title: Regenerative hair waves in aging mice and extra-follicular modulators follistatin, dkk1, and sfrp4.
abstract: Hair cycling is modulated by factors both intrinsic and extrinsic to hair follicles. Cycling defects lead to conditions such as aging-associated alopecia. Recently, we demonstrated that mouse skin exhibits regenerative hair waves, reflecting a coordinated regenerative behavior in follicle populations. Here, we use this model to explore the regenerative behavior of aging mouse skin. Old mice (>18 months) tracked over several months show that with progressing age, hair waves slow down, wave propagation becomes restricted, and hair cycle domains fragment into smaller domains. Transplanting aged donor mouse skin to a young host can restore donor cycling within a 3 mm range of the interface, suggesting that changes are due to extracellular factors. Therefore, hair stem cells in aged skin can be reactivated. Molecular studies show that extra-follicular modulators Bmp2, Dkk1, and Sfrp4 increase in early anagen. Further, we identify follistatin as an extra-follicular modulator, which is highly expressed in late telogen and early anagen. Indeed, follistatin induces hair wave propagation and its level decreases in aging mice. We present an excitable medium model to simulate the cycling behavior in aging mice and illustrate how the interorgan macroenvironment can regulate the aging process by integrating both "activator" and "inhibitor" signals.
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA; Institute of Clinical Medicine and Department of Dermatology, National Yang-Ming University, Taipei, Taiwan; Department of Dermatology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Chih-Chiang
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Division of Mathematics, University of Dundee, Scotland, UK.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Murray
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Ting Xin
authors.initials: TX
authors.lastname: Jiang
authors.affiliation: Department of Developmental and Cell Biology, Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, California, USA.
authors.forename: Maksim V
authors.initials: MV
authors.lastname: Plikus
authors.affiliation: Institute of Clinical Medicine and Department of Dermatology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yun-Ting
authors.initials: YT
authors.lastname: Chang
authors.affiliation: Institute of Clinical Medicine and Department of Dermatology, National Yang-Ming University, Taipei, Taiwan; Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei and Center for Stem Cell Research, National Yang-Ming University and Veterans General Hospital, Taipei, Taiwan.
authors.forename: Oscar K
authors.initials: OK
authors.lastname: Lee
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Randall B
authors.initials: RB
authors.lastname: Widelitz
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA; Institute of Clinical Medicine and Department of Dermatology, National Yang-Ming University, Taipei, Taiwan. Electronic address: cmchuong@usc.edu.
authors.forename: Cheng-Ming
authors.initials: CM
authors.lastname: Chuong
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000502:physiology; D038681:Follistatin / Q000502:physiology*; D018859:Hair Follicle / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D012038:Regeneration / Q000502:physiology*; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D055396:Bone Morphogenetic Protein 2; D038681:Follistatin; D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; C525719:Bmp2 protein, mouse; C501127:Dkk1 protein, mouse; C498454:Sfrp4 protein, mouse; D000094742:Secreted Frizzled-Related Proteins