Stem Cell Biology and Bioengineering Laboratory

Mechanobiology of Cardiovascular and Musculoskeletal Diseases and Cancer

A decade ago, cells were thought to primarily respond to the growth factors and other cells that make up their environment. The Engler lab, and the broader field of mechanobiology, has shown that many cells are also sensitive to physical cues from the surrounding extracellular matrix (ECM), the fibrous scaffold to which cells adhere. We set out to determine the breadth and depth of their sensitivity to ECM properties to further this understand how physical cues guide stem cells by focusing on 1) engineering niche that are more biomimetic to better understand the extent to which ECM properties regulate stem cell fate and 2) understanding the molecular signaling involved in relaying physical ECM cues to biochemical cues for the cell.

Synthetic materials typically lack spatiotemporal dynamics, which normal matrix has and which may regulate appropriate tissue development. Using Michael-type addition-, free radical-, and photoactivated-based crosslinking, we have engineered polyacrylamide-, hyaluronic acid-, diblock copolymer-, and collagen-based materials to display spatiotemporal changes in stiffness. These materials enabled us to prove that developmentally or disease-specific presentation of ECM stiffness, e.g. stiffening over time or stiffness gradients, can better direct cell fate or induce the phenotypes we expect to observe from disease. Such studies improve phenotypes observed from disease-in-a-dish models of induced pluripotent stem cells (iPSCs). Working with UC San Diego and other area cardiologists, we have used our engineered materials (e.g. heart attack-in-a-dish) to observe new phenotypes in iPSCs. Some of our past efforts in skeletal muscle are highlighted in Dr. Engler's presentation at the 2013 "Stem Cell Meeting on the Mesa."

Heart Physiology and Mechanics during Aging

Understand how aging affects heart function is very time consuming in mice and rats, which require years to become geriatric. Using model organisms with short lifespans, well characterized genetics, and similar cell biology to humans, we can alter our signaling pathways of interest and determine how they function in a matter of weeks. Given our expertise in cell mechanics, we have created several novel tools to understand how the heart of Drosophila melanogaster changes its function when aging from juvenile to geriatric. Despite being a rapidly aging, genetically tractable model organism with a cardiac proteome that is 82% conserved with mammals, the Drosophila heart is a soft, multilayered tube unlike humans. To be able to measure the stiffness of the tube, we developed the first linear transformation method to analyze individual layer elasticity within a soft, multilayered material by atomic force microscopy and applied it to the fly heart tube. We have also helped develop active mechanical measurements of fly physiology to assess contractile function. Using microarrays and these analysis methods, we are identifying several molecular mechanisms of age-associated remodeling at cell junctions and determining their function in flies and higher mammals to assess the conservation of those mechanisms. Flies also lend themselves well to longevity studies, which we have recently partnered with a local charter high school, High Tech High, to conduct. For more information about the project and our outreach efforts, please click below to find out more.

Engler Lab
Department of Bioengineering
University of California, San Diego

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