Activating Hair Follicle Stem Cells via R-spondin2 to Stimulate Hair Growth.
Wnt signaling is required for the development of the hair follicle, and for inciting the growth (anagen) phase of the hair cycle. Most strategies to enhance Wnt signaling for hair growth create a state of constitutive Wnt activation, which leads to neoplastic transformation of the epithelial hair matrix. Using Axin2(LacZ/+) and Axin2(Cre/+)R26R(mTmG/+) reporter mice and RNA analyses, we show that Wnt signaling is elevated during anagen, is reduced at the onset of catagen, and can be reamplified in the skin and surrounding hair follicles via intradermal injection of recombinant R-spondin2 protein. Using Lgr5(LacZ/+) reporter mice, we demonstrate that this amplified Wnt environment leads to activation of leucine-rich repeat-containing G-protein coupled receptor 5-positive stem cells in the hair follicle. The onset of catagen is repressed by R-spondin2 injection, and the anagen phase persists. As a consequence, hair shafts grow longer. We conclude that R-spondin2 treatment activates hair follicle stem cells and therefore may have therapeutic potential to promote hair growth.
Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford University, Stanford, California, USA.
Andrew A
AA
Smith
Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford University, Stanford, California, USA; Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Wuhou, Chengdu, Sichuan, China.
Jingtao
J
Li
Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford University, Stanford, California, USA.
Bo
B
Liu
Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford University, Stanford, California, USA.
Daniel
D
Hunter
Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford University, Stanford, California, USA.
Malcolm
M
Pyles
Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford University, Stanford, California, USA.
Martin
M
Gillette
Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford University, Stanford, California, USA.
Girija R
GR
Dhamdhere
California Institute for Regenerative Medicine (CIRM), Oakland, California, USA.
Arie
A
Abo
Department of Dermatology, Stanford School of Medicine, Stanford University, Stanford, California, USA.
Anthony
A
Oro
Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford University, Stanford, California, USA. Electronic address: jhelms@stanford.edu.
Jill A
JA
Helms
D000368:Aged; D000818:Animals; D060466:Axin Protein / Q000235:genetics*; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D017930:Genes, Reporter; D006197:Hair / Q000254:growth & development*; D018859:Hair Follicle / Q000166:cytology* / Q000637:transplantation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D007930:Leucine / Q000737:chemistry; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology*; D019699:Thrombospondins / Q000235:genetics*; D060449:Wnt Signaling Pathway; D000098907:R-Spondins
D060466:Axin Protein; D036341:Intercellular Signaling Peptides and Proteins; D007930:Leucine; D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins; D019699:Thrombospondins; C491761:AXIN2 protein, human; C111729:Axin2 protein, mouse; C116884:LGR5 protein, human; C493597:Lgr5 protein, mouse; C518904:RSPO2 protein, mouse; D000098907:R-Spondins; C557408:Rspo2 protein, human