The Thomson Lab at the Morgridge Institute for Research studies fundamental questions such as how cells maintain or change identities, how they choose between self-renewal and differentiation, how a differentiated cell with developmental potential can be reprogrammed to support human health benefits, and what the timing mechanisms are behind differences in mammalian gestation. The lab works to create physiologically stable, safe and functional cells to repair or replace diseased cells in humans, building on the vast human health potential of this field.
iPS Cell Tissue Engineered Arteries for Transplant
This is a collaborative project among WID Regenerative Biology lead Tom Turng (UW–Madison Department of Mechanical Engineering, Sam Poore (UW–Madison School of Medicine and Public Health), Naomi Chesler (UW–Madison Department of Biomedical Engineering), Igor Slukvin (UW–Madison Department of Pathology), Waisman Biomanufacturing, and the Thomson Lab. The goal is to derive each of the cellular components of the artery from iPS cells, assemble them into functional arteries on artificial scaffolds, and test their function after transplantation to monkey models as a prelude to clinical trials. Such arteries would be useful in heart bypass operations, or in transplants for peripheral artery disease, such as occurs in advanced diabetes.
This project is a dedicated effort by the Thomson Lab to better understand the timing mechanisms behind differences in mammalian gestation. While it makes sense that it takes longer to make a larger body, how the timing of developmental events is coordinated with differences in growth among species is largely unknown. Surprisingly, pluripotent stem cells recapitulate these differences in developmental timing in tissue culture, completely out of context of the intact organism; thus, making specific human cell types from pluripotent stem cells can take several months in a culture dish, with timing similar to that occurring in vivo. A basic understanding of a developmental clock will ultimately allow us to make mature physiologically normal human cells from pluripotent stem cell faster, making them more readily available for clinical applications. In addition, because developmental timing, body size, metabolic rate, and lifespan are all mathematically related, understanding what controls timing during embryogenesis may well offer insights into what controls the aging process.
Human Models for Analysis of Pathways (H-Maps) Center
A collaborative project including the Thomson Lab, Randy Ashton (UW–Madison Department of Biomedical Engineering), David Beebe (UW–Madison Department of Biomedical Engineering), Sushmita Roy (UW–Madison Department of Biostatistics and Medical Informatics) and Nader Shabani (UW–Madison Department of Ophthalmology & Visual Sciences), the goal of the establishment of the H-Maps Center is to advance the next generation of toxicity testing formats and to develop a broadly applicable set of tools for toxin screening. To that end, the Thomson Lab is seeking insight into the generation of pluripotent stem cell-derived cells that properly represent the diverse phenotypic characteristics of developing or mature human somatic cells, as well as the generation of organotypic cell culture models which are robust and reproducible. The primary goal of the project is to produce functionally mature embryonic stem cell-derived and induced pluripotent stem cell-derived hepatocytes in 3D organotypic cultures for use in toxicological studies.
This collaborative research with Igor Slukvin (UW–Madison Department of Pathology) focuses on new strategies to convert human pluripotent stem cells and somatic cells into engraftable hematopoietic stem cells (HSCs) by identifying the genetic and epigenetic programs leading to formation of pre-HSCs. In the past three decades, HSC transplantation has become the standard of care for treatment of many otherwise incurable diseases such as leukemia, lymphoma, and multiple myeloma. However, insufficient availability of donor HSCs, graft failure or graft-versus-host disease, and other challenges significantly hamper improvements in HSC use in oncology and gene therapy. We also are exploring the production of other therapeutically useful blood cells, including myeloid cells for the treatment of bone marrow suppression occurring during chemotherapy.
Human Cellular Models for Neural Toxicity and Disease
This project is a collaboration among the Thomson Lab, UW–Madison Biomedical Engineering faculty member Bill Murphy, and UW–Madison Computer Science faculty member David Page to develop improved in vitro models for predicting neural toxicity. The project is funded through the first-ever collaboration between the NIH, FDA, and DARPA to improve the speed, cost, and effectiveness of drug development. We are separately differentiating human pluripotent stem cells to early precursors of the major neural, glial, and vascular components of the forebrain, then combining them in 3D hydrogel assemblies to allow increased physiological interactions and maturation. After drug exposure, we are assessing temporal changes in gene expression by these neural-vascular assembles using highly multiplexed, deep RNA sequencing. Then, using safe drugs and known neural/developmental toxins from the University of Washington TERIS and the EPA’s Toxicity Reference Databases as training sets, we develop machine learning algorithms to predict neural toxicity of blinded drugs known to have failed in late stage animal testing or human clinical trials.
The Stewart Bioinformatics Group is one of the major strengths of the Morgridge Regenerative Biology platform, as funding for such a team is generally not available through standard NIH grants. Working closely with wet lab scientists, the Stewart Bioinformatics Group designs experiments using high-density microarrays, Illumina Next-Generation sequencing, and other methods for studying gene regulation in embryonic stem cells, induced pluripotent stem cells, and their derivatives. The Stewart Group employs an impressive array of expertise in computer science, biology, mathematics and statistics, while providing a critical tool that supports all of the Thomson Lab’s scientific projects. Frequent collaborators include UW–Madison Department of Biostatistics & Medical Informatics members Christina Kendziorski, Mark Craven, and Colin Dewey. Current areas of interest beyond the projects already mentioned include regeneration of the salamander limb and clocking mechanisms regulating development. Outstanding bioinformatics support for Regenerative Biology scientists and their UW–Madison collaborators continues to remain a major goal of the Stewart Bioinformatics Group. Learn more >
Mechanisms of self-renewal and tissue complexity
The focus of the Vereide Group and frequent collaborator David Beebe (UW–Madison Department of Biomedical Engineering, these projects examine two biological phenomena exhibited by stem or progenitor cells: their capacity to self-renew and their ability to give rise to complex tissues and organs. Self-renewal is the power to proliferate, producing daughter stem or progenitor cells. Given the proper conditions in culture in the laboratory, different types of stem or progenitor cells can self-renew endlessly. Our goal is to understand and harness the self-renewing capacity of stem cells to solve human health problems. For example, we have recently developed a novel method to propagate the human precursors of the endothelium (inner lining) of arteries, blood vessels that carry oxygen and nutrients to organs and tissues. Now equipped with a continuous supply of arterial endothelial cells, we aim to model key events during cardiovascular disease (which occurs primarily in arteries) and develop cell-based platforms for drug discovery. Stem and progenitor cells also can build structures. During development, their precise arrangements lay the foundations of all tissues and organs. Using the chick embryo as a model organism, we seek to understand the mechanisms of gastrulation (the formation of early tissue layers) and subsequent organogenesis (the formation of all major organs in the body). The ultimate goal of these studies is to use the insights obtained from the developing chick to enable the generation of complex human tissues, or even organs, to replace ones damaged by disease or trauma.