Stimuli-Responsive Substrates to Control the Immunomodulatory Potential of Stromal Cells.

Mesenchymal stromal cells (MSCs) have broad immunomodulatory properties that range from regulation, proliferation, differentiation, and immune cell activation to secreting bioactive molecules that inhibit inflammation and regulate immune response. These properties provide MSCs with high therapeutic potency that has been shown to be relevant to tissue engineering and regenerative medicine. Hence, researchers have explored diverse strategies to control the immunomodulatory potential of stromal cells using polymeric substrates or scaffolds. These substrates alter the immunomodulatory response of MSCs, especially through biophysical cues such as matrix mechanical properties. To leverage these cell-matrix interactions as a strategy for priming MSCs, emerging studies have explored the use of stimuli-responsive substrates to enhance the therapeutic value of stromal cells. This review highlights how stimuli-responsive materials, including chemo-responsive, microenvironment-responsive, magneto-responsive, mechano-responsive, and photo-responsive substrates, have specifically been used to promote the immunomodulatory potential of stromal cells by controlling their secretory activity.

Peptoid-Cross-Linked Hydrogel Stiffness Modulates Human Mesenchymal Stromal Cell Immunoregulatory Potential in the Presence of Interferon-Gamma.

Human mesenchymal stromal cell (hMSC) manufacturing requires the production of large numbers of therapeutically potent cells. Licensing with soluble cytokines improves hMSC therapeutic potency by enhancing secretion of immunoactive factors but typically decreases proliferative ability. Soft hydrogels, however, have shown promise for boosting immunomodulatory potential, which may compensate for decreased proliferation. Here, hydrogels are cross-linked with peptoids of different secondary structures to generate substrates of various bulk stiffnesses but fixed network connectivity. Secretions of interleukin 6, monocyte chemoattractive protein-1, macrophage colony-stimulating factor, and vascular endothelial growth factor are shown to depend on hydrogel stiffness in the presence of interferon gamma (IFN-γ) supplementation, with soft substrates further improving secretion. The immunological function of these secreted cytokines is then investigated via coculture of hMSCs seeded on hydrogels with primary peripheral blood mononuclear cells (PBMCs) in the presence and absence of IFN-γ. Cocultures with hMSCs seeded on softer hydrogels show decreased PBMC proliferation with IFN-γ. To probe possible signaling pathways, immunofluorescent studies probe the nuclear factor kappa B pathway and demonstrate that IFN-γ supplementation and softer hydrogel mechanics lead to higher activation of this pathway. Overall, these studies may allow for production of more efficacious therapeutic hMSCs in the presence of IFN-γ.