A multi-scale model for hair follicles reveals heterogeneous domains driving rapid spatiotemporal hair growth patterning.

Qixuan Wang,Hyunsu Lee,Jung Chul Kim,Xiaoyang Wang,Zhengquan Yu,John Foley,Krzysztof Kobielak,Xiaojie Wang,Kiarash Khosrotehrani,Eve Kandyba,Ji Won Oh,Nanda Maya Mali,Brian Vu,Ran Zhao,Tao Peng,Jonathan Le,Qing Nie,Moonkyu Kim,Kim Pham,Anukriti Dhar,Xiaoling Cao,Jung Min Park,Bogi Andersen,June Hyug Choi ,Shelby C Jocoy ,Hye Lim Lee ,Christian F Guerrero‐Juarez ,Antoni R Rossi ,Raúl Ramos ,Melisa A Fuentes ,Julien M D Legrand ,Maksim V Plikus

doi:10.7554/elife.22772

Abstract

The control principles behind robust cyclic regeneration of hair follicles (HFs) remain unclear. Using multi-scale modeling, we show that coupling inhibitors and activators with physical growth of HFs is sufficient to drive periodicity and excitability of hair regeneration. Model simulations and experimental data reveal that mouse skin behaves as a heterogeneous regenerative field, composed of anatomical domains where HFs have distinct cycling dynamics. Interactions between fast-cycling chin and ventral HFs and slow-cycling dorsal HFs produce bilaterally symmetric patterns. Ear skin behaves as a hyper-refractory domain with HFs in extended rest phase. Such hyper-refractivity relates to high levels of BMP ligands and WNT antagonists, in part expressed by ear-specific cartilage and muscle. Hair growth stops at the boundaries with hyper-refractory ears and anatomically discontinuous eyelids, generating wave-breaking effects. We posit that similar mechanisms for coupled regeneration with dominant activator, hyper-refractory, and wave-breaker regions can operate in other actively renewing organs.

Highlights

Featuring prominent growth cycles, the hair follicle (HF) is a model system of choice for studying tissue regeneration
The former only exists during telogen, while the latter only exists during anagen
We hypothesized that the essential temporal molecular dynamics in the HF operate as follows: Region II generates a signaling ligand (L) gradient; Region I detects it and transmits it into ligand-bound receptors (LR) that through a series of intermediate signaling steps not captured in the model directly

Summary

Introduction

The hair follicle (HF) is a model system of choice for studying tissue regeneration. At the level of cellular activities, the hair growth cycle consists of three consecutive phases: anagen, phase of active proliferation; catagen, apoptotic involution phase; and telogen, relative quiescence phase (Al-Nuaimi et al, 2010; Paus and Foitzik, 2004; Schneider et al, 2009; Stenn and Paus, 2001). Signals from the niche, including the dermal papilla (DP), stimulate bulge stem cells and adjacent hair germ (HG) progenitors to proliferate (Enshell-Seijffers et al, 2010; Greco et al, 2009; Legrand et al, 2016). Activated progenitors generate all lower HF structures, including the outer root sheath (ORS) and hair matrix. Since the bulge produces downward migrating progeny (Hsu et al, 2011), it effectively serves as a progenitor source, while the matrix functions as a sink, and the ORS as a channel for progenitors transiting between them

Methods

Results

Conclusion