Immuno-engineered mRNA combined with cell adhesive niche for synergistic modulation of the MSC secretome

Autor: Norman Michael Drzeniek, Nourhan Kahwaji, Stephan Schlickeiser, Petra Reinke, Sven Geißler, Hans-Dieter Volk, Manfred Gossen
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Drzeniek, N.M.; Kahwaji, N.; Schlickeiser, S.; Reinke, P.; Geißler, S.; Volk, H.-D.; Gossen, M.: Immuno-engineered mRNA combined with cell adhesive niche for synergistic modulation of the MSC secretome. In: Biomaterials. Vol. 294 (2023) 121971. (DOI: /10.1016/j.biomaterials.2022.121971)
ISSN: 0142-9612
Popis: In vitro transcribed (IVT-)mRNA has entered center stage for vaccine development due to its immune co-stimulating properties. Given the widely demonstrated safety of IVT-mRNA-based vaccines, we aimed to adopt IVT-mRNA encoding VEGF for secretory phenotype modulation of therapeutic cells. However, we observed that the immunogenicity of IVT-mRNA impairs the endogenous secretion of pro-angiogenic mediators from transfected mesenchymal stromal cells, instead inducing anti-angiogenic chemokines. This inflammatory secretome modulation limits the application potential of unmodified IVT-mRNA for cell therapy manufacturing, pro-angiogenic therapy and regenerative medicine. To uncouple immunogenicity from the protein expression functionality, we immuno-engineered IVT-mRNA with different chemically modified ribonucleotides. 5-Methoxy-uridine-modification of IVT-mRNA rescued the endogenous secretome pattern of transfected cells and prolonged secretion of IVT-mRNA-encoded VEGF. We found that high secretion of IVT-mRNA-encoded protein further depends on optimized cell adhesion. Cell encapsulation in a collagen-hyaluronic acid hydrogel increased secretion of IVT-mRNA-encoded VEGF and augmented the endogenous secretion of supporting pro-angiogenic mediators, such as HGF. Integrating minimally immunogenic mRNA technology with predesigned matrix-derived cues allows for the synergistic combination of multiple dimensions of cell manipulation and opens routes for biomaterial-based delivery of mRNA-engineered cell products. Such multimodal systems could present a more biologically relevant way to therapeutically address complex multifactorial processes such as tissue ischemia, angiogenesis, and regeneration.
Databáze: OpenAIRE
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