title: Decreased circulating progenitor cell number and failed mechanisms of stromal cell-derived factor-1alpha mediated bone marrow mobilization impair diabetic tissue repair.
abstract: OBJECTIVE
  Progenitor cells (PCs) contribute to postnatal neovascularization and tissue repair. Here, we explore the mechanism contributing to decreased diabetic circulating PC number and propose a novel treatment to restore circulating PC number, peripheral neovascularization, and tissue healing.
  
  
  METHODS
  Cutaneous wounds were created on wild-type (C57BL/J6) and diabetic (Lepr(db/db)) mice. Blood and bone marrow PCs were collected at multiple time points.
  
  
  RESULTS
  Significantly delayed wound closure in diabetic animals was associated with diminished circulating PC number (1.9-fold increase vs. 7.6-fold increase in lin(-)/sca-1(+)/ckit(+) in wild-type mice; P < 0.01), despite adequate numbers of PCs in the bone marrow at baseline (14.4 +/- 3.2% lin(-)/ckit(+)/sca1(+) vs. 13.5 +/- 2.8% in wild-type). Normal bone marrow PC mobilization in response to peripheral wounding occurred after a necessary switch in bone marrow stromal cell-derived factor-1alpha (SDF-1alpha) expression (40% reduction, P < 0.01). In contrast, a failed switch mechanism in diabetic bone marrow SDF-1alpha expression (2.8% reduction) resulted in impaired PC mobilization. Restoring the bone marrow SDF-1alpha switch (54% reduction, P < 0.01) with plerixafor (Mozobil, formerly known as AMD3100) increased circulating diabetic PC numbers (6.8 +/- 2.0-fold increase in lin(-)/ckit(+), P < 0.05) and significantly improved diabetic wound closure compared with sham-treated controls (32.9 +/- 5.0% vs. 11.9 +/- 3% at day 7, P > 0.05; 73.0 +/- 6.4% vs. 36.5 +/- 7% at day 14, P < 0.05; and 88.0 +/- 5.7% vs. 66.7 +/- 5% at day 21, P > 0.05, respectively).
  
  
  CONCLUSIONS
  Successful ischemia-induced bone marrow PC mobilization is mediated by a switch in bone marrow SDF-1alpha levels. In diabetes, this switch fails to occur. Plerixafor represents a potential therapeutic agent for improving ischemia-mediated pathology associated with diabetes by reducing bone marrow SDF-1alpha, restoring normal PC mobilization and tissue healing.
authors.affiliation: New York University School of Medicine, New York, New York, USA.
authors.forename: Oren M
authors.initials: OM
authors.lastname: Tepper
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Carr
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Allen
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Chang
authors.forename: Clarence D
authors.initials: CD
authors.lastname: Lin
authors.forename: Rica
authors.initials: R
authors.lastname: Tanaka
authors.forename: Sanjeev M
authors.initials: SM
authors.lastname: Gupta
authors.forename: Jamie P
authors.initials: JP
authors.lastname: Levine
authors.forename: Pierre B
authors.initials: PB
authors.lastname: Saadeh
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Warren
mesh_terms: D000818:Animals; D001596:Benzylamines; D001854:Bone Marrow Cells / Q000166:cytology / Q000473:pathology; D002452:Cell Count; D054426:Chemokine CXCL2 / Q000172:deficiency / Q000502:physiology*; D002633:Chemotaxis; D000080027:Cyclams; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006571:Heterocyclic Compounds; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D012867:Skin / Q000293:injuries / Q000503:physiopathology; D013234:Stem Cells / Q000473:pathology / Q000502:physiology*; D013524:Surgical Flaps; D014945:Wound Healing / Q000502:physiology*; D014947:Wounds and Injuries / Q000503:physiopathology
chemical_list: D001596:Benzylamines; D054426:Chemokine CXCL2; D000080027:Cyclams; D006571:Heterocyclic Compounds; C088327:plerixafor