CuSTOM Research Programs
CuSTOM investigators use animal models and state-of-the art single cell genomics to elucidate the cell signaling networks and genetic programs controlling normal embryonic organ development. We apply the knowledge learned from animal models to direct the differentiation of human pluripotent stem cells (hPSCs)into organoids. These organoids in turn provide an unprecedented system to study the mechanisms of human organogenesis. Our current focus includes; liver, intestine, pancreas, lungs and kidney.
Stem CellsHuman pluripotent stem cells (PSCs) can be grown indefinitely in a petri dish and have the potential to form any cell or tissue type in the body. CuSTOM scientists are using PSCs as a tool to study the normal processes that drive organ development and to uncover the molecular basis of human birth defects. Leveraging information from organogenesis in animal models we are establishing new methods to direct the differentiation PSCs into 3-dimensional organ tissues called organoids. PSCs derived from patients allow CuSTOM researchers to study human disease in an unprecedented way and are leading to better diagnoses and new avenues for improved patient care.
The Takebe lab has pioneered the development of complex liver organoids made by combining hPSC-derived hepatoblasts, endothelial cells and mesenchyme. Investigating the mechanisms of self-organizing hepatogenesis at the single cell level is providing new insight into human liver development. CuSTOM investigators are using liver organoids generated from healthy individuals and patients to model liver disease, study population variation in the pathogenesis and response to therapy, establish new models for drug screening, and ultimately to replace liver dysfunction by transplantation.
A team of CuSTOM investigators led by the Wells lab are world leaders in hPSC-derived gastrointestinal (GI) organoids. Leveraging studies on GI development in animal models the team has generated colon, stomach intestinal organoids. These complex multi-lineage organoids contain a diversity of epithelial and mesencymal cell types similar to the normal GI tract and can be reconstituted with enteric neurons. These GI organoids are being used to study human gut development, hormonal regulation of digestion and obesity, model GI disease. Watch video.
Modeling Genetic Disease
CuSTOM investigators are using organoids made from patient derived iPSCs and CRIPR/Cas-9 mediated gene editing to model pediatric diseases in a dish. In synergy with the Cincinnati Children’s Center for Pediatric Genomics we are investigating the genetic basis of pediatric diseases and studying how mutations can disrupt fetal organ development and physiology. Current studies include Trachea-esophageal birth defects as well as genetic forms of pediatric liver cholestasis, interstitial lung disease and endocrine insufficiency with the goal of understanding pathobiology. Watch video.
Modeling Neurological Disease Using Human Pluripotent Stem CellsThe Guo Lab applies cutting-edge stem cell technologies including iPSCs, organoids and transdifferentiation to study the etiology of neurodevelopmental (e.g. schizophrenia and autism) and neurodegenerative (e.g. AD and ALS) disorders in a human genetic context. The Guo Lab has generated multiple iPSC lines, including schizophrenia, autism, Fragile X syndrome and ALS. Dr. Guo and his Lab will use patient iPSCs-derived region-specific neurons (including forebrain glutamatergic, GABAergic, midbrain dopaminergic and motor neurons) and brain organoids to investigate brain disorders; combining electrophysiology, imaging, immunocytochemistry, molecular biology, and genetic approaches.
The Tchieu Lab research is focused on investigating how the support cells in our brain (such as astrocytes and microglia) are impacted in neurological disorders. Due to the inaccessibility of primary human tissue, the Tchieu Lab develops strategies to derive these support cells from human pluripotent stem cells. This work has shed light on the mechanisms behind the neurogenic-to-gliogenic switch in human neural stem cells and enables the rapid generation of astrocytes for the use in human disease modeling. With CuSTOM, the Tchieu Lab’s focus is on using stem cell-derived glial cells and innovative brain organoids to study early human neurodevelopment and apply this knowledge in understanding how neurological diseases manifest.
Modeling Vascular Abnormalities in the Heart, Lung, and Brain
The Gu Lab utilizes patient-specific iPSC derived endothelial and smooth muscle cells, as well as vessel organoids to explore the role of vascular deficiency in the etiology of heart, lung, and brain diseases. Recent efforts have largely focused on generating vascularized heart, lung, and brain organoids to better understand the cell-cell communication during development and disease. By analyzing both iPSC derivatives and patient native tissue with vascular lesion, the team has uncovered novel disease-specific cellular phenotypes and identified transcriptomic and epigenomic changes at single-cell resolution. The Gu Lab is also developing a high-throughput drug screening platform and machine learning algorithm to identify compounds that reverse the fundamental pathobiology of the disease in a personalized manner.
Translational researcher at CuSTOM use organoids derived from patients to understand mechanisms of disease and to identify new therapeutic targets. Patient-derived organoids are used for personalized drug screening and to understand how genetics variation in the population impact differences in disease progression and drug response. CuSTOM investigators in the Helmrath and Takebe labs have transplanted intestinal and liver organoids into animals as a proof of principle of tissue replacement therapy. Watch video.