title: Perivascular delivery of encapsulated mesenchymal stem cells improves postischemic angiogenesis via paracrine activation of VEGF-A.
abstract: OBJECTIVE
  To test the therapeutic activity of perivascular transplantation of encapsulated human mesenchymal stem cells (MSCs) in an immunocompetent mouse model of limb ischemia.
  
  
  RESULTS
  CD1 mice underwent unilateral limb ischemia, followed by randomized treatment with vehicle, alginate microbeads (MBs), MB-encapsulated MSCs (MB-MSCs), or MB-MSCs engineered with glucagon-like peptide-1. Treatments were applied directly in the perivascular space around the femoral artery. Laser Doppler and fluorescent microsphere assessment of blood flow showed a marked improvement of perfusion in the MB-MSCs and MB-MSCs engineered with glucagon-like peptide-1 groups, which was associated with increased foot salvage particularly in MB-MSCs engineered with glucagon-like peptide-1-treated mice. Histological analysis revealed increased capillary and arteriole density in limb muscles of the 2 MSC groups. Furthermore, MB-MSCs engineered with glucagon-like peptide-1 and, to a lesser extent, MB-MSC treatment increased functional arterial collaterals alongside the femoral artery occlusion. Analysis of expressional changes in ischemic muscles showed that MB-MSC transplantation activates a proangiogenic signaling pathway centered on vascular endothelial growth factor A. In contrast, intramuscular MB-MSCs caused inflammatory reaction, but no improvement of reparative vascularization. Importantly, nonencapsulated MSCs were ineffective either by intramuscular or perivascular route.
  
  
  CONCLUSIONS
  Perivascular delivery of encapsulated MSCs helps postischemic reperfusion. This novel biological bypass method might be useful in patients not amenable to conventional revascularization approaches.
authors.affiliation: Experimental Cardiovascular Medicine, Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Katare
authors.forename: Federica
authors.initials: F
authors.lastname: Riu
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rowlinson
authors.forename: Andrew
authors.initials: A
authors.lastname: Lewis
authors.forename: Rachel
authors.initials: R
authors.lastname: Holden
authors.forename: Marco
authors.initials: M
authors.lastname: Meloni
authors.forename: Carlotta
authors.initials: C
authors.lastname: Reni
authors.forename: Christine
authors.initials: C
authors.lastname: Wallrapp
authors.forename: Costanza
authors.initials: C
authors.lastname: Emanueli
authors.forename: Paolo
authors.initials: P
authors.lastname: Madeddu
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005240:Feasibility Studies; D005260:Female; D005263:Femoral Artery / Q000502:physiology; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007511:Ischemia / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy*; D017078:Laser-Doppler Flowmetry; D023821:Limb Salvage / Q000379:methods; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology; D051379:Mice; D018919:Neovascularization, Physiologic / Q000502:physiology*; D019899:Paracrine Communication / Q000502:physiology; D011897:Random Allocation; D012039:Regional Blood Flow / Q000502:physiology; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse
keywords: collateral circulation; peripheral artery disease; stem cells