Page 53 - Hormel Report 2023

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Human Lung Organoids for Modeling Lung Fibrosis.
Lung organoid models developed in Dr. Tan’s lab allows recapitulation of in vivo microenvironments and maintaining cellular identity within 3D co-cul- tures, providing a platform for studying pulmonary fibrosis in vitro using patient-derived lung cells or human iPSCs. S100A2 was found to be a highly up-regulated gene in IPF epithelial cells that increased in both noise and entropy, suggesting erratic up-regulation in IPF. However, S100a2 is
not induced in mice lung fibrosis models. Human lung organoid provides a good platform for those targets that are not working in animal models. Current experiments are underway to determine the effects of S100A2 in human iPSC-derived alveolar type 2 epithelial cells (iAT2) organoid culture.
PUBLICATION HIGHLIGHTS:
• Tan Q , Link, P. A., Meridew, J. A., Pham, T. X., Caporarello, N., Ligresti, G., & Tschumperlin, D. J. (2021). Spontaneous Lung Fibrosis Resolution Reveals Novel Antifibrotic Regulators. Am J Respir Cell Mol Biol, 64(4), 453-464.
• Liu, W., Meridew, J. A., Aravamudhan, A., Ligresti,
G., Tschumperlin, D. J., & Tan, Q. (2019). Targeted regulation of fibroblast state by CRISPR-mediated CEBPA expression. Respir Res, 20(1), 281.
• Tan, Q., Ma, X. Y., Liu, W., Meridew, J. A., Jones, D. L., Haak, A. J., Sicard, D., Ligresti, G., & Tschumperlin,
D. J. (2019). Nascent Lung Organoids Reveal Epithelium- and Bone Morphogenetic Protein-mediated Suppression of Fibroblast Activation. Am J Respir Cell Mol Biol, 61(5), 607-619.
• Tan, Q., & Tschumperlin, D. J. (2018). Epigenome Editing Enters the Arena. A New Tool to Reveal (and Reverse?) Pathologic Gene Regulation. Am J Respir Crit Care Med, 198(5), 549-551.
Cellular Identity and Reprogramming in Lung Regeneration.
Cell fate is not permanently locked in adult lung cells and can be manipulated to promote repair and regeneration. By mining publicly available RNA-seq datasets, we identified loss of CCAAT enhancer- binding protein alpha (C/EBPα) as a candidate contributor to idiopathic pulmonary fibrosis (IPF). We have demonstrated that C/EBPα plays a critical role in AT2 cell maintenance and tissue homeosta- sis in the mouse lung. Currently, we are working on reprogramming aberrant epithelial cells with AAV mediated gene overexpression, CRISPR activation or small molecules including epigenetic modulators, aiming to boost endogenous lung repair.
Delineating Failed Lung Repair with Next-Generation Sequencing.
Pneumonectomy is a type of surgery to remove lung lobe, which results in lung regrowth and lung regeneration without forming lung fibrosis. How- ever, lung repair often fails in aged mice. Lineage tracing of specific cell populations, and detailed analyses
of their fates with bulk RNA-seq, scRNA-seq, ATAC-seq, or ChIP-seq, are systemically identifying the homeostatic or fibrotic programs that regulate cellular fate in aged mice with pneumonectomy or experimen- tal fibrosis.
ORCID iD:
https://orcid.org/0000-0001-9504-5604
Lung Organoid Representative fluorescence image