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Abstract
Human bone marrow mesenchymal stromal cells (MSCs) are used in clinical trials for the treatment of systemic inflammatory diseases due to their regenerative and immunomodulatory properties. However, intravenous administration of MSCs is hampered by cell trapping within the pulmonary capillary networks. Here, it is hypothesized that traditional 2D plastic‐adherent cell expansion fails to result in appropriate morphorheological properties required for successful cell circulation. To address this issue, a method to culture MSCs in nonadherent 3D spheroids (mesenspheres) is adapted. The biological properties of mesensphere‐cultured MSCs remain identical to conventional 2D cultures. However, morphorheological analyses reveal a smaller size and lower stiffness of mesensphere‐derived MSCs compared to plastic‐adherent MSCs, measured using real‐time deformability cytometry and atomic force microscopy. These properties result in an increased ability to pass through microconstrictions in an ex vivo microcirculation assay. This ability is confirmed in vivo by comparison of cell accumulation in various organ capillary networks after intravenous injection of both types of MSCs in mouse. The findings generally identify cellular morphorheological properties as attractive targets for improving microcirculation and specifically suggest mesensphere culture as a promising approach for optimized MSC‐based therapies.
Highlights
Human bone marrow mesenchymal stromal cells (MSCs) are used in morphology, fibroblast colony-forming unit (CFU-F) capacity, multilineage difclinical trials for the treatment of systemic inflammatory diseases due to ferentiation potential,[1,2] and immutheir regenerative and immunomodulatory properties
Morphorheological analyses reveal a smaller size and lower stiffness of mesensphere-derived MSCs compared to plastic-adherent MSCs, measured using real-time their immunosuppressive effects and tissue regenerative potential, MSCs have been used in clinical trials testing therapies for various diseases including graft-versus-host disease (GvHD) after deformability cytometry and atomic force microscopy
Using atomic force microscopy (AFM) indentation measurement and real-time deformability cytometry (RT-DC), we found that 3D-expanded MSCs were smaller and more compliant
Summary
Mesenspheres Comprise Multipotent, Self-Renewable, and Immunomodulatory MSCs Capable of Hematopoietic Stem and Progenitor Cell Support. We found that mesenspheres exhibit multilineage differentiation potential (Figure S1A–E, Supporting Information). BM-derived MSCs have been shown to support hematopoietic stem and progenitor cell (HSPC) maintenance and engraftment.[37] We confirmed HSPC expansion with clonogenic and appropriate differentiation potential in coculture with mesenspheres (Figure S2A–G, Supporting Information). Together, these results show that the biological properties of mesensphere-derived MSCs are identical to those cultured conventionally on rigid 2D plastic surfaces. After intravenous administration of such expanded MSCs cell delivery to target tissues is limited as a result of cell trapping within the pulmonary capillary networks.[23]
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