A message in a bottle: how extracellular messages can help babies breath again
BY: Benjamin Liu
Supervisor: Dr. Zani
SURP Winner article
Before joining the Zani lab, I – like many people – had never heard of congenital diaphragmatic hernia (CDH). Therefore, I was surprised to learn that CDH is an extremely deadly congenital disease, with a mortality rate of 40%1. As a congenital disorder, CDH occurs during fetal life, whereby abdominal organs migrate through a hole in the diaphragm to physically block lung development2. While some CDH babies never take their first breath, others slowly and painfully suffocate within the first days of life. For the survivors, many suffer life-long morbidities. However, despite this high mortality, there is no established therapy. For the healthcare team, supportive care is the only option as the parents wait for the baby to live – or die from suffocation2.
The absence of a cure drew me into the Zani lab at Sick Kids Hospital and made me excited to come back for a 2nd summer because the Zani lab is pursuing a novel stem-cell-based therapy for CDH. Not just a cool sounding name, stem-cell-based regenerative medicine has attracted a lot of attention regarding its capabilities and its efficacy. However, like a plot twist in a good movie, amniotic fluid stem cells (AFSCs) have shown regenerative potential in lung underdevelopment not by directly transforming themselves into lung cells, but rather by sending regenerative messages to the dysregulated lung cells3. Our lab had previously hypothesized that the key mediators of these cell-to-cell regenerative messages are extracellular vesicles. As a result, my current project was to investigate this hypothesis in the setting of fetal lung underdevelopment. To date, I have demonstrated that AFSC extracellular vesicles (AFSC-EVs) could be administered to underdeveloped rat lungs to rescue the production of surfactant protein. This summer, I continued to advance the project by staining AFSC-EVs to visualize their entry into lung epithelial cells. I also observed that AFSC-EVs exhibit a greater beneficial effect on underdeveloped lungs when compared to the EVs from mesenchymal stem cells.
While I have learned a lot about EVs and lung development, the biggest lesson I learned is to keep the bigger picture in mind. Sometimes experiments fail and you may find yourself stressed and fatigued from working much longer than anticipated. However, the results that we discovered could lead to exciting and novel lung regeneration therapies. Whereas before newborns would suffocate to death after being born with CDH, my involvement in creating a potential new therapy could save these young lives.
Finally, EVs may not only be the cure for lung underdevelopment, but they may also be the next big innovation. During my research, I learned about applications for EVs in therapies beyond lung regeneration, including cardiac regeneration after myocardial infarctions or treating spina bifida4,5. EVs are also potential biomarkers for different types of cancer, as cancer cells release their own EVs for their nefarious purposes7. Unlocking the secrets behind these recently discovered messages could unlock a whole new field of medicine, where we could literally tell cells to get their act together and identify when they are not!
- Harting MT, Lally KP. The Congenital Diaphragmatic Hernia Study Group registry update. Semin Fetal Neonatal Med. 2014 Dec;19(6):370–5.
- Chandrasekharan PK, Rawat M, Madappa R, Rothstein DH, Lakshminrusimha S. Congenital Diaphragmatic hernia – a review. Matern Health Neonatol Perinatol. 2017 Mar 11;3:6–6.
- Pederiva F, Ghionzoli M, Pierro A, De Coppi P, Tovar JA. Amniotic fluid stem cells rescue both in vitro and in vivo growth, innervation, and motility in nitrofen-exposed hypoplastic rat lungs through paracrine effects. Cell Transplant. 2013;22(9):1683–94.
- Sahoo Susmita, Losordo Douglas W. Exosomes and Cardiac Repair After Myocardial Infarction. Circulation Research. 2014 Jan 17;114(2):333–44.
- Kumar P, Becker JC, Gao K, Carney RP, Lankford L, Keller BA, et al. Neuroprotective effect of placenta-derived mesenchymal stromal cells: role of exosomes. The FASEB Journal. 2019 Feb 12;33(5):5836–49.
- Tai Y-L, Chen K-C, Hsieh J-T, Shen T-L. Exosomes in cancer development and clinical applications. Cancer Sci. 2018 Aug;109(8):2364–74.