Multiple chronic, untreatable diseases of the airway are characterized by epithelial dysplasia in response to aberrant repair and remodeling after chronic injury. Little is known about the pathways by which cells differentiate and respond to damage, although it is thought that developmental pathways are reactivated during this repair process. As a consequence, characterizing the underlying cause of many airway diseases relies on improving the current understanding of the normal development of the lung epithelium. One cell type of particular interest is the club cell, due to its role as a key progenitor of the airwa epithelium during repair as well as the current lack of understanding about its specification and differentiation. Although genetic mouse models have begun to hint at some of the pathways relevant to club cell development in vivo, new tools are needed to allow for the precise manipulation of developmental pathways and provide access to rare cell populations. We will develop a novel in vitro system to model lung development in mouse and human systems by developing and differentiating knock-in reporter induced pluripotent stem cell lines. We hypothesize that the modulation of Wnt signaling in iPSC-derived lung progenitors will result in changes in club cell specification. This system will additionally provide the basis for the generation of efficient protocols to model monogenic airway disease in patient-derived human induced pluripotent stem cells, which remains a crucial barrier to broad applications of cell-based therapy and in vitro drug testing for patients with chronic lung disease.
Chronic lung diseases are responsible for a major burden of disease worldwide, yet few treatment options exist for patients. These diseases are often associated with changes in the types of cells that line airway, suggesting that an better understanding of how these cells develop in the lung is critical to generating new treatments. This project seeks to develop an approach to use the differentiation of pluripotent stem cells as a tool to better understand the signals required for normal lung development and to engineer an unlimited source of airway cells for therapeutic applications.
| McCauley, Katherine B; Hawkins, Finn; Kotton, Darrell N (2018) Derivation of Epithelial-Only Airway Organoids from Human Pluripotent Stem Cells. Curr Protoc Stem Cell Biol 45:e51 |
| McCauley, Katherine B; Alysandratos, Konstantinos-Dionysios; Jacob, Anjali et al. (2018) Single-Cell Transcriptomic Profiling of Pluripotent Stem Cell-Derived SCGB3A2+ Airway Epithelium. Stem Cell Reports 10:1579-1595 |
| McCauley, Katherine B; Hawkins, Finn; Serra, Maria et al. (2017) Efficient Derivation of Functional Human Airway Epithelium from Pluripotent Stem Cells via Temporal Regulation of Wnt Signaling. Cell Stem Cell 20:844-857.e6 |
| Jacob, Anjali; Morley, Michael; Hawkins, Finn et al. (2017) Differentiation of Human Pluripotent Stem Cells into Functional Lung Alveolar Epithelial Cells. Cell Stem Cell 21:472-488.e10 |
