The cycling hair follicle as an ideal systems biology research model

Abstract

In the postgenomic era, systems biology has rapidly emerged as an exciting field predicted to enhance the molecular understanding of complex biological systems by the use of quantitative experimental and mathematical approaches. Systems biology studies how the components of a biological system (e.g. genes, transcripts, proteins, metabolites) interact to bring about defined biological function or dysfunction. Living systems may be divided into five dimensions of complexity: (i) molecular; (ii) structural; (iii) temporal; (iv) abstraction and emergence; and (v) algorithmic. Understanding the details of these dimensions in living systems is the challenge that systems biology aims to address. Here, we argue that the hair follicle (HF), one of the signature features of mammals, is a perfect and clinically relevant model for systems biology research. The HF represents a stem cell-rich, essentially autonomous mini-organ, whose cyclic transformations follow a hypothetical intrafollicular "hair cycle clock" (HCC). This prototypic neuroectodermal-mesodermal interaction system, at the cross-roads of systems and chronobiology, encompasses various levels of complexity as it is subject to both intrafollicular and extrafollicular inputs (e.g. intracutaneous timing mechanisms with neural and systemic stimuli). Exploring how the cycling HF addresses the five dimensions of living systems, we argue that a systems biology approach to the study of hair growth and cycling, in man and mice, has great translational medicine potential. Namely, the easily accessible human HF invites preclinical and clinical testing of novel hypotheses generated with this approach.

Figure 1

The hair follicle enters a continuous cyclical process of organ regression (catagen), a relative ‘resting’ phase (telogen) and a growth phase (anagen) in the hair cycle. This process is altered in hair disorders such as hirsutism where hair follicles exhibit a prolonged anagen phase. The hair cycle demonstrates the dynamic nature of the HF with drastic molecular and structural changes associated with the passing of time (stage of hair cycle). DP, Dermal papilla; ORS, Outer root sheath; HS, Hair shaft; IRS, inner root sheath; SG, Sebaceous gland. Adapted after Schneider et al. 2009 Curr Biol (11).

Figure 2

Spatio-temporal simulations of the follicular automaton model (FAM) showing different patterns of hair growth. Experimental (phototrichogram) data collected over 14 years was used to approximate the distribution of durations of hair cycle stages in each hair follicle for each patient by using a log normal distribution. The FAM was defined using the assumptions that (i) each follicle is independent; (ii) each follicle traverses the cycle in the order of anagen-telogen- latency phases; and (iii) after latency the follicle may either enter a new cycle or undergo death or miniaturization. The figure shows the simulation of human hair growth over ‘25 years’ using the FAM and demonstrates how different patterns of alopecia could be achieved by simulating a population of HFs on a ‘scalp’. (a) ‘Hair follicles’ were arranged on a grid (‘scalp’) with hair follicles programmed with different mean durations of the anagen phase across a gradient as shown in left column (decreasing mean from periphery of the ‘scalp’ to the centre). The hair follicles were programmed to ‘die’ after a set number of cycles. The final hair pattern at 25 years corresponds to a diffuse alopecia commonly seen in women. (b) As in a, but steeper gradient set across the scalp to produce more dramatic balding pattern in the centre. (c) Grid programmed with temporal conditions as well as central gradient to achieve the final hair pattern consistent with androgenetic alopecia (male pattern baldness) as shown in Figures b and c. This model has limitations, for example, the phototrichogram method provides only approximate temporal information regarding the durations of hair cycle stages. The data represents observations from the skin’s surface and provides no more specific information on the molecular and temporal changes at the HF level. The assumption that the results obtained with this method can relate quantitatively to the molecular timings of the human hair cycle is tentative. This is demonstrated by the fact that catagen (which lasts a few weeks in human scalp hair) is not captured using this method. Adapted after Halloy et al. 2000 Proc Natl Acad Sci USA (77). Copyright 2000.

Figure 3

Demonstration of the emergent property of murine hair follicles exhibiting this behaviour in hair cycle domains. In situ hybridization was carried out on longitudinal sections of murine dorsal skin that were arranged spatially and temporally. These experiments revealed how the propagation of hair cycle waves on the dorsum may arise. Spatio-temporal patterns in hair follicle activity were directly linked to expression levels of the BMPs within hair cycle domains. Cyclic changes in Bmp2 and Bmp4 expression were asynchronous to hair cycle changes and that of WNT/β-catenin signalling. Noggin, a BMP antagonist, was expressed in a similar pattern to WNT. The figure shows the schematic summary of the hair cycle rhythm (in black) and the dermal rhythm (red). Together they define four new functional stages that correspond to the ability to propagate and respond to hair cycle propagation, these are; propagating anagen, autonomous anagen, refractory telogen and competent telogen. Refractory telogen is characterized by low noggin, high BMPs and low WNT signalling. Competent telogen is defined by low noggin, low BMPs whereas, during propagating anagen high noggin levels and low BMPs are found. Autonomous anagen is distinguished by the expression of high noggin and high BMPs. Catagen is omitted for simplification. Reprinted by permission from Macmillan Publishers Ltd: Plikus et al. 2008 Nature (50). Copyright 2008.