A cellular, molecular, and pharmacological basis for appendage regeneration in mice.
Regenerative medicine aims to restore normal tissue architecture and function. However, the basis of tissue regeneration in mammalian solid organs remains undefined. Remarkably, mice lacking p21 fully regenerate injured ears without discernable scarring. Here we show that, in wild-type mice following tissue injury, stromal-derived factor-1 (Sdf1) is up-regulated in the wound epidermis and recruits Cxcr4-expressing leukocytes to the injury site. In p21-deficient mice, Sdf1 up-regulation and the subsequent recruitment of Cxcr4-expressing leukocytes are significantly diminished, thereby permitting scarless appendage regeneration. Lineage tracing demonstrates that this regeneration derives from fate-restricted progenitor cells. Pharmacological or genetic disruption of Sdf1-Cxcr4 signaling enhances tissue repair, including full reconstitution of tissue architecture and all cell types. Our findings identify signaling and cellular mechanisms underlying appendage regeneration in mice and suggest new therapeutic approaches for regenerative medicine.
Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA; Department of Dermatology, Stanford University School of Medicine, Stanford, California 94305, USA;
Thomas H
TH
Leung
Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA;
Emily R
ER
Snyder
Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA;
Yinghua
Y
Liu
Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA;
Jing
J
Wang
Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA; Department of Medicine, Oncology Division, Stanford University School of Medicine, Stanford, California 94305, USA.
Seung K
SK
Kim
D000818:Animals; D001596:Benzylamines; D019070:Cell Lineage / Q000235:genetics; D054377:Chemokine CXCL12 / Q000378:metabolism; D000080027:Cyclams; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004423:Ear / Q000293:injuries / Q000502:physiology; D000078404:Epidermal Cells; D004817:Epidermis / Q000293:injuries / Q000502:physiology; D005121:Extremities / Q000293:injuries / Q000502:physiology*; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D051379:Mice; D021381:Protein Transport / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D014945:Wound Healing / Q000235:genetics / Q000502:physiology*
D001596:Benzylamines; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C088327:plerixafor
developmental biology; genetics; molecular biology; regenerative medicine; tissue regeneration