The Modulatable Stem Cell Niche: Tissue Interactions during Hair and Feather Follicle Regeneration

Abstract

Hair and feathers are unique because 1) their stem cells are contained within a follicle structure, 2) they undergo cyclic regeneration repetitively throughout life, 3) regeneration occurs physiologically in healthy individuals and 4) regeneration is also induced in response to injury. Precise control of this cyclic regeneration process is essential for maintaining the homeostasis of living organisms. While stem cells are regulated by the intra-follicle adjacent micro-environmental niche, this niche is also modulated dynamically by extra-follicular macro-environmental signals, allowing stem cells to adapt to a larger changing environment and physiological needs. Here we review several examples of macro-environments that communicate with the follicles: intradermal adipose tissue, innate immune system, sex hormones, aging, circadian rhythm and seasonal rhythms. Related diseases are also discussed. Unveiling the mechanisms of how stem cell niches are modulated provides clues for regenerative medicine. Given that stem cells are hard to manipulate, focusing translational therapeutic applications at the environments appears to be a more practical approach.

The hair follicle enigma

“…It is the delicate balance of these opposite influences which defines the Yin-Yang of the hair follicle. [8,9] Local gradients, half-life, diffusion at distance, storage and release of these various factors are key parameters which will have to be taken into consideration if one wants to understand their functional role. Huge progress has been made in the identification of the repertoire of most of the actors involved in hair follicle biology and expressed during the different phases of the hair follicle, [10] but description of a definite role of this or that factor remains very scarce and scientific articles are full of wordings like "could be involved" or "might play a role".…”

Protective Mechanism of Adipose-Derived Stem Cells in Remodelling of the Skin Stem Cell Niche During Photoaging

“…Skin stem cells are present in the epidermis, sebaceous glands and adult hair follicles [2]. As a mini-organ, the hair follicle is an ideal model to explore the nature of stem cells due to its lifelong cyclic regeneration [3]. In this study, the hair follicle was used as a research model to investigate local environmental changes in skin stem cells during photoaging.…”

“…Alteration of ECM structure and composition, especially that of collagen fibres, during ageing will reduce tissue stiffness and elasticity. In addition to the microenvironment, stem cells are also regulated by macroenvironmental signals to adapt to physiological changes [3]. Compared with other signalling pathways, the Wnt (activator)/BMP (inhibitor) signalling pathway has been shown to have a major role in modulating periodic hair follicle regeneration [6].…”

“…Plikus et al found that the periodic expression of extrafollicular Bmp2 and Bmp4 was regulated by the surrounding microenvironment, or niche [7]. The regeneration cycle of stem cells can be delayed due to changes in signalling factors in ageing mice [3]. Ageing weakens stem cell capacity by altering the microenvironmental structure and macroenvironmental signalling pathways in niches.…”

Hair follicles’ transit-amplifying cells govern concurrent dermal adipocyte production through Sonic Hedgehog

“…The skin harbors a rich array of cell types, including epidermis, hair follicles, dermal fibroblasts, and adipocytes (Blanpain and Fuchs 2009;Hsu et al 2014a;Chen et al 2016;Shook et al 2016;Xin et al 2016). Among them, hair follicles undergo cyclical rounds of growth (anagen), regression (catagen), and rest (telogen).…”