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Recovery of Therapeutically Ablated Engineered Blood-Vessel Networks on a Plug-and-Play Platform
Lisa A Krattiger1,2, Lukas O Moser1, Rodi Odabasi1
1Department of Obstetrics, University Hospital Zurich, University of Zurich, Schmelzbergstrasse 12, Zurich, 8091, Switzerland.
Abstract:
Limiting the availability of key angiogenesis-promoting factors is a successful strategy to ablate tumor-supplying blood vessels or to reduce excessive vasculature in diabetic retinopathy. However, the efficacy of such anti-angiogenic therapies (AATs) varies with tumor type, and regrowth of vessels is observed upon termination of treatment. The ability to understand and develop AATs remains limited by a lack of robust in vitro systems for modeling the recovery of vascular networks. Here, complex 3D micro-capillary networks are engineered by sequentially seeding human bone marrow-derived mesenchymal stromal cells and human umbilical vein endothelial cells (ECs) on a previously established, synthetic plug-and-play hydrogel platform. In the tightly interconnected vascular networks that form this way, the two cell types share a basement membrane-like layer and can be maintained for several days of co-culture. Pre-formed networks degrade in the presence of bevacizumab. Upon treatment termination, vessel structures grow back to their original positions after replenishment with new ECs, which also integrate into unperturbed established networks. The data suggest that this plug-and-play platform enables the screening of drugs with blood-vessel inhibiting functions. It is believed that this platform could be of particular interest in studying resistance or recovery mechanisms to AAT treatment.
Insights
Researchers developed a 3D hydrogel platform to model blood vessel regrowth after anti-angiogenic therapies (AATs). This system aids in understanding treatment resistance and recovery for better AAT development.
Area of Science:
- Biomedical Engineering
- Vascular Biology
- Drug Discovery
Background:
- Anti-angiogenic therapies (AATs) are used to treat conditions like cancer and diabetic retinopathy by limiting blood vessel growth.
- The effectiveness of AATs varies, and blood vessels often regrow after treatment cessation.
- Current in vitro models are insufficient for studying vascular network recovery after AATs.
Purpose of the Study:
- To engineer a robust 3D in vitro system for modeling vascular network recovery after anti-angiogenic treatment.
- To investigate the mechanisms of blood vessel regrowth and potential resistance to AATs.
- To provide a platform for screening drugs that inhibit blood vessel formation.
Main Methods:
- Engineered complex 3D micro-capillary networks using human bone marrow-derived mesenchymal stromal cells and human umbilical vein endothelial cells (ECs).
- Utilized a synthetic, plug-and-play hydrogel platform for sequential cell seeding and network formation.
- Treated pre-formed vascular networks with bevacizumab to induce degradation and then assessed recovery upon treatment withdrawal and EC replenishment.
Main Results:
- Successfully created interconnected 3D vascular networks co-cultured for several days.
- Observed degradation of vascular networks in the presence of bevacizumab.
- Demonstrated that vessel structures regrew to original positions upon bevacizumab removal and new EC addition, with new ECs integrating into existing networks.
Conclusions:
- The developed plug-and-play hydrogel platform effectively models vascular network recovery after anti-angiogenic therapy.
- This system facilitates the screening of drugs targeting blood vessel formation and inhibiting functions.
- The platform holds promise for studying AAT resistance and recovery mechanisms.
