title: Controlled activation of morphogenesis to generate a functional human microvasculature in a synthetic matrix.
abstract: Understanding the role of the extracellular matrix (ECM) in vascular morphogenesis has been possible using natural ECMs as in vitro models to study the underlying molecular mechanisms. However, little is known about vascular morphogenesis in synthetic matrices where properties can be tuned toward both the basic understanding of tubulogenesis in modular environments and as a clinically relevant alternative to natural materials for regenerative medicine. We investigated synthetic, tunable hyaluronic acid (HA) hydrogels and determined both the adhesion and degradation parameters that enable human endothelial colony-forming cells (ECFCs) to form efficient vascular networks. Entrapped ECFCs underwent tubulogenesis dependent on the cellular interactions with the HA hydrogel during each stage of vascular morphogenesis. Vacuole and lumen formed through integrins α(5)β(1) and α(V)β(3), while branching and sprouting were enabled by HA hydrogel degradation. Vascular networks formed within HA hydrogels containing ECFCs anastomosed with the host's circulation and supported blood flow in the hydrogel after transplantation. Collectively, we show that the signaling pathways of vascular morphogenesis of ECFCs can be precisely regulated in a synthetic matrix, resulting in a functional microvasculature useful for the study of 3-dimensional vascular biology and toward a range of vascular disorders and approaches in tissue regeneration.
authors.affiliation: Department of Chemical and Biomolecular Engineering, Johns Hopkins Physical Sciences-Oncology Center and Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Donny
authors.initials: D
authors.lastname: Hanjaya-Putra
authors.forename: Vivek
authors.initials: V
authors.lastname: Bose
authors.forename: Yu-I
authors.initials: YI
authors.lastname: Shen
authors.forename: Jane
authors.initials: J
authors.lastname: Yee
authors.forename: Sudhir
authors.initials: S
authors.lastname: Khetan
authors.forename: Karen
authors.initials: K
authors.lastname: Fox-Talbot
authors.forename: Charles
authors.initials: C
authors.lastname: Steenbergen
authors.forename: Jason A
authors.initials: JA
authors.lastname: Burdick
authors.forename: Sharon
authors.initials: S
authors.lastname: Gerecht
mesh_terms: D001807:Blood Vessel Prosthesis; D002448:Cell Adhesion / Q000502:physiology; D018929:Cell Culture Techniques / Q000379:methods; D042783:Endothelial Cells / Q000166:cytology* / Q000502:physiology*; D005109:Extracellular Matrix / Q000502:physiology; D005312:Fetal Blood / Q000166:cytology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D055806:Microvessels / Q000166:cytology / Q000254:growth & development* / Q000502:physiology; D009024:Morphogenesis / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000502:physiology*; D023822:Tissue Engineering / Q000379:methods*
chemical_list: D020136:Hydrogel, Polyethylene Glycol Dimethacrylate