Implanted synthetic cells trigger tissue angiogenesis through de novo production of recombinant growth factors

Author:

Chen Gal12ORCID,Levin Rotem1,Landau Shira3ORCID,Kaduri Maya1,Adir Omer14ORCID,Ianovici Iris3,Krinsky Nitzan1,Doppelt-Flikshtain Ofri15,Shklover Jeny1,Shainsky-Roitman Janna1,Levenberg Shulamit3ORCID,Schroeder Avi1

Affiliation:

1. The Luis Family Laboratory for Targeted Drug Delivery and Personalized Medicine Technologies, Department of Chemical Engineering, Technion, Haifa 32000, Israel

2. The Interdisciplinary Program for Biotechnology, Technion, Haifa 32000, Israel

3. Department of Biomedical Engineering, Technion, Haifa 32000, Israel

4. The Norman Seiden Multidisciplinary Program for Nanoscience and Nanotechnology, Technion, Haifa 32000, Israel

5. The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel

Abstract

Progress in bottom-up synthetic biology has stimulated the development of synthetic cells (SCs), autonomous protein-manufacturing particles, as dynamic biomimetics for replacing diseased natural cells and addressing medical needs. Here, we report that SCs genetically encoded to produce proangiogenic factors triggered the physiological process of neovascularization in mice. The SCs were constructed of giant lipid vesicles and were optimized to facilitate enhanced protein production. When introduced with the appropriate genetic code, the SCs synthesized a recombinant human basic fibroblast growth factor (bFGF), reaching expression levels of up to 9⋅106protein copies per SC. In culture, the SCs induced endothelial cell proliferation, migration, tube formation, and angiogenesis-related intracellular signaling, confirming their proangiogenic activity. Integrating the SCs with bioengineered constructs bearing endothelial cells promoted the remodeling of mature vascular networks, supported by a collagen-IV basement membrane–like matrix. In vivo, prolonged local administration of the SCs in mice triggered the infiltration of blood vessels into implanted Matrigel plugs without recorded systemic immunogenicity. These findings emphasize the potential of SCs as therapeutic platforms for activating physiological processes by autonomously producing biological drugs inside the body.

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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