Plikus MV, Widelitz RB, Maxson R et al.Analyses of regenerative wave patterns in adult hair follicle populations reveal macro-environmental regulation of stem cell activity. Int J Dev Biol 53:857-868

Department of Pathology, University of Southern California, Los Angeles, 90033, USA.
The International journal of developmental biology (Impact Factor: 1.9). 03/2009; 53(5-6):857-68. DOI: 10.1387/ijdb.072564mp
Source: PubMed


The control of hair growth in the adult mammalian coat is a fascinating topic which has just begun to be explored with molecular genetic tools. Complex hair cycle domains and regenerative hair waves are present in normal adult (> 2 month) mice, but more apparent in mutants with cyclic alopecia phenotypes. Each hair cycle domain consists of initiation site(s), a propagating wave and boundaries. By analyzing the dynamics of hair growth, time required for regeneration after plucking, in situ hybridization and reporter activity, we showed that there is oscillation of intra-follicular Wnt signaling which is synchronous with hair cycling, and there is oscillation of dermal bone morphogenetic protein (BMP) signaling which is asynchronous with hair cycling. The interactions of these two rhythms lead to the recognition of refractory and competent phases in the telogen, and autonomous and propagating phases in the anagen. Boundaries form when propagating anagen waves reach follicles which are in refractory telogen. Experiments showed that Krt14-Nog mice have shortened refractory telogen and simplified wave dynamics. Krt14-Nog skin grafts exhibit non-autonomous interactions with surrounding host skin. Implantation of BMP coated beads into competent telogen skin prevents hair wave propagation around the bead. Thus, we have developed a new molecular understanding of the classic early concepts of inhibitory "chalone", suggesting that stem cells within the hair follicle micro-environment, or other organs, are subject to a higher level of macro-environmental regulation. Such a novel understanding has important implications in the field of regenerative medicine. The unexpected links with Bmp2 expression in subcutaneous adipocytes has implications for systems biology and Evo-Devo.

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    • "This can be easily observed in Foxn1 mutant mice whose hair follicles are rapidly discharged after pigment deposition stimulating a new round of regeneration (Suzuki et al., 2003). The waves can also be observed in normal mice after hair clipping (Plikus et al., 2009). In Foxn1 mutant mice, the waves have regular spacing, sharing characteristics with the Belousov- Zhabotinskii pattern of reacting and diffusing chemicals (Zaikin and Zhabotinsky, 1970). "
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    ABSTRACT: How tissue patterns form in development and regeneration is a fundamental issue remaining to be fully understood. The integument often forms repetitive units in space (periodic patterning) and time (cyclic renewal), such as feathers and hairs. Integument patterns are visible and experimentally manipulatable, helping us reveal pattern formative processes. Variability is seen in regional phenotypic specificities and temporal cycling at different physiological stages. Here we show some cellular/molecular bases revealed by analyzing integument patterns. 1) Localized cellular activity (proliferation, rearrangement, apoptosis, differentiation) transforms prototypic organ primordia into specific shapes. Combinatorial positioning of different localized activity zones generates diverse and complex organ forms. 2) Competitive equilibrium between activators and inhibitors regulates stem cells through cyclic quiescence and activation. Dynamic interactions between stem cells and their adjacent niche regulate regenerative behavior, modulated by multi-layers of macro-environmental factors (dermis, body hormone status and external environment). Genomics studies may reveal how positional information of localized cellular activity is stored. In vivo skin imaging and lineage tracing unveils new insights into stem cell plasticity. Principles of self-assembly obtained from the integumentary organ model can be applied to help restore damaged patterns during regenerative wound healing and for tissue engineering to rebuild tissues. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
    Developmental Dynamics 04/2015; 244(8). DOI:10.1002/dvdy.24281 · 2.38 Impact Factor
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    • "After completion of the second telogen, which can last up to thirty days, the coat begins to grow asynchronously in complex domains created by waves of anagen moving through the domain until a wave reaches "refractory" telogen, an area of skin unresponsive to the propagating anagen stimulus. As the mouse ages, this process creates increasingly complex patterns of hair growth with each domain consisting of a telogen competent to be activated, a propagating anagen wave, a catagen, and a refractive telogen [3,25]. In preliminary experiments, we did not observe differential expression of clock controlled genes in skin corresponding to different hair growth phases in asynchronously cycling skin, suggesting the possibility that hair cycle related regulation of clock gene expression may be particularly important in synchronized hair follicle cycling. "
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    ABSTRACT: Hair follicles undergo continuous cycles of growth, involution and rest. This process, referred to as the hair growth cycle, has a periodicity of weeks to months. At the same time, skin and hair follicles harbor a functional circadian clock that regulates gene expression with a periodicity of approximately twenty four hours. In our recent study we found that circadian clock genes play a role in regulation of the hair growth cycle during synchronized hair follicle cycling, uncovering an unexpected connection between these two timing systems within skin. This work, therefore, indicates a role for circadian clock genes in a cyclical process of much longer periodicity than twenty four hours.
    Aging 03/2010; 2(3):122-8. · 6.43 Impact Factor
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    • "How the cycling of these hair follicles are coordinated (simultaneously, randomly, or in waves) has not been addressed before. By analyzing hair cycle domains, Plikus et al., 2008, 2009) reveals a new macro-environmental regulation of hair stem cell activity. Hair patterns, as well as most spatial patterns observed in nature, are established during development. "
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    ABSTRACT: Patterns are orders embedded in randomness. They may appear as spatial arrangements or temporal series, and the elements may appear identical or with variations. Patterns exist in the physical world as well as in living systems. In the biological world, patterns can range from simple to complex, forming the basic building blocks of life. The process which generates this ordering in the biological world was termed pattern formation. Since Wolpert promoted this concept four decades ago, scientists from molecular biology, developmental biology, stem cell biology, tissue engineering, theoretical modeling and other disciplines have made remarkable progress towards understanding its mechanisms. It is time to review and re-integrate our understanding. Here, we explore the origin of pattern formation, how the genetic code is translated into biological form, and how complex phenotypes are selected over evolutionary time. We present four topics: Principles, Evolution, Development, and Stem Cells and Regeneration. We have interviewed several leaders in the field to gain insight into how their research and the field of pattern formation have shaped each other. We have learned that both molecular process and physico-chemical principles are important for biological pattern formation. New understanding will emerge through integration of the analytical approach of molecular-genetic manipulation and the systemic approach of model simulation. We regret that we could not include every major investigator in the field, but hope that this Special Issue of the Int. J. Dev. Biol. represents a sample of our knowledge of pattern formation today, which will help to stimulate more research on this fundamental process.
    The International journal of developmental biology 02/2009; 53(5-6):653-8. DOI:10.1387/ijdb.082594cc · 1.90 Impact Factor
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