title: Regeneration of three layers vascular wall by using BMP2-treated MSC involving HIF-1α and Id1 expressions through JAK/STAT pathways.
abstract: Engineering living, multilayered blood vessels to form in vivo arteries is a promising alternative to peripheral artery bypass using acellular grafts restricted by thrombosis and occlusion at long term. Bone Morphogenetic Protein 2 (BMP2) is a growth factor determining in the early vascular embryonic development. The aim of the present study was evaluate the collaborative effect of recombinant human--BMP2 and Bone marrow--Mesenchymal stem cells (BM-MSCs) seeded on vascular patch to regenerate a vascular arterial wall in a rat model. BM-MSCs expressing green fluorescent protein (GFP) seeded on vascular patch were cultured in presence of recombinant human-BMP2 [100 ng/mL] during 1 week before their implantation on the abdominal aorta of Wistar rats. We observed after 2 weeks under physiological arterial flow a regeneration of a three layers adult-like arterial wall with a middle layer expressing smooth muscle proteins and a border layer expressing endothelial marker. In vitro study, using Matrigel assay and co-culture of BM-MSCs with endothelial cells demonstrated that rh-BMP2 promoted tube-like formation even at long term (90 days) allowing the organization of thick rails. We demonstrated using inhibitors and siRNAs that rh-BMP2 enhanced the expression of HIF-1α and Id1 through, at least in part, the stimulation of JAK2/STAT3/STAT5 signaling pathways. Rh-BMP2 by mimicking embryological conditions allowed vascular BM-MSCs differentiation.
authors.affiliation: Faculty of Medicine, University François Rabelais, Labpart EA 3852, IFR 135 Tours, France. karimbelmokhtar@hotmail.fr
authors.forename: Karim
authors.initials: K
authors.lastname: Belmokhtar
authors.forename: Thierry
authors.initials: T
authors.lastname: Bourguignon
authors.forename: Morel E
authors.initials: ME
authors.lastname: Worou
authors.forename: Georges
authors.initials: G
authors.lastname: Khamis
authors.forename: Pierre
authors.initials: P
authors.lastname: Bonnet
authors.forename: Jorge
authors.initials: J
authors.lastname: Domenech
authors.forename: Véronique
authors.initials: V
authors.lastname: Eder
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000166:cytology / Q000378:metabolism / Q000637:transplantation; D015415:Biomarkers / Q000378:metabolism; D001807:Blood Vessel Prosthesis; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D002454:Cell Differentiation; D018920:Coculture Techniques; D003598:Cytoskeletal Proteins / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism*; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects; D023421:Models, Animal; D009124:Muscle Proteins / Q000378:metabolism; D018919:Neovascularization, Physiologic; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D012038:Regeneration; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection / Q000379:methods
chemical_list: C525718:BMP2 protein, human; D015415:Biomarkers; D055396:Bone Morphogenetic Protein 2; D003598:Cytoskeletal Proteins; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C497454:ID1 protein, rat; D051798:Inhibitor of Differentiation Protein 1; D009124:Muscle Proteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C470305:Smooth muscle protein, rat; D049452:Green Fluorescent Proteins; D053612:Janus Kinases