Differentiation of stem cells and muscle cells: computational insights into effects of matrix elasticity & role of adhesive signaling protein

Mr. Shamik Sen, Ph.D. Candidate
Advisor: Prof. Dennis Discher
Department of Mechanical Engineering and Applied Mechanics
University of Pennsylvania

Abstract
Microenvironments would appear to be broadly important in cell biology, but can be difficult to physically characterize and understand with soft tissues. Mesenchymal stem cells (MSCs) are first shown to specify lineage and commit to phenotypes with extreme sensitivity to tissue level elasticity. Soft matrices that mimic brain are neurogenic, stiffer matrices that mimic muscle are myogenic, and comparatively rigid matrices that mimic collagenous bone prove osteogenic. A computational framework is developed within the small strain regime to understand the role of cell geometry, prestress, matrix thickness, and cell density on the extracellular stress-strain distributions that seem likely to be factors in differentiation. By varying the cell and gel compliances we compare the strain distributions in the gel that would potentially elicit cytoskeletal reorganization in the cell. Since adhesion and its downstream effects appear key to the tactile responses of cells, we overexpress an adhesion "scaffolding" protein known as paxillin in muscle cells.

Paxillin overexpression leads to hypercontractile and stiffer myotubes, promotes differentiation and protects against pharmacological dedifferentiation, but it has no physically measurable effect on adhesions. Together with signaling insights from a library of proteins in normal and diseased muscle, we map out the dynamic mechano-activating signaling of paxillin in survival and differentiation.  The results collectively show that cells adhere to and collect mechanical signals from soft elastic microenvironments in ways that influence differentiation and disease.

Thursday, November 30th
2 PM, 337 Towne Bldg.