title: Epigenetic profile of human adventitial progenitor cells correlates with therapeutic outcomes in a mouse model of limb ischemia.
abstract: OBJECTIVE
  We investigated the association between the functional, epigenetic, and expressional profile of human adventitial progenitor cells (APCs) and therapeutic activity in a model of limb ischemia.
  
  
  RESULTS
  Antigenic and functional features were analyzed throughout passaging in 15 saphenous vein (SV)-derived APC lines, of which 10 from SV leftovers of coronary artery bypass graft surgery and 5 from varicose SV removal. Moreover, 5 SV-APC lines were transplanted (8×10(5) cells, IM) in mice with limb ischemia. Blood flow and capillary and arteriole density were correlated with functional characteristics and DNA methylation/expressional markers of transplanted cells. We report successful expansion of tested lines, which reached the therapeutic target of 30 to 50 million cells in ≈10 weeks. Typical antigenic profile, viability, and migratory and proangiogenic activities were conserved through passaging, with low levels of replicative senescence. In vivo, SV-APC transplantation improved blood flow recovery and revascularization of ischemic limbs. Whole genome screening showed an association between DNA methylation at the promoter or gene body level and microvascular density and to a lesser extent with blood flow recovery. Expressional studies highlighted the implication of an angiogenic network centered on the vascular endothelial growth factor receptor as a predictor of microvascular outcomes. FLT-1 gene silencing in SV-APCs remarkably reduced their ability to form tubes in vitro and support tube formation by human umbilical vein endothelial cells, thus confirming the importance of this signaling in SV-APC angiogenic function.
  
  
  CONCLUSIONS
  DNA methylation landscape illustrates different therapeutic activities of human APCs. Epigenetic screening may help identify determinants of therapeutic vasculogenesis in ischemic disease.
authors.affiliation: From the Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, UK (M.G., S.C.S., H.L.S., F.R., J.R., E.A., R.K., G.M., A.O., C.R., C.E., G.A., P.M.); The Institute of Cancer Research, Evolutionary Genomics and Modelling Team, Centre for Evolution and Cancer, Sutton, UK (I.S., A.S.); Imperial College, London, UK (P.C., C.E., G.A.); MultiMedica Research Institute, Milan, Italy (G.S.); Cancer Research UK Cambridge Institute, Cambridge, UK (A.T., S.T.); Centro Cardiologico Monzino, Milan, Italy (F.P., M.P.); and Austrian Institute of Technology, Vienna, Austria (M.H., V.K.).
authors.forename: Miriam
authors.initials: M
authors.lastname: Gubernator
authors.affiliation: From the Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, UK (M.G., S.C.S., H.L.S., F.R., J.R., E.A., R.K., G.M., A.O., C.R., C.E., G.A., P.M.); The Institute of Cancer Research, Evolutionary Genomics and Modelling Team, Centre for Evolution and Cancer, Sutton, UK (I.S., A.S.); Imperial College, London, UK (P.C., C.E., G.A.); MultiMedica Research Institute, Milan, Italy (G.S.); Cancer Research UK Cambridge Institute, Cambridge, UK (A.T., S.T.); Centro Cardiologico Monzino, Milan, Italy (F.P., M.P.); and Austrian Institute of Technology, Vienna, Austria (M.H., V.K.).
authors.forename: Sadie C
authors.initials: SC
authors.lastname: Slater
authors.affiliation: From the Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, UK (M.G., S.C.S., H.L.S., F.R., J.R., E.A., R.K., G.M., A.O., C.R., C.E., G.A., P.M.); The Institute of Cancer Research, Evolutionary Genomics and Modelling Team, Centre for Evolution and Cancer, Sutton, UK (I.S., A.S.); Imperial College, London, UK (P.C., C.E., G.A.); MultiMedica Research Institute, Milan, Italy (G.S.); Cancer Research UK Cambridge Institute, Cambridge, UK (A.T., S.T.); Centro Cardiologico Monzino, Milan, Italy (F.P., M.P.); and Austrian Institute of Technology, Vienna, Austria (M.H., V.K.).
authors.forename: Helen L
authors.initials: HL
authors.lastname: Spencer
authors.affiliation: From the Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, UK (M.G., S.C.S., H.L.S., F.R., J.R., E.A., R.K., G.M., A.O., C.R., C.E., G.A., P.M.); The Institute of Cancer Research, Evolutionary Genomics and Modelling Team, Centre for Evolution and Cancer, Sutton, UK (I.S., A.S.); Imperial College, London, UK (P.C., C.E., G.A.); MultiMedica Research Institute, Milan, Italy (G.S.); Cancer Research UK Cambridge Institute, Cambridge, UK (A.T., S.T.); Centro Cardiologico Monzino, Milan, Italy (F.P., M.P.); and Austrian Institute of Technology, Vienna, Austria (M.H., V.K.).
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Spiteri
authors.affiliation: From the Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, UK (M.G., S.C.S., H.L.S., F.R., J.R., E.A., R.K., G.M., A.O., C.R., C.E., G.A., P.M.); The Institute of Cancer Research, Evolutionary Genomics and Modelling Team, Centre for Evolution and Cancer, Sutton, UK (I.S., A.S.); Imperial College, London, UK (P.C., C.E., G.A.); MultiMedica Research Institute, Milan, Italy (G.S.); Cancer Research UK Cambridge Institute, Cambridge, UK (A.T., S.T.); Centro Cardiologico Monzino, Milan, Italy (F.P., M.P.); and Austrian Institute of Technology, Vienna, Austria (M.H., V.K.).
authors.forename: Andrea
authors.initials: A
authors.lastname: Sottoriva
authors.affiliation: From the Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, UK (M.G., S.C.S., H.L.S., F.R., J.R., E.A., R.K., G.M., A.O., C.R., C.E., G.A., P.M.); The Institute of Cancer Research, Evolutionary Genomics and Modelling Team, Centre for Evolution and Cancer, Sutton, UK (I.S., A.S.); Imperial College, London, UK (P.C., C.E., G.A.); MultiMedica Research Institute, Milan, Italy (G.S.); Cancer Research UK Cambridge Institute, Cambridge, UK (A.T., S.T.); Centro Cardiologico Monzino, Milan, Italy (F.P., M.P.); and Austrian Institute of Technology, Vienna, Austria (M.H., V.K.).
authors.forename: Federica
authors.initials: F
authors.lastname: Riu
authors.affiliation: From the Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, UK (M.G., S.C.S., H.L.S., F.R., J.R., E.A., R.K., G.M., A.O., C.R., C.E., G.A., P.M.); The Institute of Cancer Research, Evolutionary Genomics and Modelling Team, Centre for Evolution and Cancer, Sutton, UK (I.S., A.S.); Imperial College, London, UK (P.C., C.E., G.A.); MultiMedica Research Institute, Milan, Italy (G.S.); Cancer Research UK Cambridge Institute, Cambridge, UK (A.T., S.T.); Centro Cardiologico Monzino, Milan, Italy (F.P., M.P.); and Austrian Institute of Technology, Vienna, Austria (M.H., V.K.).
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rowlinson
authors.affiliation: From the Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, UK (M.G., S.C.S., H.L.S., F.R., J.R., E.A., R.K., G.M., A.O., C.R., C.E., G.A., P.M.); The Institute of Cancer Research, Evolutionary Genomics and Modelling Team, Centre for Evolution and Cancer, Sutton, UK (I.S., A.S.); Imperial College, London, UK (P.C., C.E., G.A.); MultiMedica Research Institute, Milan, Italy (G.S.); Cancer Research UK Cambridge Institute, Cambridge, UK (A.T., S.T.); Centro Cardiologico Monzino, Milan, Italy (F.P., M.P.); and Austrian Institute of Technology, Vienna, Austria (M.H., V.K.).
authors.forename: Elisa
authors.initials: E
authors.lastname: Avolio
authors.affiliation: From the Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, UK (M.G., S.C.S., H.L.S., F.R., J.R., E.A., R.K., G.M., A.O., C.R., C.E., G.A., P.M.); The Institute of Cancer Research, Evolutionary Genomics and Modelling Team, Centre for Evolution and Cancer, Sutton, UK (I.S., A.S.); Imperial College, London, UK (P.C., C.E., G.A.); MultiMedica Research Institute, Milan, Italy (G.S.); Cancer Research UK Cambridge Institute, Cambridge, UK (A.T., S.T.); Centro Cardiologico Monzino, Milan, Italy (F.P., M.P.); and Austrian Institute of Technology, Vienna, Austria (M.H., V.K.).
authors.forename: Rajesh
authors.initials: R
authors.lastname: Katare
authors.affiliation: From the Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, UK (M.G., S.C.S., H.L.S., F.R., J.R., E.A., R.K., G.M., A.O., C.R., C.E., G.A., P.M.); The Institute of Cancer Research, Evolutionary Genomics and Modelling Team, Centre for Evolution and Cancer, Sutton, UK (I.S., A.S.); Imperial College, London, UK (P.C., C.E., G.A.); MultiMedica Research Institute, Milan, Italy (G.S.); Cancer Research UK Cambridge Institute, Cambridge, UK (A.T., S.T.); Centro Cardiologico Monzino, Milan, Italy (F.P., M.P.); and Austrian Institute of Technology, Vienna, Austria (M.H., V.K.).
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Mangialardi
authors.affiliation: From the Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, UK (M.G., S.C.S., H.L.S., F.R., J.R., E.A., R.K., G.M., A.O., C.R., C.E., G.A., P.M.); The Institute of Cancer Research, Evolutionary Genomics and Modelling Team, Centre for Evolution and Cancer, Sutton, UK (I.S., A.S.); Imperial College, London, UK (P.C., C.E., G.A.); MultiMedica Research Institute, Milan, Italy (G.S.); Cancer Research UK Cambridge Institute, Cambridge, UK (A.T., S.T.); Centro Cardiologico Monzino, Milan, Italy (F.P., M.P.); and Austrian Institute of Technology, Vienna, Austria (M.H., V.K.).
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Oikawa
authors.affiliation: From the Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, UK (M.G., S.C.S., H.L.S., F.R., J.R., E.A., R.K., G.M., A.O., C.R., C.E., G.A., P.M.); The Institute of Cancer Research, Evolutionary Genomics and Modelling Team, Centre for Evolution and Cancer, Sutton, UK (I.S., A.S.); Imperial College, London, UK (P.C., C.E., G.A.); MultiMedica Research Institute, Milan, Italy (G.S.); Cancer Research UK Cambridge Institute, Cambridge, UK (A.T., S.T.); Centro Cardiologico Monzino, Milan, Italy (F.P., M.P.); and Austrian Institute of Technology, Vienna, Austria (M.H., V.K.).
authors.forename: Carlotta
authors.initials: C
authors.lastname: Reni
authors.affiliation: From the Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, UK (M.G., S.C.S., H.L.S., F.R., J.R., E.A., R.K., G.M., A.O., C.R., C.E., G.A., P.M.); The Institute of Cancer Research, Evolutionary Genomics and Modelling Team, Centre for Evolution and Cancer, Sutton, UK (I.S., A.S.); Imperial College, London, UK (P.C., C.E., G.A.); MultiMedica Research Institute, Milan, Italy (G.S.); Cancer Research UK Cambridge Institute, Cambridge, UK (A.T., S.T.); Centro Cardiologico Monzino, Milan, Italy (F.P., M.P.); and Austrian Institute of Technology, Vienna, Austria (M.H., V.K.).
authors.forename: Paola
authors.initials: P
authors.lastname: Campagnolo
authors.affiliation: From the Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, UK (M.G., S.C.S., H.L.S., F.R., J.R., E.A., R.K., G.M., A.O., C.R., C.E., G.A., P.M.); The Institute of Cancer Research, Evolutionary Genomics and Modelling Team, Centre for Evolution and Cancer, Sutton, UK (I.S., A.S.); Imperial College, London, UK (P.C., C.E., G.A.); MultiMedica Research Institute, Milan, Italy (G.S.); Cancer Research UK Cambridge Institute, Cambridge, UK (A.T., S.T.); Centro Cardiologico Monzino, Milan, Italy (F.P., M.P.); and Austrian Institute of Technology, Vienna, Austria (M.H., V.K.).
authors.forename: Gaia
authors.initials: G
authors.lastname: Spinetti
authors.affiliation: From the Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, UK (M.G., S.C.S., H.L.S., F.R., J.R., E.A., R.K., G.M., A.O., C.R., C.E., G.A., P.M.); The Institute of Cancer Research, Evolutionary Genomics and Modelling Team, Centre for Evolution and Cancer, Sutton, UK (I.S., A.S.); Imperial College, London, UK (P.C., C.E., G.A.); MultiMedica Research Institute, Milan, Italy (G.S.); Cancer Research UK Cambridge Institute, Cambridge, UK (A.T., S.T.); Centro Cardiologico Monzino, Milan, Italy (F.P., M.P.); and Austrian Institute of Technology, Vienna, Austria (M.H., V.K.).
authors.forename: Anestis
authors.initials: A
authors.lastname: Touloumis
authors.affiliation: From the Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, UK (M.G., S.C.S., H.L.S., F.R., J.R., E.A., R.K., G.M., A.O., C.R., C.E., G.A., P.M.); The Institute of Cancer Research, Evolutionary Genomics and Modelling Team, Centre for Evolution and Cancer, Sutton, UK (I.S., A.S.); Imperial College, London, UK (P.C., C.E., G.A.); MultiMedica Research Institute, Milan, Italy (G.S.); Cancer Research UK Cambridge Institute, Cambridge, UK (A.T., S.T.); Centro Cardiologico Monzino, Milan, Italy (F.P., M.P.); and Austrian Institute of Technology, Vienna, Austria (M.H., V.K.).
authors.forename: Simon
authors.initials: S
authors.lastname: Tavaré
authors.affiliation: From the Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, UK (M.G., S.C.S., H.L.S., F.R., J.R., E.A., R.K., G.M., A.O., C.R., C.E., G.A., P.M.); The Institute of Cancer Research, Evolutionary Genomics and Modelling Team, Centre for Evolution and Cancer, Sutton, UK (I.S., A.S.); Imperial College, London, UK (P.C., C.E., G.A.); MultiMedica Research Institute, Milan, Italy (G.S.); Cancer Research UK Cambridge Institute, Cambridge, UK (A.T., S.T.); Centro Cardiologico Monzino, Milan, Italy (F.P., M.P.); and Austrian Institute of Technology, Vienna, Austria (M.H., V.K.).
authors.forename: Francesca
authors.initials: F
authors.lastname: Prandi
authors.affiliation: From the Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, UK (M.G., S.C.S., H.L.S., F.R., J.R., E.A., R.K., G.M., A.O., C.R., C.E., G.A., P.M.); The Institute of Cancer Research, Evolutionary Genomics and Modelling Team, Centre for Evolution and Cancer, Sutton, UK (I.S., A.S.); Imperial College, London, UK (P.C., C.E., G.A.); MultiMedica Research Institute, Milan, Italy (G.S.); Cancer Research UK Cambridge Institute, Cambridge, UK (A.T., S.T.); Centro Cardiologico Monzino, Milan, Italy (F.P., M.P.); and Austrian Institute of Technology, Vienna, Austria (M.H., V.K.).
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pesce
authors.affiliation: From the Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, UK (M.G., S.C.S., H.L.S., F.R., J.R., E.A., R.K., G.M., A.O., C.R., C.E., G.A., P.M.); The Institute of Cancer Research, Evolutionary Genomics and Modelling Team, Centre for Evolution and Cancer, Sutton, UK (I.S., A.S.); Imperial College, London, UK (P.C., C.E., G.A.); MultiMedica Research Institute, Milan, Italy (G.S.); Cancer Research UK Cambridge Institute, Cambridge, UK (A.T., S.T.); Centro Cardiologico Monzino, Milan, Italy (F.P., M.P.); and Austrian Institute of Technology, Vienna, Austria (M.H., V.K.).
authors.forename: Manuela
authors.initials: M
authors.lastname: Hofner
authors.affiliation: From the Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, UK (M.G., S.C.S., H.L.S., F.R., J.R., E.A., R.K., G.M., A.O., C.R., C.E., G.A., P.M.); The Institute of Cancer Research, Evolutionary Genomics and Modelling Team, Centre for Evolution and Cancer, Sutton, UK (I.S., A.S.); Imperial College, London, UK (P.C., C.E., G.A.); MultiMedica Research Institute, Milan, Italy (G.S.); Cancer Research UK Cambridge Institute, Cambridge, UK (A.T., S.T.); Centro Cardiologico Monzino, Milan, Italy (F.P., M.P.); and Austrian Institute of Technology, Vienna, Austria (M.H., V.K.).
authors.forename: Vierlinger
authors.initials: V
authors.lastname: Klemens
authors.affiliation: From the Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, UK (M.G., S.C.S., H.L.S., F.R., J.R., E.A., R.K., G.M., A.O., C.R., C.E., G.A., P.M.); The Institute of Cancer Research, Evolutionary Genomics and Modelling Team, Centre for Evolution and Cancer, Sutton, UK (I.S., A.S.); Imperial College, London, UK (P.C., C.E., G.A.); MultiMedica Research Institute, Milan, Italy (G.S.); Cancer Research UK Cambridge Institute, Cambridge, UK (A.T., S.T.); Centro Cardiologico Monzino, Milan, Italy (F.P., M.P.); and Austrian Institute of Technology, Vienna, Austria (M.H., V.K.).
authors.forename: Costanza
authors.initials: C
authors.lastname: Emanueli
authors.affiliation: From the Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, UK (M.G., S.C.S., H.L.S., F.R., J.R., E.A., R.K., G.M., A.O., C.R., C.E., G.A., P.M.); The Institute of Cancer Research, Evolutionary Genomics and Modelling Team, Centre for Evolution and Cancer, Sutton, UK (I.S., A.S.); Imperial College, London, UK (P.C., C.E., G.A.); MultiMedica Research Institute, Milan, Italy (G.S.); Cancer Research UK Cambridge Institute, Cambridge, UK (A.T., S.T.); Centro Cardiologico Monzino, Milan, Italy (F.P., M.P.); and Austrian Institute of Technology, Vienna, Austria (M.H., V.K.).
authors.forename: Gianni
authors.initials: G
authors.lastname: Angelini
authors.affiliation: From the Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, UK (M.G., S.C.S., H.L.S., F.R., J.R., E.A., R.K., G.M., A.O., C.R., C.E., G.A., P.M.); The Institute of Cancer Research, Evolutionary Genomics and Modelling Team, Centre for Evolution and Cancer, Sutton, UK (I.S., A.S.); Imperial College, London, UK (P.C., C.E., G.A.); MultiMedica Research Institute, Milan, Italy (G.S.); Cancer Research UK Cambridge Institute, Cambridge, UK (A.T., S.T.); Centro Cardiologico Monzino, Milan, Italy (F.P., M.P.); and Austrian Institute of Technology, Vienna, Austria (M.H., V.K.). mdprm@bristol.ac.uk.
authors.forename: Paolo
authors.initials: P
authors.lastname: Madeddu
mesh_terms: D063194:Adventitia / Q000166:cytology / Q000637:transplantation*; D000818:Animals; D001783:Blood Flow Velocity; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D019175:DNA Methylation; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling / Q000379:methods; D006614:Hindlimb; D061307:Human Umbilical Vein Endothelial Cells / Q000502:physiology; D006801:Humans; D007511:Ischemia / Q000235:genetics / Q000503:physiopathology / Q000601:surgery*; D051379:Mice; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic / Q000235:genetics; D020127:Recovery of Function; D012039:Regional Blood Flow; D012501:Saphenous Vein / Q000166:cytology / Q000637:transplantation*; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors
keywords: angiogenesis inhibitors; epigenomics; pericytes