Engineered microtissues for the bystander therapy against cancer

Thymidine kinase expressing human adipose mesenchymal stem cells (TK-hAMSCs) in combination with ganciclovir (GCV) are an effective platform for antitumor bystander therapy in mice models. However, this strategy requires multiple TK-hAMSCs administrations and a substantial number of cells. Therefore, for clinical translation, it is necessary to find a biocompatible scaffold providing TK-hAMSCs retention in the implantation site against their rapid wash-out. We have developed a microtissue (MT) composed by TKhAMSCs and a scaffold made of polylactic acid microparticles and cell-derived extracellular matrix deposited by hAMSCs. The efficacy of these MTs as vehicles for TK-hAMSCs/GCV bystander therapy was evaluated in a rodent model of human prostate cancer. Subcutaneously implanted MTs were integrated in the surrounding tissue, allowing neovascularization and maintenance of TK-hAMSCs viability. Furthermore, MTs implanted beside tumors allowed TK-hAMSCs migration towards tumor cells and, after GCV administration, inhibited tumor growth. These results indicate that TK-hAMSCs-MTs are promising cell reservoirs for clinical use of therapeutic MSCs in bystander therapies.
This work was supported by the Severo Ochoa Program for Centers of Excellence in R&D 2016–2019, the European Commission-ERANET (nAngioderm JTC2018-103), the Spanish network of cell therapy (TERCEL), the Spanish Ministry of Science, Innovation and Universities (MAT2015-68906-R), the Spanish State Research Agency (AEI) and the European Regional Development Fund (FEDER) grants. BBF acknowledge finanical support through the BEST Postdoctoral Program, funded by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie (grant agreement no. 712754) and from the Spanish Ministry of Economy and Competitiveness under Severo Ochoa grants (SEV-2014-0425 and CEX2018-000789-S). GRS is thankful to the Spanish Ministry of Economy, Industry and Competitiveness for his fellowship (BES-2016-077182). The authors specially thank Dr. Josep Roca, from Delfos hospital (Dr. Roca I Noguera aesthetic surgery team), for the kind donation of liposuction for hAMSCs preparation; and to the Services of cell culture (IQAC-CISC), animal care (IQAC-CSIC) and cell sorting (CCiT-University of Barcelona) for their technician and specialized support.