Billie Hwang

Dr. Billanna Hwang (Billie) is a Research Scientist heading toward the faculty track under the mentorship of Dr. Michael S. Mulligan in the Department of Surgery at the University of Washington. Her research focuses on the role of exosomes in immune modulation, and as biomarkers and a potential immunotherapeutic for a variety of inflammatory processes, including lung ischemia reperfusion injury. We sat down with Dr. Hwang to discuss how she stumbled into the world of exosome research.

What led you to begin looking at mesenchymal stem cells (MSCs) as a possible immunotherapy to mitigate lung ischemia reperfusion?

Good question. I got my training at Fred Hutchinson Cancer Research Center studying bone marrow and solid organ transplant immunology with a focus on regulatory T cells and graft versus host disease (GvHD). MSCs became a secondary research area when I came over to work with Dr. Mulligan. As you said, we wanted to try to develop an immunotherapy to mitigate lung ischemia reperfusion, and we thought that MSCs would be interesting due to their progenitor-like functions that are capable of immunomodulating cellular responses.

What happened when you tested their ability to protect against reperfusion?

We took four MSC cell lines that Dr. Beverly Torok-Storb at Fred Hutch generated for us, and we tested them. Interestingly, not all of the MSC lines functioned similarly. We identified two of them as protective, and two of them as not, which was great for our in vivo and in vitro assessments and downstream analytics.

Eventually you discovered that the MSCs themselves aren’t even necessary. How did that happen?

We just stumbled on it. In addition to administering the cells alone, we tested the effects of MSC-conditioned media, and found that this showed protection as well. So, the natural question was what component or components of the conditioned media are mediating this effect? When we investigated, we found that exosomes were present, and that they were responsible. Since then, we’ve applied exosomes to everything. We’ve looked at using them as a therapeutic base for lung ischemia reperfusion, but also in the context of cystic fibrosis, and their role in lung transplant rejection and tolerance. We’ve even looked at using them as a base for vaccines. You name it, we’re trying it.

The administration of MSC-derived exosomes to provide protection against lung ischemia reperfusion in small animal models is an important first step, and transitioning into a larger animal model is beneficial to move this therapeutic to the clinic. There are a few significant hurdles that this therapeutic would address. Firstly, the idea of salvaging lungs that have been deemed “unusable”, and secondly, priming the tissue towards a more anti-inflammatory or regulatory state, which would have significant impacts on downstream transplant outcomes. We’re also investigating the use of primary MSCs, and testing their byproducts to see if they provide the same type of protection as those derived from cell lines.

Do you know how these exosomes are providing protection?

Not yet, but we’re trying to figure it out. The interesting aspect of exosomes is their ability to participate in numerous immune mechanisms. Whole exosomes can play a part in receptor-exosome signaling, and they can be phagocytosed and elicit another response in another type of cell. We’re also investigating the contents of the exosomes and how they facilitate immune modulation.

Since we are a lung transplant group, we’re especially interested in how exosomes dictate alloimmune responses. Our work is all done in a clinical lung transplantation setting, but we have a collaborator at Fred Hutch who performs vascular composite allografts, and is trying to figure out the mechanisms of exosome allorecognition through that preclinical model as well.

Why do you think MSCs evolved to secrete exosomes that function in promoting this type of protection?

That’s a great question! There is a lot of speculation on how and why cells are secreting these exosomes. But the easy answer is that nobody really knows. Initially, exosomes were thought to be the “garbage” that cells secreted. Now, it seems that this “garbage” is more important than initially thought. Personally, I think that’s one of the novelties about exosome research right now. Nobody really knows, which makes the field really exciting!

Having said that, I personally think that they’re the missing link in cell-to-cell communication. Researchers have so much data on phenotyping cells through flow cytometry and “omics” approaches, but there hasn’t been a convincing, strong correlation between cell profiling or biomarkers with outcomes.

In addition to regular facilities, your lab also has a CT clinical CORE and will soon be launching an EXOCORE. How do these work?

Our new Cardiothoracic (CT) Research CORE merges benchwork and clinical work, which is something that has disappeared in the CT department. The research that is currently under investigation in this group includes studies focused on the clinical aspects, and a series of studies investigating exosomes and their role in lung transplantation. The CT research core is novel because there is a unique dynamic between the bench science and clinical aspects, providing an arena for both disciplines to be more impactful in the way we look at disease progression and mechanisms that drive certain immune responses. This will result in a stronger approach toward developing therapeutics and better patient care for the clinicians. Currently, we are in the planning stages of building an EXOCORE infrastructure, which will provide an additional resource for investigators at the UW as well as other institutions.  

In 2017, you founded the Westco Exosortium, which is a west coast-based collective that connects researchers in the exosome field. Why did you feel that this was important?

I started the group to address some of the problems we have identified in the exosome research field. One of the main issues is that different groups were using different methods for exosome isolation and analytics. When there’s so much heterogeneity, how can we really analyze data and compare results? I realized that a consortium would be a great way to pool the masses together and generate standardized approaches. We’ve now not only standardized many of our protocols, but we use each other as resources. We’re also planning on publishing together as a group to showcase what we’re all about. Excitingly, two junior researchers in the consortium have received funding for their exosome research, and our group was able to provide assistance and support for these proposals.

Thank you for taking the time to discuss your research with us, Dr. Hwang!