期刊
STEM CELLS TRANSLATIONAL MEDICINE
卷 10, 期 8, 页码 1184-1201出版社
OXFORD UNIV PRESS
DOI: 10.1002/sctm.19-0414
关键词
bone marrow stromal cells; cell therapy; cytokines; MSCs
资金
- National Science Foundation [DMR-1306482, DGE-1256259]
- U.S. Environmental Protection Agency [83573701]
- Biotechnology Training Program NIGMS [5T32-GM08349]
- National Institutes of Health [R01HL093282]
- UW-Madison [P30 CA014520]
This study compared MSC aggregates generated via three different methods and found differences in their structure and immunomodulatory phenotype under resting conditions and in response to inflammatory stimulus. The methods with faster aggregation kinetics formed aggregates with higher cell packing density and reduced ECM synthesis.
Human mesenchymal stromal cells (MSCs) are promising candidates for cell therapy due to their ease of isolation and expansion and their ability to secrete antiapoptotic, pro-angiogenic, and immunomodulatory factors. Three-dimensional (3D) aggregation self-activates MSCs to augment their pro-angiogenic and immunomodulatory potential, but the microenvironmental features and culture parameters that promote optimal MSC immunomodulatory function in 3D aggregates are poorly understood. Here, we generated MSC aggregates via three distinct methods and compared them with regard to their (a) aggregate structure and (b) immunomodulatory phenotype under resting conditions and in response to inflammatory stimulus. Methods associated with fast aggregation kinetics formed aggregates with higher cell packing density and reduced extracellular matrix (ECM) synthesis compared to those with slow aggregation kinetics. While all three methods of 3D aggregation enhanced MSC expression of immunomodulatory factors compared to two-dimensional culture, different aggregation methods modulated cells' temporal expression of these factors. A Design of Experiments approach, in which aggregate size and aggregation kinetics were systematically covaried, identified a significant effect of both parameters on MSCs' ability to regulate immune cells. Compared to small aggregates formed with fast kinetics, large aggregates with slow assembly kinetics were more effective at T-cell suppression and macrophage polarization toward anti-inflammatory phenotypes. Thus, culture parameters including aggregation method, kinetics, and aggregate size influence both the structural properties of aggregates and their paracrine immunomodulatory function. These findings underscore the utility of engineering strategies to control properties of 3D MSC aggregates, which may identify new avenues for optimizing the immunomodulatory function of MSC-based cell therapies.
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