title: Mesenchymal stem cells induce endothelial cell quiescence and promote capillary formation.
abstract: BACKGROUND
  Rapid establishment of functional blood vessels is a prerequisite for successful tissue engineering. During vascular development, endothelial cells (ECs) and perivascular cells assemble into a complex regulating proliferation of ECs, vessel diameter and production of extracellular matrix proteins. The aim of this study was to evaluate the ability of mesenchymal stem cells (MSCs) to establish an endothelial-perivascular complex in tissue-engineered constructs comprising ECs and MSCs.
  
  
  METHODS
  Primary human ECs and MSCs were seeded onto poly(L-lactide-co-1,5-dioxepan-2-one) (poly(LLA-co-DXO)) scaffolds and grown in dynamic culture before subcutaneous implantation in immunocompromised mice for 1 and 3 weeks. Cellular activity, angiogenic stimulation and vascular assembly in cell/scaffold constructs seeded with ECs or ECs/MSCs in a 5:1 ratio was monitored with real-time RT-PCR, ELISA and immunohistochemical microscopy analysis.
  
  
  RESULTS
  A quiescent phenotype of ECs was generated, by adding MSCs to the culture system. Decreased proliferation of ECs, in addition to up-regulation of selected markers for vascular maturation was demonstrated. Baseline expression of VEGFa was higher for MSCs compared with EC (P<0.001), with subsequent up-regulated VEGFa-expression for EC/MSC constructs before (P<0.05) and after implantation (P<0.01). Furthermore, an inflammatory response with CD11b+cells was generated from implantation of human cells. At the end of the 3 week experimental period, a higher vascular density was shown for both cellular constructs compared with empty control scaffolds (P<0.01), with the highest density of capillaries being generated in constructs comprising both ECs and MSCs.
  
  
  CONCLUSIONS
  Induction of a quiescent phenotype of ECs associated with vascular maturation can be achieved by co-seeding with MSCs. Hence, MSCs can be appropriate perivascular cells for tissue-engineered constructs.
authors.forename: Torbjorn O
authors.initials: TO
authors.lastname: Pedersen
authors.forename: Anna L
authors.initials: AL
authors.lastname: Blois
authors.forename: Ying
authors.initials: Y
authors.lastname: Xue
authors.forename: Zhe
authors.initials: Z
authors.lastname: Xing
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.forename: Anna
authors.initials: A
authors.lastname: Finne-Wistrand
authors.forename: James B
authors.initials: JB
authors.lastname: Lorens
authors.forename: Inge
authors.initials: I
authors.lastname: Fristad
authors.forename: Knut N
authors.initials: KN
authors.lastname: Leknes
authors.forename: Kamal
authors.initials: K
authors.lastname: Mustafa
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D016220:Fibroblast Growth Factor 1 / Q000235:genetics / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018919:Neovascularization, Physiologic; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D023822:Tissue Engineering; D054457:Tissue Scaffolds / Q000737:chemistry; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D010982:Platelet-Derived Growth Factor; D042461:Vascular Endothelial Growth Factor A; D016220:Fibroblast Growth Factor 1