Mechanical Programming of Mesenchymal Stromal Cells for Immunomodulation

Mesenchymal stem/stromal cells (MSCs) have been tested in a number of clinical trials due to their anti-inflammatory efficacy even in the absence of major donor cell engraftment. This highlights the importance of better understanding how adoptively transferred MSCs respond to inflammatory environments and modulate the immune system in the host. While hydrogels have been used for prolonged donor cell delivery by physical protection from the host, it remains unclear whether mechanical parameters of hydrogels can be leveraged to biophysically control cytokine production from donor MSCs through mechanotransduction. We have begun to uncover relationships between different parameters of matrix mechanics and specific immunomodulatory mechanisms by MSCs. Matrix stiffness modulates the ability of MSCs to respond to TNFα and recruit immune cells by regulating NF-kB activation. In contrast, the volume ratio between the matrix and the cell, not matrix stiffness, regulates the ability of MSCs to respond to IFNγ. In the absence of inflammatory stimulation, matrix stiffness influences constitutive secretion of some cytokines from MSCs and primes them for anti-inflammatory functions. The results thus provide a mechanistic basis for encapsulating MSCs in hydrogels with defined mechanical parameters to achieve maximal immunomodulatory efficacy. Controlling matrix mechanics at the single cell level will not only enable the translation of these insights into MSC therapy but also help reveal cell-to-cell heterogeneity in mechanical regulation of immunomodulation.