Effects of Matrix Mechanics on Secretion of Leukocyte Chemoattractants From Bone-Marrow Derived Mesenchymal Stromal Cells

Abstract

Recent advances in biology have revealed that inflammation may be a key link between a number of prevalent diseases including cardiovascular disease and cancer. That hypothesis is strengthened by the fact that inflammation is also associated with changes in tissue stiffness due to swelling and matrix deposition. Furthermore, inflammation stimulates hematopoiesis from the bone marrow and mobilizes leukocytes into the bloodstream. In bone marrow, mesenchymal stromal or stem cells (MSCs) located at sinusoids regulate leukocyte retention and mobilization by secreting chemoattractants. In addition, it is well known that MSCs have potent anti-inflammatory effects and that they can sense and respond to changes in matrix stiffness. However, little research has been done to explore how protein secretions are affected by mechanics. This study explores the hypothesis that changes in ma- trix stiffness regulate secretion of chemoattractants from MSCs under inflammatory conditions, which in turn regulate leukocyte migration. In vitro studies culturing MSCs in tunable, 3D alginate hydrogels show that the initial rate of secretion and maximal secretion levels of some chemokines are enhanced by matrix softening. In vitro leukocyte migration suggests increased migration of monocytes toward MSCs grown in this soft, stimulated condition. These results suggest that matrix mechanics is a key determinant that regulates the secretion of soluble proteins from MSCs and, in consequence, their role in regulating leukocyte migration. This research represents the power of combining material science and stem cell biology to lend insight into human biology and to advance cell based therapies like the use of MSCs as immunomodulatory agents.