Understanding the Tissue Microenvironment with Tiny Technologies
Human tissues are composed of mixtures of cells that cooperate in a healthy microenvironment to perform the necessary functions of that organ. In contrast, altered microenvironments are a hallmark of disease. While cell-specific processes such as those controlled by a cell's genes certainly influence the balance between health and disease, our focus is on interactions between cells and their microenvironment that occur on the length scales of receptor interactions (10 nm) to multicellular interactions (100 µm). We leverage engineering tools that have been created by the semiconductor community to speed rates of computation through miniaturized manufacturing capabilities. These micro-and nanotechnology tools, by virtue of their spatial resolution, enable the precise synthesis, interrogation, and perturbation of tissue microenvironments. Thus, we aim to dissect the role of the tissue microenvironment in both health and disease using engineering tools. Specifically, we focus on tissue microenvironments of clinical importance in liver biology and cancer, and we seek to translate our findings into new therapies for patients.
Hepatic Tissue Engineering
The liver has over 500 functions, including protein, carbohydrate, and lipid metabolism; detoxification of endogenous and exogenous compounds; production of bile for digestion; and secretion of many serum proteins (i.e. albumin, coagulation factors). Each year, over 40,000 people die due to liver failure in the US alone, with over 2 million deaths estimated worldwide. Orthotopic liver transplantation is the only proven therapy for liver failure; however, there is a severe shortage of donor organs. Cell-based therapies have been proposed as an alternative to whole organ transplantation, as a temporary bridge to transplantation, and/or an adjunct to traditional therapies during liver regeneration. The three main approaches that have been proposed are: transplantation of isolated hepatocytes, implantable tissue-engineered constructs, and perfusion of blood through an extracorporeal bioartifical liver device containing parenchymal liver cells called hepatocytes. Despite significant investigations into each of these areas, progress has been stymied due to the propensity for isolated hepatocytes to rapidly lose viability and key liver-specific functions upon isolation from the native microenvironment of the liver.
Our group uses microtechnology tools and biomaterials to synthesize 2D and 3D hepatic microenvironments to study determinants of cell fate and function and then perturb and interrogate these to model human disease. We have focused on (i) synthesizing human liver microenvironments for in vitro and in vivo interrogation and (ii) perturbing liver microenvironments with pathogens to model human disease. Some of our notable contributions include the discovery of small molecules that drive proliferation of adult hepatocytes and maturation of stem-cell derived progeny to enable sourcing of human hepatocytes (Shan, J. et al. Nat Chem Bio), and the development of the first high-throughput model systems to study hepatotropic pathogens (March, S. et al. 2013 Cell Host Mic; Ploss, A. et al. 2010 PNAS).
Cancer cells are embedded in a complex microenvironment that includes extracellular matrix and other cell types including endothelial cells, fibroblasts, and immune cells. Our research program exploits bioengineering tools to synthesize tumor microenvironments ex vivo to systematically probe the role of individual cues on cell fate, to interrogate the tumor microenvironment in situ, and to perturb the tumor by delivering therapeutic cargo that penetrates the tumor microenvironment. Some of our recent contributions have been to develop a new class of 'synthetic biomarkers' composed of peptide-decorated nanoparticles to monitor the tumor microenvironment noninvasively in the urine , and the discovery that tumor-penetrating peptides can deliver siRNA into tumors and silence 'undruggable' gene products with therapeutic impact.
Like hepatocytes, the fate of cancer cells is highly dependent on their interactions with the microenvironment. This recognition led us to apply the same technologies developed for dissecting the liver to understand how tumor microenvironments influence disease progression and suggest possible interventions. Paralleling our approach in the liver, we have focused on (i) synthesizing artificial tumor microenvironments, (ii) interrogating in vivo microenvironments with nanoparticle probes, and (iii) perturbing the tumor by delivering therapeutic cargo that penetrates the tumor microenvironment.
Some of this work was partially supported by grants from the National Institutes of Health, the National Science Foundation, the David and Lucile Packard Foundation, and the Bill and Melinda Gates Foundation.
As of March 8, 2016