Generating Humanized Lungs in Mice for Disease Modeling and Development of Personalized Medicine Therapies

Millions of people worldwide suffer from incurable lung diseases; the only viable option for patients with end-stage lung disease is lung transplantation. Currently, patients with end-stage refractory lung disease have inadequate treatment options for three reasons: (1) lung transplantation is restricted due to the absolute scarcity of available donor lungs; (2) there are no known records of successful regeneration of functional lung organs; (3) there are limited in vivo animal models for studying human refractory diseases leaving a knowledge gap in understanding disease processes. To overcome these issues, we established innovative bioengineering approaches for generating functional lungs in vivo in mice via a conditional blastocyst complementation technique (CBC) and a novel, efficient pluripotent stem cell (PSC) maintenance culture condition. We also established a method to enrich multipotent human lung cells derived from patient cells by a unique cell surface marker that may allow the formation of functional humanized lungs in our CBC mice. Although challenging, we will further advance our CBC technology by guiding human lung progenitors specifically into the lung organ niche. In this study, we will determine how to proficiently guide exogenous stem cells, such as human tissue lung cells, into the desired lung organ niche. If successful, we ideally would be able to obtain humanized lungs in mice and facilitate our understanding of the fundamental mechanisms for reconstructing tissue architecture with desired cells in the targeted progenitor niche by controlling the position of the donor cells. Our strategy using chimeric mouse models in vivo will provide fundamental insights into interspecies lung organogenesis and interspecies cell competition to reach the lung organ niche during development. This will open the door for a personalized medicine approach using patient-derived iPS cells in vivo, in particular, in small animals as an ideal platform for drug-screening or gene-therapy for non-treatable lung diseases.