Notch‐inducing hydrogels reveal a perivascular switch of mesenchymal stem cell fate

• Published in: EMBO reports 2018-08, Vol.19 (8), p.n/a
• Main Authors: Blache, Ulrich, Vallmajo‐Martin, Queralt, Horton, Edward R, Guerrero, Julien, Djonov, Valentin, Scherberich, Arnaud, Erler, Janine T, Martin, Ivan, Snedeker, Jess G, Milleret, Vincent, Ehrbar, Martin
• Format: Article
• Language: English
• Subjects: Biomimetics; Bone Marrow Cells - cytology; Capillaries; Capillaries - drug effects; Capillaries - physiology; Capillaries - ultrastructure; Cell culture; Cell fate; Cell Lineage - drug effects; Cellular Microenvironment - drug effects; Coculture Techniques; EMBO37; EMBO39; EMBO46; Endothelial cells; Extracellular matrix; Extracellular Matrix - metabolism; Extracellular Matrix - ultrastructure; Gene expression; Human Umbilical Vein Endothelial Cells - cytology; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Human Umbilical Vein Endothelial Cells - ultrastructure; Humans; Hydrogels; Hydrogels - pharmacology; Jagged1 protein; mesenchymal stem cell; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - drug effects; Mesenchymal Stem Cells - metabolism; Mesenchymal Stem Cells - ultrastructure; Mesenchyme; Microenvironments; Mimicry; Neovascularization, Physiologic - drug effects; Notch signaling; perivascular niche; Phenotypes; Polyethylene glycol; Polyethylene Glycols - pharmacology; Receptors, Notch - metabolism; Stem cells; Switching theory; synthetic hydrogel
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.201845964

The fate of mesenchymal stem cells (MSCs) in the perivascular niche, as well as factors controlling their fate, is poorly understood. Here, we study MSCs in the perivascular microenvironment of endothelial capillaries by modifying a synthetic 3D biomimetic poly(ethylene glycol) (PEG)‐hydrogel system in vitro . We show that MSCs together with endothelial cells form micro‐capillary networks specifically in soft PEG hydrogels. Transcriptome analysis of human MSCs isolated from engineered capillaries shows a prominent switch in extracellular matrix (ECM) production. We demonstrate that the ECM phenotypic switch of MSCs can be recapitulated in the absence of endothelial cells by functionalizing PEG hydrogels with the Notch‐activator Jagged1. Moreover, transient culture of MSCs in Notch‐inducing microenvironments reveals the reversibility of this ECM switch. These findings provide insight into the perivascular commitment of MSCs by use of engineered niche‐mimicking synthetic hydrogels. Synopsis Synthetic hydrogels serve as microenvironments for the formation of micro‐capillaries by endothelial cells and mesenchymal stem cells. Perivascular MSCs change phenotype and extracellular matrix, a reversible switch also induced in Jagged1‐modified hydrogels. MSCs support micro‐capillary formation of endothelial cells in synthetic PEG‐hydrogels. Micro‐capillary MSCs undergo perivascular commitment including an ECM switch. Notch‐inducing hydrogels induce the reversible ECM switch in MSCs in the absence of endothelial cells. Graphical Abstract Synthetic hydrogels serve as microenvironments for the formation of micro‐capillaries by endothelial cells and mesenchymal stem cells. Perivascular MSCs change phenotype and extracellular matrix, a reversible switch also induced in Jagged1‐modified hydrogels.