CAREER: Decoding the Developmental Extracellular Niche for Instructing Lung Tissue Engineering

How we engineer human tissues is usually inspired by how these tissues are induced in the body during embryonic development and how they regenerate following an injury. The objective of this CAREER project is to uncover the dynamic changes in the extracellular biomolecular environment that support lung tissue maturation during development and during surgical resection induced regeneration.

This information will then be used to guide the engineering of novel extracellular biomaterials to enable directed lung tissue maturation in the laboratory setting from human induced pluripotent stem cells (hiPSCs). By identifying and validating the essential extracellular factors, this project will lay the foundation for deriving functional human lung tissues to help patients suffering from end-stage lung diseases and will inspire novel therapeutics promoting lung repair and regeneration following injuries.

The research efforts of the CAREER project are integrated with educational and outreach objectives to promote active learning and automated student behavior analysis in the biomedical engineering classroom, to develop an outreach program to encourage and inspire local high school students by hosting educational poster sessions, and to promote biomedical engineering research and education towards the general public through collaboration with a local museum focusing on biological arts.

The investigator's long-term research goal is to engineer lung tissues that meet unique physiological and functional requirements. Towards this goal, the objective of this CAREER project is to catalog the dynamic synthesis and secretion of extracellular matrix (ECM) glycoproteins over native lung alveologenesis and use this information to instruct the induction of alveolar cells and tissues from hiPSCs.

Emerging evidence suggests that the developmentally regulated ECM deposition is pivotal to the maturation of alveolar cells and proper lung tissue morphogenesis. However, a comprehensive survey of de novo ECM synthesis throughout lung development and regeneration has been challenging to obtain, due to the limited sensitivity in detecting the production of new ECM proteins.

To address this bottleneck, this research will develop and implement a novel newly synthesized ECM (newsECM) profiling approach for uncovering the dynamic ECM synthetic programs accompanying alveologenesis. This strategy, by selective labeling and enrichment of newsECM proteins free from the bulk pre-existing ECM, will enable ultrasensitive identification of new ECM synthesis with unprecedented daily temporal resolution.

This addresses the critical limitation of current ECM proteomics and is well suited for studying highly dynamic processes such as alveologenesis. Building on this technological innovation, this CAREER project will (1) decode the dynamic ECM production during native lung alveologenesis (neonatal and adult post-pneumonectomy), and (2) engineer hiPSC-derived alveologenesis using developmentally inspired ECM scaffolds.

Achieving directed alveolar specification from hiPSCs will provide fundamental insights regarding lung development and facilitate the generation of patient-specific lung tissues for drug discovery and regenerative medicine.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.