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Review
. 2012 Apr;27(2):61-72.
doi: 10.1152/physiol.00028.2011.

Physiological regeneration of skin appendages and implications for regenerative medicine

Cheng-Ming Chuong  1 , Valerie A Randall, Randall B Widelitz, Ping Wu, Ting-Xin Jiang
Affiliations
Review

Physiological regeneration of skin appendages and implications for regenerative medicine

Cheng-Ming Chuong et al. Physiology (Bethesda). 2012 Apr.

Abstract

The concept of regenerative medicine is relatively new, but animals are well known to remake their hair and feathers regularly by normal regenerative physiological processes. Here, we focus on 1) how extrafollicular environments can regulate hair and feather stem cell activities and 2) how different configurations of stem cells can shape organ forms in different body regions to fulfill changing physiological needs.

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Figures

Fig 1
Fig 1. Physiological regeneration of hairs and feathers
A) Hair follicle and cycling. B) Feather follicle and cycling. C) Hair follicle cells show circadian fluctuation (day and night are shown as alternating black and white bands) (40). The length of the hair cycle is affected by seasonal changes, so that the phenotypes of hairs and feathers can change under different physiological conditions depending on the need for thermoregulation or attracting mates. D) Each animal goes through physiological changes during different stages of its life cycle. Human beings, chickens, and deer (Cervus elaphus) all have different skin appendage patterns (spatial differences) in youth and adult stages (temporal differences). Different size and pigmented skin appendages are generated from the same follicle. How the hair/feather cycle integrates with different physiological signals is a fundamental biological question, and the mechanisms remain to be worked out. Understanding this process is critical to managing these regenerative ectodermal organs after illness, injury or disease.
Fig 2
Fig 2. Macro-environmental regulation of mouse, hair cycles
A) Progression of regenerative hair waves is affected by the ratio of activators and inhibitors in the dermal macro-environment. P, propagatory anagen; A, autonomous anagen; R, refractory telogen; C, competent telogen. B. Hair waves are reset during pregnancy and restart after lactation. C. Many of the macro-environment modulators such as BMP2 (blue) are present in the subcutaneous, sudan red positive adipocytes (red). D) Schematic representation of the hair cycle rhythm (black) and the dermal rhythm (red) which define the four functional stages of the hair cycle (Catagen is omitted for simplification). E) A bison with thick fur in Yellowstone during winter. F, Regenerative hair wave patterns in different animals. Y axis is the frequency of cycling of a single follicle. X axis shows the level of coupling in a hair follicle population, i.e. how much the cycling stages of one hair follicle affect the cycling behaviour of adjacent follicles. Toward the right, there is much higher coupling. This means that a hair follicle can enter anagen either via intra-follicular or extra-follicular signals. Toward the left, follicles are not coupled and behave independently. Therefore, follicle stem cells can only get activated via their own intra-follicle signals. In human babies, hair waves are seen in occipital regions. See legend of panel A for P, A, R C abbreviations. A, F are from Plikus et al., 2011; B, C, D are from Plikus et al., 2008. Photo in E, by Cheng-Ming Chuong.
Fig 3
Fig 3. Micro-environmental shaping of feather morphology
A) Feather morphology can vary from radially symmetric (i.e., downy feathers) to bilaterally symmetric (i.e., contour feathers) to asymmetric (i.e., flight feathers). B) In radially symmetric feathers, the feather stem cell ring is horizontally placed at the base of the follicle. In bilaterally symmetric feathers, the stem cell ring is tilted to a certain angle. This breaks the symmetry and TA cells (transient amplifying cells) become asymmetric at the ramogenic or rachidogenic zones where the rachis and barbs (feather branches) form. C) A male adult peacock in the blossoming Los Angeles Arboretum shows off spectacular plumages in different body regions. A, from Lucas and Stettenheim, 1972; B, From Yue et al., 2006. Photo in C, by Cheng-Ming Chuong.
Fig 4
Fig 4. Intra-follicular regeneration and regeneration of new follicles
A) Hair and feather cycling involves only regeneration of stem cells in that particular follicle. B) In addition to the influence of the intra-follicular micro-environment, the regeneration of hair stem cells is modulated by the extra-follicular macro-environment, which includes the subcutaneous adipose layer, body hormone conditions as well as seasonal variation in temperature and light:dark cycles. C) Following the formation of a large wound in the mouse, new hair follicles can reform through the hair germ stage. D) Deer antlers regenerate every year as seen in Fig. 1D. It is another splendid example of physiological regeneration. It involves both cartilage regeneration and regeneration of new hair follicles. A is from Plikus et al., 2008; C is from Chuong, 2007; D is modified from Randall and Croft, 2003.
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