Engineered anomaterials including carbon nanotubes (CNTs) have emerged as one of the most important classes of new materials having enormous potential to create new and better products. Accumulating evidence indicates that pulmonary exposure to CNTs induces lung fibrosis, a fetal and incurable lung disease with no known effective treatments. The long-term objective of this project is to enable safe nanotechnology through the understanding of underlying mechanisms of fibrogenesis and determining key physicochemical factors controlling the fibrogenic effect of nanomaterials. Evolving research indicates that fibroblast stem cells (FSCs) with unlimited proliferative potential are likely a driing force of fibrosis, but the underlying mechanisms and their role in CNT fibrogenesis are not known. We have obtained breakthrough evidence showing the ability of CNTs to induce FSCs with a functional phenotype of activated fibroblasts that are responsible for extracellular matrix accumulation, a hallmark of lung fibrosis. We hypothesize that CNTs induce lung fibrosis through a process that involves FSC induction and that such induction is dependent on specific physicochemical properties of CNT.
Three specific aims are proposed to test the hypotheses.
In Aim 1, we will characterize FSC acquisition in CNT-treated fibroblasts and animals and determine their role in fibrogenesis.
Aim 2 will develop 3D high-throughput fibroblastic nodule models for quantitative assessment of CNT fibrogenicity and document the impact of CNT characteristics on FSC acquisition and fibrogenesis.
This Aim will also identify specific FSC biomarkers and validate the in vitro models in animals.
Aim 3 will examine redox regulation of FSC development and fibrogenesis, and determine specific oxidative species and key regulatory enzymes involved in the process. Our expectations are that at the conclusion of this project, we will have determined the role of FSCs in CNT fibrogenesis and identified specific biomarkers and key physicochemical properties of CNTs that influence their fibroticity. This work is important because of the overall impact it will have on the development of safe nanomaterials as well as on risk assessment, early detection and prevention of nanomaterial-induced fibrosis. We expect this impact to be broad since the findings from this project are highly applicable to other fibrogenic agents, nanomaterials and xenobiotics. The proposed work is innovative because it is the first to study FSCs and their role in fibrosis. It will also develop novel experimental models and assay methods for rapid assessment of nanomaterial fibrogenicity and for their potential utility in various stem cell applications.

Public Health Relevance

Nanotechnology presents enormous opportunities to create new and better products for industrial and commercial applications. However, the potential adverse health effects of nanomaterials are unclear, which limit their safe use in humans. This project addresses the NIH goals and public health needs by 1) determining the fibrogenicity of nanomaterials and identifying key physicochemical properties and biological factors influencing the fibrogenicity, 2) developing novel high throughput assays for predictive screening of nanomaterial fibrogenicity, and 3) elucidating the underlying mechanisms of fibrogenesis and identifying specific biomarkers and molecular targets for risk assessment, prevention and treatment of the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB018857-02
Application #
9212809
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Hunziker, Rosemarie
Project Start
2016-02-01
Project End
2020-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
2
Fiscal Year
2017
Total Cost
$303,750
Indirect Cost
$101,250
Name
West Virginia University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
191510239
City
Morgantown
State
WV
Country
United States
Zip Code
26506
He, Xiaoqing; Kiratipaiboon, Chayanin; Porter, Dale W et al. (2018) Predicting Nanotube Fibrogenicity through Stem Cell-Mediated Fibroblast Focus and Spheroid Formation. Nano Lett 18:6500-6508
Wang, Peng; Voronkova, Maria; Luanpitpong, Sudjit et al. (2017) Induction of Slug by Chronic Exposure to Single-Walled Carbon Nanotubes Promotes Tumor Formation and Metastasis. Chem Res Toxicol 30:1396-1405
Powan, Phattrakorn; Luanpitpong, Sudjit; He, Xiaoqing et al. (2017) Detachment-induced E-cadherin expression promotes 3D tumor spheroid formation but inhibits tumor formation and metastasis of lung cancer cells. Am J Physiol Cell Physiol 313:C556-C566
Wang, Kai; He, Xiaoqing; Linthicum, Will et al. (2017) Carbon Nanotubes Induced Fibrogenesis on Nanostructured Substrates. Environ Sci Nano 4:689-699
Stueckle, Todd A; Davidson, Donna C; Derk, Ray et al. (2017) Effect of surface functionalizations of multi-walled carbon nanotubes on neoplastic transformation potential in primary human lung epithelial cells. Nanotoxicology 11:613-624
He, Xiaoqing; Wang, Liying; Riedel, Heimo et al. (2017) Mesothelin promotes epithelial-to-mesenchymal transition and tumorigenicity of human lung cancer and mesothelioma cells. Mol Cancer 16:63
Voronkova, Maria A; Luanpitpong, Sudjit; Rojanasakul, Liying Wang et al. (2017) SOX9 Regulates Cancer Stem-Like Properties and Metastatic Potential of Single-Walled Carbon Nanotube-Exposed Cells. Sci Rep 7:11653
Stueckle, Todd A; Davidson, Donna C; Derk, Raymond et al. (2017) Evaluation of tumorigenic potential of CeO2 and Fe2O3 engineered nanoparticles by a human cell in vitro screening model. NanoImpact 6:39-54
He, Xiaoqing; Despeaux, Emily; Stueckle, Todd A et al. (2016) Role of mesothelin in carbon nanotube-induced carcinogenic transformation of human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 311:L538-49
Luanpitpong, Sudjit; Wang, Liying; Castranova, Vincent et al. (2016) Induction of cancer-associated fibroblast-like cells by carbon nanotubes dictates its tumorigenicity. Sci Rep 6:39558

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