Temporal changes guided by mesenchymal stem cells on a 3D microgel platform enhance angiogenesis in vivo at a low-cell dose

• DOI: 10.1073/pnas.2008245117
• Publication Date: 2020-07-25T00:10:46Z
• Authors: Dilip Thomas; Grazia Marsico; Isma Liza Mohd Isa; Arun Thirumaran; Xizhe Chen; Bartlomiej Lukasz; Gianluca Fontana; Brian Rodriguez; Martina Marchetti...; Timothy O’Brien; Abhay Pandit
• Keywords: Integrins; Cells; Nude; Mice, Nude; Neovascularization, Physiologic; Bioengineering; Regenerative Medicine; Cardiovascular; Mesenchymal Stem Cell Transplantation; angiogenesis; Mice; Stem Cell Research - Nonembryonic - Human; biopolymer; Ischemia; Animals; Humans; Physiologic; Neovascularization; paracrine secretome; Cell Proliferation; Transplantation; Microgels; Mesenchymal Stem Cells; Cells, Immobilized; Stem Cell Research; Immobilized; Extracellular Matrix; Hindlimb; Physical Sciences; mechanosensing; limb ischemia; Biotechnology

Significance An optimal 3D cell-delivery platform is key for cytoprotection and prolonged cell function in vivo for sustained delivery of therapeutic factors as “cell factories.” However, little is known about stem-cell phenotype and behavior resulting from in vitro preconditioning in engineered extracellular matrices. We demonstrate a close relationship between macromolecular concentration and mesenchymal stem cell behavior that drives morphological changes, modulation of integrin expression, and matrix rigidity after 96 h of in vitro preconditioning. Changes induced by the optimal microenvironment influence a proangiogenic phenotype of mesenchymal stem cells in a concentration-dependent manner and play a key role in promoting angiogenesis in vivo at a 20 times lower cell dose than the preclinical standard, tested in a severe, double-ligation model of CLI.