Pluripotent Stem Cell Modeling of Airway Epithelial Differentiation

Boston University Medical Campus, Boston MA

Investigators

Linked publications & trials

Abstract

? DESCRIPTION (provided by applicant): 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.