progeny that grow down to form the lower portion of HFs. HFs progress through catagen (regressing phase), telogen (resting phase) and anagen (growing phase) cyclically. Matrix cells in the hair bulb actively proliferate and differentiate to support the continued elongation of the hair shaft in anagen. In catagen, the hair bulb shrinks and the lower portion of the HF regresses through a progressively shortened epithelial strand into the telogen HF. In telogen, HFSCs in the secondary hair germ and bulge remain inactivated

Fig. 2

Hair follicle stem cell niche. The HFSC niche is composed of various component cells, such as dermal papilla, preadipocytes, adipocytes, immune cells and nerves. Systemic hormones also regulate HFSCs directly or indirectly through the HFSC niche cells. Both activating and suppressive signals are present within the HFSC niche. The probability of HFSC activation depends on the summation of all the activating and inhibitory signals

Fig. 3

Functional categorization of HFSC niche cells. According to the functions of niche cells, they are categorized into 3 groups: signaling modules, sensing modules, message-relaying modules. These functionally distinct modules are assembled into a multifunctional niche. Signaling modules regulate HFSC activity via cell-cell contact or paracrine secretion. Sensory modules detect environmental cues. Message-relaying modules transmit signals from remote cells/tissues to HFSCs. Sensory modules and message-relaying modules can directly signal to HFSCs or indirectly regulate HFSC activity through the signaling modules

Fig. 4

Sympathetic nerves relay external light signals to HFSCs. Sympathetic nerves are a gateway for the communication between internal HFSC niche and external environment. Intense light irradiation to eyes promotes HFSC activation through an ipRGC-SCN-sympathetic nervous circuit. Increased norepinephrine release from cutaneous sympathetic nerves facilitates HFSC activation by upregulating hedgehog signaling