Institute for Airway Sciences

The COVID-19 pandemic brought the importance of establishing a multidisciplinary airway collaborative to the forefront. Most disease outbreaks, including COVID-19, swine flu, and avian influenza, are transmitted through the nose or mouth, and then impact the lungs. Understanding how respiratory viruses and bacteria spread is critical for developing strategies to prevent transmission. Our researchers are focusing on better understanding transmission routes, identifying factors that facilitate spread to new hosts, and determining ways to prevent viruses from entering the respiratory tract through measures like masks, improved ventilation, and nasal antivirals.

Lung transplantation poses considerable challenges in terms of quality, suitability, and patient outcomes. The majority of donated lungs are rejected due to minor injury or edema, with only 20 percent deemed suitable for transplantation. Moreover, approximately 40 percent of patients who undergo lung transplantation will experience rejection within the first year, and the five-year survival rate among all patients is estimated to be between 50 and 60 percent.

Our researchers at the Institute for Airway Sciences are investigating the potential of using human pluripotent cells to study the mechanisms of lung injury repair, cell-based therapy, disease modeling, and regenerative medicine. The research marks significant progress from traditional research on lung development, regeneration, and repair, which was conducted on mouse lungs. It also has the potential to reduce the risk of rejection among patients who undergo transplantation or to eliminate the requirement for transplantation. We are also exploring the potential of bioengineering the trachea using human pluripotent cells.

Human pluripotent stem cells (hPSC) are cells that have the potential to develop into any cell or tissue in the body. They include embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs)–cells from an adult that have been reprogrammed back to stem cells. Similar to other stem cells, hPSCs are capable of self-renewal. Thus, stem-cell based therapy theoretically offers an opportunity to explore regenerative medicine.

Using directed differentiation—a bioengineering methodology in which pluripotent stem cells are given specific instructions through growth factors or small molecules—researchers are working to explore the potential of mimicking the necessary in vivo signaling in these cells to grow a lung from a donor’s pluripotent stem cells. If successful, it could virtually eliminate the complications traditionally associated with lung transplantation, such as rejection, or enable repair of rejected lungs to qualify for transplantation. It could also enable lung repair or the growth of a lung using a patient’s own hPSCs, resulting in more easily tolerated therapeutic approaches to traditional transplantation.

Our researchers are innovators in the field of hPSC, having developed the first human mini lung organoid model from human pluripotent cells. The lung organoid mimics aspects of the structure and respiratory composition of the human lung in vitro and in vivo. It offers a unique opportunity to explore the molecular mechanisms that initiate diseases such as COVID-19, influenza, measles, respiratory syncytial virus, and fibrosis within the lungs, and to conduct therapeutic screening to identify agents that have preventative or curative potential. Researchers are also using the lung organoid model to explore cell response to different viral or chemical insults and to hypoxia, and the mechanisms these phenomena trigger for repair.

Airway Regeneration
Airway damage is becoming more common due to increases in viruses, cancer, bacterial infections, and trauma. Our pulmonary team at Icahn Mount Sinai is dedicated to understanding how the lung epithelium is impacted by injury and the ways in which the organ and body work together to respond to injury, often through the repair and building of tissue. Researchers are employing a multifaceted approach, encompassing basic, translational, and clinical studies, to unravel the intricate processes that govern the development of epithelial tissues during embryonic development and their regenerative and repair capacities in adult life. The knowledge gained from these investigations is being leveraged to create innovative therapeutic strategies for treating disorders affecting epithelial tissues, including the airways and lungs.

Trachea Transplant Rejection
Tracheal transplantation is considered a vascularized composite allograft (VCA), which means it involves the transfer of a body part containing multiple tissue types from a donor to a recipient. Although VCA transplantation has changed the lives of thousands of patients, acute rejection occurs in approximately 80 percent of transplant recipients and chronic rejection occurs in approximately half. That rejection is triggered by epithelial cells in the airway.

Our researchers are attempting to create a tissue-engineered trachea from human pluripotent cells. We have pioneered a new way to use human pluripotent cells to generate and expand basal cells–the progenitor cells of the airway–to reconstruct the trachea’s epithelial cells and thus the trachea. This creates the potential to replace the trachea donor’s epithelial cells with those bioengineered from the recipient and thus reduce the risk of immune rejection or lower the requirement to administer immunosuppressants. It also creates the potential to eliminate the requirement for transplantation among certain patients through direct delivery of the therapeutic cells to the airway to effect injury repair.

To assess this potential, researchers create a bioengineered tracheal replacement and transplant it in mice to assess the cell’s ability to grow, differentiate, and support a fully functioning organ. If successful, it will be an optimal method to fuse these cells to the host tissues, resulting in a chimera that will prevent organ rejection, representing a significant advance in airway reconstruction. This research is funded by the United States Department of Defense and an anonymous philanthropic fund.