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Our lab studies assemblies that occur in the spaces between cells. These extracellular structures range from nanoscale cell membrane-tethered assemblies to macroscopic components of the extracellular matrix (Fig. 1). They are the infrastructure that a community of cells builds. Like our roads, houses, and spaceships, they help cells combine their individual efforts and survive in their environment.
Figure 1. All multicellular systems, from bacterial colonies to human brains, deposit molecular assemblies in the spaces between their cells. These assemblies form an interconnected, organism-wide network, which includes the glycocalyx (nanoscale cell membrane-tethered structures), basement membranes (sheet-like structures separating cell populations), interstitial matrix (hydrogel and fibrous structures permeating intercellular spaces), and connective tissues (larger structures such as tendons, cartilage, and bone). Generally, the glycocalyx is distinguished from the other three categories, which are collectively called the extracellular matrix (ECM).
Extracellular assemblies are involved in most multicellular processes, from embryonic tissue patterning to wound healing, and drive progression of diseases including fibroses, muscular dystrophies, autoimmunity, neurodegeneration, and cancer. They feature three core properties (Fig. 2):
(i) Multicellular deposition. Extracellular structures are often built by multiple cells using dozens of secreted components that self-assemble in extracellular spaces.
(ii) Combinatorial biosynthesis. Nearly all extracellular biomolecules are glycoconjugates, meaning they are modified with complex glycans that are synthesized via a combinatorial enzymatic process in the ER and Golgi.
(iii) Formation of architectures. Functional attributes of a given assembly depend not only on the identities of its components but also on their spatial arrangements, which define aggregate biochemical characteristics (e.g., avidity pockets) and bulk physical characteristics (e.g., stiffness).
Figure 2. Three core properties of extracellular assemblies, which present both challenges and opportunities to researchers and biotechnologists.
As a result of these properties, workhorse methods such as genetics, sequencing, and in vitro biochemistry, when applied alone, have historically been underpowered for studying extracellular assemblies. Our lab is taking a bet on methods rooted in chemical biology and advanced imaging, which allow us to measure and modulate structures and events in situ. Current projects center on imaging-based screens of extracellular phenotypes, biosensor development for functional imaging, electron microscopy (EM) methods that better preserve the glycocalyx and ECM, and cryo-EM approaches for atomic-scale characterization of disease-driving extracellular assemblies (Fig. 3-4). Broadly, we aim to discover principles by which extracellular assemblies govern mammalian biology across spatial scales, develop therapies that take advantage of the unique and underexplored properties of extracellular biomolecules, and widely distribute methods that will allow others to join those long-term efforts.
Figure 3. 2-photon fluoroscence microscopy of live mouse tissue, with fibers of the extracellular matrix labeled using Rhobo6.
Figure 4. Transmission electron micrograph of the glycocalyx (G) of a mouse capillary, stained with lanthanum nitrate.
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