Engineering mesenchymal stromal cell constructs to enhance immunomodulation
Zimmermann, Joshua A.
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Mesenchymal stem/stromal cells (MSCs) are potent modulators of inflammatory and immune responses due to their ability to secrete soluble paracrine factors that regulate both innate and adaptive immunity and repolarize cells from pro-inflammatory to anti-inflammatory or pro-resolving phenotypes. The ability of MSCs to modulate multiple components that contribute to the complexity of an immune response further motivates the use of MSCs to treat diseases such as graft-versus host disease, inflammatory bowel disease, and autoimmune disorders. Multiple paracrine and immunomodulatory factors are expressed by MSCs that mediate suppression of immune cells and the coordinated action of the immunomodulatory secretome of MSCs is necessary to regulate complex immune responses. Importantly, many of these immunomodulatory factors are not constitutively expressed by resting MSCs and their expression is strongly induced by exposure of MSCs to inflammatory cytokines. Thus, MSC immunomodulation is highly dependent on the local inflammatory milieu to activate immunomodulatory factor expression and the efficacy of MSC-based cellular therapies is therefore highly dependent on the in vivo environment they are exposed to after injection. This environment may be highly variable based on the individual and disease being treated, the stage of inflammation, and the site of MSC transplantation. Therefore, the objective of this dissertation was to develop strategies to enhance intrinsic MSC immunomodulatory activity to improve cellular therapies for the treatment of inflammatory and immune diseases. Three-dimensional MSC constructs offer a promising approach to control the microenvironment and thereby the immunomodulatory activity of MSCs while also enhancing acute cell survival and persistence after transplantation in vivo. Furthermore, engineering the physical and chemical elements of the MSC construct microenvironment through biomaterial-based approaches serves as a novel route to regulate the temporal presentation of inflammatory factors in order to sustain immunomodulatory activity in vivo. Altogether, this strategy offers a novel translatable means of controlling MSC paracrine activity post-transplantation and therefore, improve the efficacy of MSC-based treatment strategies for inflammatory and immune diseases.