title: Diminished Schwann cell repair responses underlie age-associated impaired axonal regeneration.
abstract: The regenerative capacity of the peripheral nervous system declines with age. Why this occurs, however, is unknown. We demonstrate that 24-month-old mice exhibit an impairment of functional recovery after nerve injury compared to 2-month-old animals. We find no difference in the intrinsic growth capacity between aged and young sensory neurons in vitro or in their ability to activate growth-associated transcriptional programs after injury. Instead, using age-mismatched nerve transplants in vivo, we show that the extent of functional recovery depends on the age of the nerve graft, and not the age of the host. Molecular interrogation of the sciatic nerve reveals that aged Schwann cells (SCs) fail to rapidly activate a transcriptional repair program after injury. Functionally, aged SCs exhibit impaired dedifferentiation, myelin clearance, and macrophage recruitment. These results suggest that the age-associated decline in axonal regeneration results from diminished Schwann cell plasticity, leading to slower myelin clearance.
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Immunology Program, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Michio W
authors.initials: MW
authors.lastname: Painter
authors.affiliation: Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Brosius Lutz
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yung-Chih
authors.initials: YC
authors.lastname: Cheng
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alban
authors.initials: A
authors.lastname: Latremoliere
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Duong
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Joslin Diabetes Center, Boston, MA 02215, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Miller
authors.affiliation: Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Posada
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Enrique J
authors.initials: EJ
authors.lastname: Cobos
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alice X
authors.initials: AX
authors.lastname: Zhang
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Joslin Diabetes Center, Boston, MA 02215, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wagers
authors.affiliation: Departments of Anesthesiology & Perioperative Care, Neurology and Anatomy & Neurobiology, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Leif A
authors.initials: LA
authors.lastname: Havton
authors.affiliation: Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Ben
authors.initials: B
authors.lastname: Barres
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Takao
authors.initials: T
authors.lastname: Omura
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: clifford.woolf@childrens.harvard.edu.
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Woolf
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D051379:Mice; D008810:Mice, Inbred C57BL; D009416:Nerve Regeneration / Q000502:physiology*; D059348:Peripheral Nerve Injuries / Q000503:physiopathology*; D020127:Recovery of Function / Q000502:physiology*; D012583:Schwann Cells / Q000502:physiology*; D012584:Sciatic Nerve / Q000293:injuries