Matrix stiffness and viscoelasticity influence human mesenchymal stem cell immunomodulation

Human mesenchymal stem cells (hMSCs) have immense wound healing potential due to their immunomodulatory behavior. To control this behavior and reduce heterogeneity, researchers look to biomaterials, as matrix stiffness and viscoelasticity have been shown to control hMSC immunomodulation. However, the understanding of the effects of these biophysical cues on hMSC immunomodulation remains limited; a broad study investigating the potentially synergistic effects of matrix stiffness and viscoelasticity on hMSC immunomodulation is needed in order to support future work developing biomaterials for hMSC wound healing applications. We developed polyacrylamide (PAAm) gels with varying matrix stiffnesses with or without a viscoelastic element and explored the effects of these on hMSC-matrix interactions and immunomodulatory cytokine expression in both a normal growth media and an immunomodulatory growth media mimetic of a chronic, non-healing wound. Expression of IL-10, VEGF, and PGE₂ were upregulated in immunomodulatory growth media over normal growth media, demonstrating the synergistic effects of biochemical signaling on hMSC immunomodulatory behavior. In addition, the addition of a viscoelastic element had both inhibitory and accentuating effects based on the cytokine and biochemical signaling in the cell culture media. Overall, this study provides a broad perspective on the immunomodulatory behavior of hMSCs due to stiffness and viscoelasticity.