Dynamic Stiffness Reveals New Cardiac Phenotypes in Patient‐Derived iPSCs

Abstract

After nearly a decade of recognition that extracellular matrix (ECM) properties can influence cell behavior to similar degree as growth factors, in particular ECM composition, topography, porosity, and stiffness, biologists have come to recognize its importance. However matrix is highly dynamic, changing how much of it is secreted and assembled during development and disease. Most synthetic ECM mimics made initially to study this phenomenon were static but there is growing interest in making matrices that have tunable properties with time. To accomplish this, my lab has created hyaluronic acid (HA)‐based materials that crosslink themselves spontaneously or via UV‐sensitive reactions to provide slow or “on‐demand” changes in stiffness. By knowing the dynamics of matrix assembly during heart development as well as heart remodeling post‐heart attack, we have used these HA materials to model how the heart tube stiffens or the onset of fibrosis (i.e. “heart attack‐in‐a‐dish”), respectively, to understand how temporal changes in stiffness better instruct differentiation and function. Using an embryonic heart model, we have found that developmentally appropriate stiffening can drive maturation and sarcomere assembly in pre‐cardiac mesoderm. Conversely using patient‐derived induced pluripotent stem cells (iPSCs) in HA that models a “heart attack‐in‐a‐dish,” we have identified new cardiac phenotypes in diseased cardiomyocytes that were previous masked by other conditions in patients. We have also used the materials to study cardiac disease mechanisms, since often phenotypes do not appear until cells are stressed by the “heart attack‐in‐a‐dish” conditions. Based on these exciting results, we believe that any in vitro culture system should employ dynamic materials that change as the niche does in vivo.Support or Funding InformationNIA/NIH, NHLBI/NIH, NSF, and AHA