Matrix and Bioreactors for Human Lung Regeneration
Laura Niklason, PhD, MD (Contact PI)
Eric Stephen White, MD
University of Michigan
Advanced or end-stage lung diseases, such as pulmonary fibrosis, emphysema, and cystic fibrosis, are a major cause of morbidity and mortality in the United States. Although lung transplantation is a viable alternative for some patients, the 5-year survival rate of approximately 50% (primarily due to chronic allograft rejection and/or infection) limits this modality as a long-term therapy. Moreover, the scarcity of donated lungs and the short graft viability times post-explant are major limitations. Thus, there is a desperate need both for understanding pathophysiologic mechanisms in chronic lung diseases as well as for devising innovative methods to repair or bioengineer functional lungs. This proposal will test the hypothesis that the lung extracellular matrix (ECM) drives the proper localization, differentiation, and function of lung cells and is the key contributor to normal lung repair and regeneration. With a long-term goal of regenerating a functional human lung, this initiative will critically examine the constitutive makeup of the decellularized lung ECM and develop new tools for assessing lung matrix structure and function. Further, it will develop a human lung bioreactor that allows for optimal preparation of decellularized human lung matrices while maintaining physiologic ventilation and perfusion. Among the questions to be addressed are: 1) What are the key components of lung ECM that drive cellular behavior and function? 2) How can the barrier function and structure of lung ECM be better assessed? 3) Can a bioreactor be developed that will allow a human lung to be decellularized and subsequently recellularized while undergoing mechanical ventilation and vascular perfusion? Work in this area will be instrumental for the success of the Lung Regeneration Consortium, because this initiative will generate a basic and comprehensive understanding of the lung matrix that is used as a substrate for lung growth. Tools and bioreactors that will enable other Consortium members to utilize and leverage our findings will also be developed.
The relevance of this research is to begin studying the feasibility of regenerating a functional human lung in the laboratory. Studies proposed will comprehensively define the protein makeup of the normal human lung, will devise novel methods of imaging the cellular repopulation of human lung tissues, and will develop a novel bioreactor in which human lungs can be regenerated.