title: Matrix metalloproteinase-13 mediated degradation of hyaluronic acid-based matrices orchestrates stem cell engraftment through vascular integration.
abstract: A critical design parameter for the function of synthetic extracellular matrices is to synchronize the gradual cell-mediated degradation of the matrix with the endogenous secretion of natural extracellular matrix (ECM) (e.g., creeping substitution). In hyaluronic acid (HyA)-based hydrogel matrices, we have investigated the effects of peptide crosslinkers with different matrix metalloproteinases (MMP) sensitivities on network degradation and neovascularization in vivo. The HyA hydrogel matrices consisted of cell adhesive peptides, heparin for both the presentation of exogenous and sequestration of endogenously synthesized growth factors, and MMP cleavable peptide linkages (i.e., QPQGLAK, GPLGMHGK, and GPLGLSLGK). Sca1(+)/CD45(-)/CD34(+)/CD44(+) cardiac progenitor cells (CPCs) cultured in the matrices with the slowly degradable QPQGLAK hydrogels supported the highest production of MMP-2, MMP-9, MMP-13, VEGF165, and a range of angiogenesis related proteins. Hydrogels with QPQGLAK crosslinks supported prolonged retention of these proteins via heparin within the matrix, stimulating rapid vascular development, and anastomosis with the host vasculature when implanted in the murine hindlimb.
authors.affiliation: Department of Bioengineering, University of California, Berkeley, CA 94720, USA; Department of Material Science and Engineering, University of California, Berkeley, CA 94720, USA.
authors.forename: Amit K
authors.initials: AK
authors.lastname: Jha
authors.affiliation: Department of Nutritional Science and Toxicology, University of California, Berkeley, CA 94720, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Tharp
authors.affiliation: Department of Bioengineering, University of California, Berkeley, CA 94720, USA; Department of Material Science and Engineering, University of California, Berkeley, CA 94720, USA; Centre for Research in Medical Devices (CÚRAM), National University of Ireland Galway, Ireland.
authors.forename: Shane
authors.initials: S
authors.lastname: Browne
authors.affiliation: Department of Medicine, University of California, San Francisco, CA 94143, USA.
authors.forename: Jianqin
authors.initials: J
authors.lastname: Ye
authors.affiliation: Department of Nutritional Science and Toxicology, University of California, Berkeley, CA 94720, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Stahl
authors.affiliation: Department of Medicine, University of California, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143, USA; Cardiovascular Research Institute, University of California, San Francisco, CA 94143, USA.
authors.forename: Yerem
authors.initials: Y
authors.lastname: Yeghiazarians
authors.affiliation: Department of Bioengineering, University of California, Berkeley, CA 94720, USA; Department of Material Science and Engineering, University of California, Berkeley, CA 94720, USA. Electronic address: kehealy@berkeley.edu.
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Healy
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry / Q000378:metabolism*; D002448:Cell Adhesion; D049109:Cell Proliferation; D002478:Cells, Cultured; D006820:Hyaluronic Acid / Q000737:chemistry / Q000378:metabolism*; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000166:cytology; D018919:Neovascularization, Physiologic; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D033581:Stem Cell Transplantation / Q000379:methods; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D054457:Tissue Scaffolds / Q000737:chemistry
chemical_list: D001672:Biocompatible Materials; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D006820:Hyaluronic Acid; D053509:Matrix Metalloproteinase 13
keywords: Growth factor sequestration; Hyaluronic acid hydrogel; MMP cleavable peptide; Neovascularization; Stem cell transplantation; TGFβ1