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% deemed suitable for transplantation. Moreover, approximately 40% 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%.
Researchers in the Ya-Wen Chen Lab in the Black Family Stem Cell Institute and the Institute for Airway Sciences at the Icahn School of Medicine at Mount Sinai 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 lab’s research marks a significant advance 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.
The Ya-Wen Chen Lab is also exploring the potential of bioengineering the trachea using human pluripotent cells in collaboration with the Institute for Airway Sciences.
Stem Cells and Lung Regeneration
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, which means they can create more copies of themselves indefinitely. 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 exploring 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.
Innovation in Lung Disease: Organoid Modeling for Repair Research
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, which means they can create more copies of themselves indefinitely. 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 in Ya-Wen Chen’s lab are working with the Black Family Stem Cell Institute 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.
Innovation in Lung Disease: Organoid Modeling for Repair Research
The Ya-Wen Chen Lab is an innovator in the field of hPSC in studying the mechanisms of lung disease and repair, 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. Thus, 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 Research Grants
Leveraging Personalized Stem Cell Therapy to Overcome 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.
The Chen Lab is partnering with the Institute of Airway Sciences, for a research project that attempts to create a tissue-engineered trachea from human pluripotent cells. The Chen Lab has 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, the Chen Lab will 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. The anticipated result will be an optimal method to fuse these cells to the host tissues, resulting in a chimera that will prevent organ rejection. This would represent a significant advance in airway reconstruction.
This research is funded by the United States Department of Defense and an anonymous philanthropic fund.
SARS-CoV-2 Assessment of Antibodies to Block the Virus from Entering the Lungs
In early 2020, a new virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began spreading worldwide. Studies have revealed that the virus uses the TMPRSS2 protease and the ACE2 receptor to enter cells. Studies have also shown that ACE2 and TMPRSS2 are expressed in lung cells, thus leading to lung involvement.
The Ya-Wen Chen Lab is using a lung organoid model to study the molecular mechanism by which SARS-CoV-2 enters the lungs and assess the potential of using TMPRSS2 antibodies to block that entry into lung cells, specifically lung alveolar type II (AT2) cells, the progenitor cells of the distal lung. The lab’s researchers will first test whether TMPRSS2 antibodies are toxic to the lung cells they have grown. Once they have established a safe dosage for the antibodies, the researchers will investigate the potential to block the virus and, if successful, whether that is achieved by reducing the amount of TMPRSS2 on the cell surface or blocking the function of TMPRSS2. Finally, the team will transform the TMPRSS2 antibodies that can safely be used in humans and test their efficacy using lung organoids and animal models.
If successful, the Chen Lab’s research has the potential to deliver crucial insights into the mechanism whereby TMPRSS2 regulates SARS-CoV-2 entry and identify therapeutic candidates to impede that phenomenon. That could impact the lives of millions of people who have been affected by COVID-19 and other respiratory viruses, such as influenza A, that use TMPRSS2 to enter cells. In addition, since most of the coronavirus family heavily relies on TMPRSS2 to infect our lung cells, finding a way to block the function of TMPRSS2 could potentially protect us from the next coronavirus outbreak.