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BiomaterialsVolume 154, February 2018, Pages 34-47

Guiding morphogenesis in cell-instructive microgels for therapeutic angiogenesis(Article)

  • ai3S – Instituto de Inovação e Investigação em Saúde, Rua Alfredo Allen, 208, Porto, 4200-135, Portugal
  • bINEB – Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, Porto, 4200-135, Portugal
  • cICBAS – Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, Porto, 4050-313, Portugal
  • dIPATIMUP – Instituto Patologia e Imunologia Molecular, Universidade do Porto, Rua Alfredo Allen, 208, Porto, 4200-135, Portugal
  • eDepartment of Biomedical Engineering, University of California - Davis, One Shields Avenue, Davis, CA 95616, United States

Abstract

Efficient cell delivery strategies are urgently needed to improve the outcome of cell-based pro-angiogenic therapies. This study describes the design of an injectable cell delivery platform, based on biomaterial-guided morphogenesis principles. Soft high-mannuronic acid alginate microgels, oxidized and functionalized with integrin-binding peptides, provided adequate biochemical/biomechanical cues for the co-assembly of mesenchymal stem cells and outgrowth endothelial cells (OEC) into pre-vascularized microtissues. In vitro priming conditions regulated OEC tubulogenesis, which only occurred under normoxia (+O2) in the presence of angiogenic factors (+GF) and, importantly, did not revert in an ischemic-like environment. Primed (+O2+GF) microgel-entrapped cells secreted a large variety of angiogenesis-related proteins and produced endogenous extracellular-matrix, rich in fibronectin and collagen type I, fostering cell-cell/cell-matrix interactions and establishing a stable angiogenic niche. Extending the pre-culture time resulted in higher cell outward migration and in vivo angiogenic potential. Microgels partially disintegrated upon implantation in chick embryos, promoting interaction between pre-vascularized microtissues and the host. Preserved human vascular structures were still detected in vivo, and human cells showed the ability to migrate and integrate with the chick vasculature. Our results suggest that an integrated approach combining pro-angiogenic cells, cell-instructive microgels and adequate in vitro priming may provide the basis for successful therapeutic angiogenesis. © 2017 Elsevier Ltd

Author keywords

Cell therapyCell-instructiveInjectable biomaterialMicrotissuePre-vascularization

Indexed keywords

Engineering controlled terms:BiomaterialsCell cultureGelsMolecular interactionsMorphologyProteinsStem cells
Engineering uncontrolled termsCell therapyExtracellular matricesInjectable biomaterialsMesenchymal stem cellMicrotissuePro-angiogenic therapiesTherapeutic angiogenesisVascularization
Engineering main heading:Endothelial cells
EMTREE drug terms:alginic acidarginylglycylaspartic acidbiomaterialcollagen type 1fibronectingrowth factormannuronic acidoxygenalginic acidarginyl-glycyl-aspartic acidglucuronic acidhexuronic acidoligopeptideoxygensignal peptide
EMTREE medical terms:angiogenesisanimal tissueArticlebiochemical compositionbiomechanicscell growthcell hypoxiacell interactioncell maturationcell migrationcontrolled studyembryoendothelium cellextracellular matrixgelhumanhuman cellin vitro studyin vivo studymesenchymal stem cellmicrogelmorphogenesisnonhumanpriority journalstem cell nicheangiogenesisanimalcell motionchemistrychick embryocytologydrug effectgelmesenchymal stroma cellmetabolismneovascularization (pathology)pathologytumor microenvironment
MeSH:AlginatesAnimalsCell MovementCellular MicroenvironmentChick EmbryoEndothelial CellsExtracellular MatrixGelsGlucuronic AcidHexuronic AcidsHumansIntercellular Signaling Peptides and ProteinsMesenchymal Stromal CellsMorphogenesisNeovascularization, PathologicNeovascularization, PhysiologicOligopeptidesOxygen

Chemicals and CAS Registry Numbers:

alginic acid, 28961-37-7, 29894-36-8, 9005-32-7, 9005-38-3; arginylglycylaspartic acid, 99896-85-2; fibronectin, 86088-83-7; oxygen, 7782-44-7; glucuronic acid, 36116-79-7, 576-37-4, 6556-12-3;

Alginates; alginic acid; arginyl-glycyl-aspartic acid; Gels; Glucuronic Acid; Hexuronic Acids; Intercellular Signaling Peptides and Proteins; Oligopeptides; Oxygen

Funding details

Funding sponsor Funding number Acronym
Office of Electricity Delivery and Energy ReliabilityPTDC/BBB-ECT/251872014OE
European Regional Development FundPOCI-01-0145-FEDER-016627,3DEMT
Fundação para a Ciência e a Tecnologia
See opportunities
POCI
Ministério da Ciência, Tecnologia e Ensino SuperiorNORTE-01-0145-FEDER-000012,POCI-01-0145-FEDER-007274MCTES
American Heart Association
See opportunities		SFRH/BD/94306/2013,15BGIA25730057 / Eduardo Silva/ 2015

  • 1

    This work was supported by FEDER - Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 - Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, by Portuguese funds through FCT - Fundaçao para a Ciencia e a Tecnologia/ Ministerio da Ciencia, Tecnologia e Ensino Superior in the framework of the project “Institute for Research and Innovation in Health Sciences” ( POCI-01-0145-FEDER-007274 ) and by NORTE-01-0145-FEDER-000012 funded by North Portugal Regional Operational Program (Norte2020) under PORTUGAL2020 Partnership Agreement through Regional Development Fund (FEDER) . Project 3DEMT funded by POCIvia FEDER ( POCI-01-0145-FEDER-016627 ) and by FCT via OE ( PTDC/BBB-ECT/251872014 ). This work was also supported by the American Heart Association Grant # 15BGIA25730057 / Eduardo Silva/ 2015. ALT thanks FCT for the doctoral grant SFRH/BD/94306/2013 and the BiotechHealth PhD Programme. SJB thanks FCT for the post-doctoral grant SFRH/BPD/80571/2011 . CCB thanks FCT for the IF research position IF/00296/2015 . Appendix A

  • ISSN: 01429612
  • CODEN: BIMAD
  • Source Type: Journal
  • Original language: English
  • DOI: 10.1016/j.biomaterials.2017.10.051
  • PubMed ID: 29120817
  • Document Type: Article
  • Publisher: Elsevier Ltd

  Barrias, C.C.; i3S – Instituto de Inovação e Investigação em Saúde, Rua Alfredo Allen, 208, Porto, Portugal;
© Copyright 2018 Elsevier B.V., All rights reserved.

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