title: Clinical-grade human neural stem cells promote reparative neovascularization in mouse models of hindlimb ischemia.
abstract: OBJECTIVE
  CTX0E03 (CTX) is a clinical-grade human neural stem cell (hNSC) line that promotes angiogenesis and neurogenesis in a preclinical model of stroke and is now under clinical development for stroke disability. We evaluated the therapeutic activity of intramuscular CTX hNSC implantation in murine models of hindlimb ischemia for potential translation to clinical studies in critical limb ischemia.
  
  
  RESULTS
  Immunodeficient (CD-1 Fox(nu/nu)) mice acutely treated with hNSCs had overall significantly increased rates and magnitude of recovery of surface blood flow (laser Doppler), limb muscle perfusion (fluorescent microspheres, P<0.001), and capillary and small arteriole densities in the ischemic limb (fluorescence immunohistochemistry, both P<0.001) when compared with the vehicle-treated group. Hemodynamic and anatomic improvements were dose related and optimal at a minimum dose of 3×10(5) cells. Dose-dependent improvements in blood flow and increased vessel densities by hNSC administration early after ischemia were confirmed in immunocompetent CD-1 and streptozotocin-induced diabetic mice, together with marked reductions in the incidence of necrotic toes (P<0.05). Delayed administration of hNSCs, 7 days after occlusion, produced restorative effects when comparable with acute treatment of 35 days after hindlimb ischemia. Histological studies in hindlimb ischemia immunocompetent mice for the first 7 days after treatment revealed short-term hNSC survival, transient elevation of early host muscle inflammatory, and angiogenic responses and acceleration of myogenesis.
  
  
  CONCLUSIONS
  hNSC therapy represents a promising treatment option for critical limb ischemia.
authors.affiliation: From the School of Clinical Sciences, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom (R.K., P.M.); and ReNeuron Limited, Guildford, United Kingdom (P.S., C.H., L.S., S.P., R.C., E.M., I.V., J.S.).
authors.forename: Rajesh
authors.initials: R
authors.lastname: Katare
authors.forename: Paul
authors.initials: P
authors.lastname: Stroemer
authors.forename: Caroline
authors.initials: C
authors.lastname: Hicks
authors.forename: Lara
authors.initials: L
authors.lastname: Stevanato
authors.forename: Sara
authors.initials: S
authors.lastname: Patel
authors.forename: Randolph
authors.initials: R
authors.lastname: Corteling
authors.forename: Erik
authors.initials: E
authors.lastname: Miljan
authors.forename: Indira
authors.initials: I
authors.lastname: Vishnubhatla
authors.forename: John
authors.initials: J
authors.lastname: Sinden
authors.forename: Paolo
authors.initials: P
authors.lastname: Madeddu
mesh_terms: D000818:Animals; D001160:Arterioles / Q000503:physiopathology; D001783:Blood Flow Velocity; D002196:Capillaries / Q000503:physiopathology; D002460:Cell Line; D002470:Cell Survival; D017719:Diabetic Foot / Q000276:immunology / Q000503:physiopathology / Q000601:surgery*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006614:Hindlimb; D006801:Humans; D007121:Immunocompetence; D007511:Ischemia / Q000235:genetics / Q000276:immunology / Q000503:physiopathology / Q000601:surgery*; D017078:Laser-Doppler Flowmetry; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic; D058953:Neural Stem Cells / Q000276:immunology / Q000637:transplantation*; D012039:Regional Blood Flow; D013997:Time Factors
keywords: angiogenesis inducing agents; neural stem cells; peripheral arterial disease; renal circulation