title: Combination therapy accelerates diabetic wound closure.
abstract: BACKGROUND
  Non-healing foot ulcers are the most common cause of non-traumatic amputation and hospitalization amongst diabetics in the developed world. Impaired wound neovascularization perpetuates a cycle of dysfunctional tissue repair and regeneration. Evidence implicates defective mobilization of marrow-derived progenitor cells (PCs) as a fundamental cause of impaired diabetic neovascularization. Currently, there are no FDA-approved therapies to address this defect. Here we report an endogenous PC strategy to improve diabetic wound neovascularization and closure through a combination therapy of AMD3100, which mobilizes marrow-derived PCs by competitively binding to the cell surface CXCR4 receptor, and PDGF-BB, which is a protein known to enhance cell growth, progenitor cell migration and angiogenesis.
  
  
  RESULTS
  Wounded mice were assigned to 1 of 5 experimental arms (n = 8/arm): saline treated wild-type, saline treated diabetic, AMD3100 treated diabetic, PDGF-BB treated diabetic, and AMD3100/PDGF-BB treated diabetic. Circulating PC number and wound vascularity were analyzed for each group (n = 8/group). Cellular function was assessed in the presence of AMD3100. Using a validated preclinical model of type II diabetic wound healing, we show that AMD3100 therapy (10 mg/kg; i.p. daily) alone can rescue diabetes-specific defects in PC mobilization, but cannot restore normal wound neovascularization. Through further investigation, we demonstrate an acquired trafficking-defect within AMD3100-treated diabetic PCs that can be rescued by PDGF-BB (2 μg; topical) supplementation within the wound environment. Finally, we determine that combination therapy restores diabetic wound neovascularization and accelerates time to wound closure by 40%.
  
  
  CONCLUSIONS
  Combination AMD3100 and PDGF-BB therapy synergistically improves BM PC mobilization and trafficking, resulting in significantly improved diabetic wound closure and neovascularization. The success of this endogenous, cell-based strategy to improve diabetic wound healing using FDA-approved therapies is inherently translatable.
authors.affiliation: Institute of Reconstructive Plastic Surgery, New York University Langone Medical Center, New York, New York, United States of America.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Allen
authors.affiliation: Institute of Reconstructive Plastic Surgery, New York University Langone Medical Center, New York, New York, United States of America.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Soares
authors.affiliation: Institute of Reconstructive Plastic Surgery, New York University Langone Medical Center, New York, New York, United States of America.
authors.forename: Ilyse D
authors.initials: ID
authors.lastname: Haberman
authors.affiliation: Institute of Reconstructive Plastic Surgery, New York University Langone Medical Center, New York, New York, United States of America.
authors.forename: Caroline
authors.initials: C
authors.lastname: Szpalski
authors.affiliation: Institute of Reconstructive Plastic Surgery, New York University Langone Medical Center, New York, New York, United States of America.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Schachar
authors.affiliation: Institute of Reconstructive Plastic Surgery, New York University Langone Medical Center, New York, New York, United States of America.
authors.forename: Clarence D
authors.initials: CD
authors.lastname: Lin
authors.affiliation: Institute of Reconstructive Plastic Surgery, New York University Langone Medical Center, New York, New York, United States of America.
authors.forename: Phuong D
authors.initials: PD
authors.lastname: Nguyen
authors.affiliation: Institute of Reconstructive Plastic Surgery, New York University Langone Medical Center, New York, New York, United States of America.
authors.forename: Pierre B
authors.initials: PB
authors.lastname: Saadeh
authors.affiliation: Institute of Reconstructive Plastic Surgery, New York University Langone Medical Center, New York, New York, United States of America.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Warren
mesh_terms: D000818:Animals; D000077214:Becaplermin; D001596:Benzylamines; D000080027:Cyclams; D048909:Diabetes Complications / Q000628:therapy*; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D004195:Disease Models, Animal; D006571:Heterocyclic Compounds / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D018919:Neovascularization, Physiologic; D020574:Proto-Oncogene Proteins c-sis / Q000008:administration & dosage / Q000494:pharmacology; D012883:Skin Ulcer / Q000209:etiology / Q000628:therapy; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014945:Wound Healing; D014947:Wounds and Injuries / Q000209:etiology* / Q000628:therapy*
chemical_list: D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; C088327:plerixafor