Stem Cell Biology and Bioengineering Laboratory

Stem Cell Mechanobiology

A decade ago, stem 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 stem 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 3 areas: 1) engineering niche that are more biomimetic to better understand the extent to which ECM properties regulate stem cell fate, 2) understanding the molecular signaling involved in relaying physical ECM cues to biochemical cues for the cell, and 3) using our understanding of ECM regulation and environment to better engineer stem cells and use them therapeutically with degenerative muscle diseases.

1) Developing New Engineered Microenvironments

Synthetic matrices 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 spatially appropriate presentation of ECM stiffness, e.g. stiffening over time or stiffness gradients, can itself improve cell maturation absent specific growth factors or instruct cells to form complex structures, e.g. mammary acinus. In addition to stiffness, we have examined other matrix cues, including topography, dynamically regulated topography, and ligand presentation. For examples, we created a foam scaffold with nano-scopic cell adhesive and non-cell adhesive domains to mimic the “patchy” adhesive regions within native ECM. Unlike uniformly adhesive substrates, interspersed adhesive spots support better cell adhesion, contractility, and more robust bone formation.

2) Mechanically-induced Cell Signaling

We have also tackled a vexing question in mechanotransduction: how do stem cells interpret ECM stiffness and convert it to a biochemical signal? While both cell contractility and transcription factors have been implicated, neither addresses what the actual sensor is. We hypothesized that some focal adhesion proteins could act as “molecular strain gauges” where under varying amounts of force, signaling sites could be exposed, initiating new signals that regulate stem cell differentiation. For example, we confirmed this hypothesis by showing that MAPK1-regulated muscle differentiation could be initiated via a conformational change in vinculin under force. Thus mechano-sensors are likely lineage-specific and require contractile force to expose cryptic signaling cites.

3) Cell-based Therapies for Degenerative Muscle Diseases

Clinically viable stem cell sources for therapies must be capable of harvesting large quantities of cells or expand them without loss of their abilities. Adult stem cells from fat (from the abdomen and rotator cuff) have become a promising source due to their availability and ability to become more mature muscle better than other adult counterparts. We are currently improving our ability to commit these cells into muscle and using them in in vivo muscle disease models including muscular dystrophy. For more information about our translational efforts, please click below to hear 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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