Bioinspired three-dimensional multifunctional systems to enhance the therapeutic potential of mesenchymal stromal cells

Abstract

Mesenchymal stromal cells (MSCs) present the ability to secrete important immunomodulatory factors, and therefore, hold great potential for the treatment of multiple inflammatory and immune disorders. However, for the success of MSC-based therapies, the optimization of administration protocols is fundamental. In such regard, three-dimensional (3D) cell encapsulation emerges as a valuable strategy for MSC administration, since it overcomes the important hurdles of nude cell administration and represents a versatile platform to mimic the natural niche of cells. In the present doctoral thesis, we focused on the design of a multifunctional system consisting of a hydrogel incorporating alginate-poly-L-lysine-alginate (APA) microencapsulated MSCs, an adequate biofunctionalization strategy and the continuous presence of interferon-¿ (IFN-¿), hypothesizing that it would represent an integrated solution to (1) protect MSCs from the host immune system, (2) to promote their viability and (3) to boost their immunomodulatory properties. Therefore, here, we studied in depth and optimized each one of the three main elements. In particular, we established a tight control on APA-microencapsulated MSC behavior enhancing the biosafety of the therapy, we designed a biosensor that provides essential information about the specific MSC biofunctionalization requirements and we developed a strategy to boost the immunomodulatory properties of MSCs based on the inclusion of IFN-¿ and the 3D cell culture itself. These data represent an important step forward in the development of cell encapsulation systems, having significant implications in MSC therapies. // Mesenchymal stromal cells (MSCs) present the ability to secrete important immunomodulatory factors, and therefore, hold great potential for the treatment of multiple inflammatory and immune disorders. However, for the success of MSC-based therapies, the optimization of administration protocols is fundamental. In such regard, three-dimensional (3D) cell encapsulation emerges as a valuable strategy for MSC administration, since it overcomes the important hurdles of nude cell administration and represents a versatile platform to mimic the natural niche of cells. In the present doctoral thesis, we focused on the design of a multifunctional system consisting of a hydrogel incorporating alginate-poly-L-lysine-alginate (APA) microencapsulated MSCs, an adequate biofunctionalization strategy and the continuous presence of interferon-¿ (IFN-¿), hypothesizing that it would represent an integrated solution to (1) protect MSCs from the host immune system, (2) to promote their viability and (3) to boost their immunomodulatory properties. Therefore, here, we studied in depth and optimized each one of the three main elements. In particular, we established a tight control on APA-microencapsulated MSC behavior enhancing the biosafety of the therapy, we designed a biosensor that provides essential information about the specific MSC biofunctionalization requirements and we developed a strategy to boost the immunomodulatory properties of MSCs based on the inclusion of IFN-¿ and the 3D cell culture itself. These data represent an important step forward in the development of cell encapsulation systems, having significant implications in MSC therapies.