title: Combined intramyocardial delivery of human pericytes and cardiac stem cells additively improves the healing of mouse infarcted hearts through stimulation of vascular and muscular repair.
abstract: BACKGROUND
  Optimization of cell therapy for cardiac repair may require the association of different cell populations with complementary activities.
  
  
  OBJECTIVE
  Compare the reparative potential of saphenous vein-derived pericytes (SVPs) with that of cardiac stem cells (CSCs) in a model of myocardial infarction, and investigate whether combined cell transplantation provides further improvements.
  
  
  RESULTS
  SVPs and CSCs were isolated from vein leftovers of coronary artery bypass graft surgery and discarded atrial specimens of transplanted hearts, respectively. Single or dual cell therapy (300 000 cells of each type per heart) was tested in infarcted SCID (severe combined immunodeficiency)-Beige mice. SVPs and CSCs alone improved cardiac contractility as assessed by echocardiography at 14 days post myocardial infarction. The effect was maintained, although attenuated at 42 days. At histological level, SVPs and CSCs similarly inhibited infarct size and interstitial fibrosis, SVPs were superior in inducing angiogenesis and CSCs in promoting cardiomyocyte proliferation and recruitment of endogenous stem cells. The combination of cells additively reduced the infarct size and promoted vascular proliferation and arteriogenesis, but did not surpass single therapies with regard to contractility indexes. SVPs and CSCs secrete similar amounts of hepatocyte growth factor, vascular endothelial growth factor, fibroblast growth factor, stem cell factor, and stromal cell-derived factor-1, whereas SVPs release higher quantities of angiopoietins and microRNA-132. Coculture of the 2 cell populations results in competitive as well as enhancing paracrine activities. In particular, the release of stromal cell-derived factor-1 was synergistically augmented along with downregulation of stromal cell-derived factor-1-degrading enzyme dipeptidyl peptidase 4.
  
  
  CONCLUSIONS
  Combinatory therapy with SVPs and CSCs may complementarily help the repair of infarcted hearts.
authors: From the Experimental Cardiovascular Medicine (E.A., H.L.S., F.R., R.K., G.M., A.O., I.R.-A., Z.D., K.M., C.R., V.V.A., J.R., P.M.) and Vascular Pathology and Regeneration (M.M., C.E.), School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; Institute of Cardiovascular and Medical Sciences (M.M.), University of Glasgow, Glasgow, United Kingdom; Department of Physiology, University of Otago, Dunedin, New Zealand (R.K.); Department of Medical and Biological Sciences (D.C., A.P.B.) and Department of Experimental Medical and Clinical Sciences (U.L.), University of Udine, Udine, Italy; and Cardiac Surgery, Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom (G.A.).
authors: Elisa
authors: E
authors: Avolio
authors: From the Experimental Cardiovascular Medicine (E.A., H.L.S., F.R., R.K., G.M., A.O., I.R.-A., Z.D., K.M., C.R., V.V.A., J.R., P.M.) and Vascular Pathology and Regeneration (M.M., C.E.), School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; Institute of Cardiovascular and Medical Sciences (M.M.), University of Glasgow, Glasgow, United Kingdom; Department of Physiology, University of Otago, Dunedin, New Zealand (R.K.); Department of Medical and Biological Sciences (D.C., A.P.B.) and Department of Experimental Medical and Clinical Sciences (U.L.), University of Udine, Udine, Italy; and Cardiac Surgery, Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom (G.A.).
authors: Marco
authors: M
authors: Meloni
authors: From the Experimental Cardiovascular Medicine (E.A., H.L.S., F.R., R.K., G.M., A.O., I.R.-A., Z.D., K.M., C.R., V.V.A., J.R., P.M.) and Vascular Pathology and Regeneration (M.M., C.E.), School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; Institute of Cardiovascular and Medical Sciences (M.M.), University of Glasgow, Glasgow, United Kingdom; Department of Physiology, University of Otago, Dunedin, New Zealand (R.K.); Department of Medical and Biological Sciences (D.C., A.P.B.) and Department of Experimental Medical and Clinical Sciences (U.L.), University of Udine, Udine, Italy; and Cardiac Surgery, Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom (G.A.).
authors: Helen L
authors: HL
authors: Spencer
authors: From the Experimental Cardiovascular Medicine (E.A., H.L.S., F.R., R.K., G.M., A.O., I.R.-A., Z.D., K.M., C.R., V.V.A., J.R., P.M.) and Vascular Pathology and Regeneration (M.M., C.E.), School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; Institute of Cardiovascular and Medical Sciences (M.M.), University of Glasgow, Glasgow, United Kingdom; Department of Physiology, University of Otago, Dunedin, New Zealand (R.K.); Department of Medical and Biological Sciences (D.C., A.P.B.) and Department of Experimental Medical and Clinical Sciences (U.L.), University of Udine, Udine, Italy; and Cardiac Surgery, Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom (G.A.).
authors: Federica
authors: F
authors: Riu
authors: From the Experimental Cardiovascular Medicine (E.A., H.L.S., F.R., R.K., G.M., A.O., I.R.-A., Z.D., K.M., C.R., V.V.A., J.R., P.M.) and Vascular Pathology and Regeneration (M.M., C.E.), School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; Institute of Cardiovascular and Medical Sciences (M.M.), University of Glasgow, Glasgow, United Kingdom; Department of Physiology, University of Otago, Dunedin, New Zealand (R.K.); Department of Medical and Biological Sciences (D.C., A.P.B.) and Department of Experimental Medical and Clinical Sciences (U.L.), University of Udine, Udine, Italy; and Cardiac Surgery, Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom (G.A.).
authors: Rajesh
authors: R
authors: Katare
authors: From the Experimental Cardiovascular Medicine (E.A., H.L.S., F.R., R.K., G.M., A.O., I.R.-A., Z.D., K.M., C.R., V.V.A., J.R., P.M.) and Vascular Pathology and Regeneration (M.M., C.E.), School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; Institute of Cardiovascular and Medical Sciences (M.M.), University of Glasgow, Glasgow, United Kingdom; Department of Physiology, University of Otago, Dunedin, New Zealand (R.K.); Department of Medical and Biological Sciences (D.C., A.P.B.) and Department of Experimental Medical and Clinical Sciences (U.L.), University of Udine, Udine, Italy; and Cardiac Surgery, Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom (G.A.).
authors: Giuseppe
authors: G
authors: Mangialardi
authors: From the Experimental Cardiovascular Medicine (E.A., H.L.S., F.R., R.K., G.M., A.O., I.R.-A., Z.D., K.M., C.R., V.V.A., J.R., P.M.) and Vascular Pathology and Regeneration (M.M., C.E.), School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; Institute of Cardiovascular and Medical Sciences (M.M.), University of Glasgow, Glasgow, United Kingdom; Department of Physiology, University of Otago, Dunedin, New Zealand (R.K.); Department of Medical and Biological Sciences (D.C., A.P.B.) and Department of Experimental Medical and Clinical Sciences (U.L.), University of Udine, Udine, Italy; and Cardiac Surgery, Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom (G.A.).
authors: Atsuhiko
authors: A
authors: Oikawa
authors: From the Experimental Cardiovascular Medicine (E.A., H.L.S., F.R., R.K., G.M., A.O., I.R.-A., Z.D., K.M., C.R., V.V.A., J.R., P.M.) and Vascular Pathology and Regeneration (M.M., C.E.), School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; Institute of Cardiovascular and Medical Sciences (M.M.), University of Glasgow, Glasgow, United Kingdom; Department of Physiology, University of Otago, Dunedin, New Zealand (R.K.); Department of Medical and Biological Sciences (D.C., A.P.B.) and Department of Experimental Medical and Clinical Sciences (U.L.), University of Udine, Udine, Italy; and Cardiac Surgery, Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom (G.A.).
authors: Iker
authors: I
authors: Rodriguez-Arabaolaza
authors: From the Experimental Cardiovascular Medicine (E.A., H.L.S., F.R., R.K., G.M., A.O., I.R.-A., Z.D., K.M., C.R., V.V.A., J.R., P.M.) and Vascular Pathology and Regeneration (M.M., C.E.), School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; Institute of Cardiovascular and Medical Sciences (M.M.), University of Glasgow, Glasgow, United Kingdom; Department of Physiology, University of Otago, Dunedin, New Zealand (R.K.); Department of Medical and Biological Sciences (D.C., A.P.B.) and Department of Experimental Medical and Clinical Sciences (U.L.), University of Udine, Udine, Italy; and Cardiac Surgery, Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom (G.A.).
authors: Zexu
authors: Z
authors: Dang
authors: From the Experimental Cardiovascular Medicine (E.A., H.L.S., F.R., R.K., G.M., A.O., I.R.-A., Z.D., K.M., C.R., V.V.A., J.R., P.M.) and Vascular Pathology and Regeneration (M.M., C.E.), School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; Institute of Cardiovascular and Medical Sciences (M.M.), University of Glasgow, Glasgow, United Kingdom; Department of Physiology, University of Otago, Dunedin, New Zealand (R.K.); Department of Medical and Biological Sciences (D.C., A.P.B.) and Department of Experimental Medical and Clinical Sciences (U.L.), University of Udine, Udine, Italy; and Cardiac Surgery, Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom (G.A.).
authors: Kathryn
authors: K
authors: Mitchell
authors: From the Experimental Cardiovascular Medicine (E.A., H.L.S., F.R., R.K., G.M., A.O., I.R.-A., Z.D., K.M., C.R., V.V.A., J.R., P.M.) and Vascular Pathology and Regeneration (M.M., C.E.), School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; Institute of Cardiovascular and Medical Sciences (M.M.), University of Glasgow, Glasgow, United Kingdom; Department of Physiology, University of Otago, Dunedin, New Zealand (R.K.); Department of Medical and Biological Sciences (D.C., A.P.B.) and Department of Experimental Medical and Clinical Sciences (U.L.), University of Udine, Udine, Italy; and Cardiac Surgery, Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom (G.A.).
authors: Carlotta
authors: C
authors: Reni
authors: From the Experimental Cardiovascular Medicine (E.A., H.L.S., F.R., R.K., G.M., A.O., I.R.-A., Z.D., K.M., C.R., V.V.A., J.R., P.M.) and Vascular Pathology and Regeneration (M.M., C.E.), School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; Institute of Cardiovascular and Medical Sciences (M.M.), University of Glasgow, Glasgow, United Kingdom; Department of Physiology, University of Otago, Dunedin, New Zealand (R.K.); Department of Medical and Biological Sciences (D.C., A.P.B.) and Department of Experimental Medical and Clinical Sciences (U.L.), University of Udine, Udine, Italy; and Cardiac Surgery, Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom (G.A.).
authors: Valeria V
authors: VV
authors: Alvino
authors: From the Experimental Cardiovascular Medicine (E.A., H.L.S., F.R., R.K., G.M., A.O., I.R.-A., Z.D., K.M., C.R., V.V.A., J.R., P.M.) and Vascular Pathology and Regeneration (M.M., C.E.), School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; Institute of Cardiovascular and Medical Sciences (M.M.), University of Glasgow, Glasgow, United Kingdom; Department of Physiology, University of Otago, Dunedin, New Zealand (R.K.); Department of Medical and Biological Sciences (D.C., A.P.B.) and Department of Experimental Medical and Clinical Sciences (U.L.), University of Udine, Udine, Italy; and Cardiac Surgery, Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom (G.A.).
authors: Jonathan
authors: J
authors: Rowlinson
authors: From the Experimental Cardiovascular Medicine (E.A., H.L.S., F.R., R.K., G.M., A.O., I.R.-A., Z.D., K.M., C.R., V.V.A., J.R., P.M.) and Vascular Pathology and Regeneration (M.M., C.E.), School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; Institute of Cardiovascular and Medical Sciences (M.M.), University of Glasgow, Glasgow, United Kingdom; Department of Physiology, University of Otago, Dunedin, New Zealand (R.K.); Department of Medical and Biological Sciences (D.C., A.P.B.) and Department of Experimental Medical and Clinical Sciences (U.L.), University of Udine, Udine, Italy; and Cardiac Surgery, Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom (G.A.).
authors: Ugolini
authors: U
authors: Livi
authors: From the Experimental Cardiovascular Medicine (E.A., H.L.S., F.R., R.K., G.M., A.O., I.R.-A., Z.D., K.M., C.R., V.V.A., J.R., P.M.) and Vascular Pathology and Regeneration (M.M., C.E.), School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; Institute of Cardiovascular and Medical Sciences (M.M.), University of Glasgow, Glasgow, United Kingdom; Department of Physiology, University of Otago, Dunedin, New Zealand (R.K.); Department of Medical and Biological Sciences (D.C., A.P.B.) and Department of Experimental Medical and Clinical Sciences (U.L.), University of Udine, Udine, Italy; and Cardiac Surgery, Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom (G.A.).
authors: Daniela
authors: D
authors: Cesselli
authors: From the Experimental Cardiovascular Medicine (E.A., H.L.S., F.R., R.K., G.M., A.O., I.R.-A., Z.D., K.M., C.R., V.V.A., J.R., P.M.) and Vascular Pathology and Regeneration (M.M., C.E.), School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; Institute of Cardiovascular and Medical Sciences (M.M.), University of Glasgow, Glasgow, United Kingdom; Department of Physiology, University of Otago, Dunedin, New Zealand (R.K.); Department of Medical and Biological Sciences (D.C., A.P.B.) and Department of Experimental Medical and Clinical Sciences (U.L.), University of Udine, Udine, Italy; and Cardiac Surgery, Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom (G.A.).
authors: Gianni
authors: G
authors: Angelini
authors: From the Experimental Cardiovascular Medicine (E.A., H.L.S., F.R., R.K., G.M., A.O., I.R.-A., Z.D., K.M., C.R., V.V.A., J.R., P.M.) and Vascular Pathology and Regeneration (M.M., C.E.), School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; Institute of Cardiovascular and Medical Sciences (M.M.), University of Glasgow, Glasgow, United Kingdom; Department of Physiology, University of Otago, Dunedin, New Zealand (R.K.); Department of Medical and Biological Sciences (D.C., A.P.B.) and Department of Experimental Medical and Clinical Sciences (U.L.), University of Udine, Udine, Italy; and Cardiac Surgery, Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom (G.A.).
authors: Costanza
authors: C
authors: Emanueli
authors: From the Experimental Cardiovascular Medicine (E.A., H.L.S., F.R., R.K., G.M., A.O., I.R.-A., Z.D., K.M., C.R., V.V.A., J.R., P.M.) and Vascular Pathology and Regeneration (M.M., C.E.), School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; Institute of Cardiovascular and Medical Sciences (M.M.), University of Glasgow, Glasgow, United Kingdom; Department of Physiology, University of Otago, Dunedin, New Zealand (R.K.); Department of Medical and Biological Sciences (D.C., A.P.B.) and Department of Experimental Medical and Clinical Sciences (U.L.), University of Udine, Udine, Italy; and Cardiac Surgery, Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom (G.A.).
authors: Antonio P
authors: AP
authors: Beltrami
authors: From the Experimental Cardiovascular Medicine (E.A., H.L.S., F.R., R.K., G.M., A.O., I.R.-A., Z.D., K.M., C.R., V.V.A., J.R., P.M.) and Vascular Pathology and Regeneration (M.M., C.E.), School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; Institute of Cardiovascular and Medical Sciences (M.M.), University of Glasgow, Glasgow, United Kingdom; Department of Physiology, University of Otago, Dunedin, New Zealand (R.K.); Department of Medical and Biological Sciences (D.C., A.P.B.) and Department of Experimental Medical and Clinical Sciences (U.L.), University of Udine, Udine, Italy; and Cardiac Surgery, Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom (G.A.). Paolo.Madeddu@bristol.ac.uk.
authors: Paolo
authors: P
authors: Madeddu
mesh_terms: D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005355:Fibrosis; D006439:Hemodynamics; D006801:Humans; D016513:Mice, SCID; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D018919:Neovascularization, Physiologic; D019899:Paracrine Communication; D020286:Pericytes / Q000378:metabolism / Q000637:transplantation*; D010641:Phenotype; D020127:Recovery of Function; D012038:Regeneration; D012501:Saphenous Vein / Q000166:cytology; D033581:Stem Cell Transplantation; D013997:Time Factors; D020257:Ventricular Remodeling
chemical_list: D042501:Angiogenic Proteins
keywords: acute inferior myocardial infarction; cardiac remodeling, ventricular; cell transplantation; cell- and tissue-based therapy; pericytes; stem cells