title: Dedifferentiated Schwann Cell Precursors Secreting Paracrine Factors Are Required for Regeneration of the Mammalian Digit Tip.
abstract: Adult mammals have lost multi-tissue regenerative capacity, except for the distal digit, which is able to regenerate via mechanisms that remain largely unknown. Here, we show that, after adult mouse distal digit removal, nerve-associated Schwann cell precursors (SCPs) dedifferentiate and secrete growth factors that promote expansion of the blastema and digit regeneration. When SCPs were dysregulated or ablated, mesenchymal precursor proliferation in the blastema was decreased and nail and bone regeneration were impaired. Transplantation of exogenous SCPs rescued these regeneration defects. We found that SCPs secrete factors that promote self-renewal of mesenchymal precursors, and we used transcriptomic and proteomic analysis to define candidate factors. Two of these, oncostatin M (OSM) and platelet-derived growth factor AA (PDGF-AA), are made by SCPs in the regenerating digit and rescued the deficits in regeneration caused by loss of SCPs. As all peripheral tissues contain nerves, these results could have broad implications for mammalian tissue repair and regeneration.
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada. Electronic address: adjohnston@upei.ca.
authors.forename: Adam P W
authors.initials: AP
authors.lastname: Johnston
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Yuzwa
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON M5G 1A8, Canada.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Carr
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada; Department of Physiology, University of Toronto, Toronto, ON M5G 1A8, Canada.
authors.forename: Neemat
authors.initials: N
authors.lastname: Mahmud
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada.
authors.forename: Mekayla A
authors.initials: MA
authors.lastname: Storer
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Krause
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada.
authors.forename: Karen
authors.initials: K
authors.lastname: Jones
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada.
authors.forename: Smitha
authors.initials: S
authors.lastname: Paul
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON M5G 1A8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1A8, Canada.
authors.forename: David R
authors.initials: DR
authors.lastname: Kaplan
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON M5G 1A8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1A8, Canada; Department of Physiology, University of Toronto, Toronto, ON M5G 1A8, Canada. Electronic address: fredam@sickkids.ca.
authors.forename: Freda D
authors.initials: FD
authors.lastname: Miller
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D054337:Cell Dedifferentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000066673:Cell Self Renewal / Q000187:drug effects; D003714:Denervation; D005121:Extremities / Q000294:innervation / Q000502:physiology*; D017353:Gene Deletion; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008322:Mammals / Q000502:physiology*; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000166:cytology* / Q000637:transplantation; D053683:Oncostatin M / Q000494:pharmacology; D019899:Paracrine Communication / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D051381:Rats; D012038:Regeneration / Q000187:drug effects; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D012583:Schwann Cells / Q000166:cytology* / Q000637:transplantation; D012867:Skin / Q000473:pathology; D014945:Wound Healing / Q000187:drug effects
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D010982:Platelet-Derived Growth Factor; D055748:SOXB1 Transcription Factors; C075278:platelet-derived growth factor A; D053683:Oncostatin M