Using Lung Organoids and ALI to Understand Complex Cellular Interactions in the Lung

Joo-Hyeon Lee, Ph.D., Group Leader, University of Cambridge
Joo-Hyeon Lee, PhD

Dr. Joo-Hyeon Lee's passion for stem cell research began during her PhD. She studied embryonic development of epithelial organs under the supervision of Professor Daesik Lim in South Korea at Korea Advanced Institute of Science and Technology (KAIST). Dr. Lee then went on to Dr. Carla Kim's lab at Harvard Medical School for her post-doctoral work. She continued pursuing her passion in the study of adult lung stem cells, specifically around how microenvironment regulates stem cells during injury repair and regeneration. In 2016 Dr. Lee set up her own laboratory at Wellcome Trust - MRC Stem Cell Institute in University of Cambridge to further understand the cellular behavior and regulatory networks of adult stem cells and niche cells in the lung.


The Scientist

Dr. Joo-Hyeon Lee's passion for stem cell research began during her PhD. She studied embryonic development of epithelial organs under the supervision of Professor Daesik Lim in South Korea at Korea Advanced Institute of Science and Technology (KAIST). Dr. Lee then went on to Dr. Carla Kim's lab at Harvard Medical School for her post-doctoral work. She continued pursuing her passion in the study of adult lung stem cells, specifically around how microenvironment regulates stem cells during injury repair and regeneration. In 2016 Dr. Lee set up her own laboratory at Wellcome Trust - MRC Stem Cell Institute in University of Cambridge to further understand the cellular behavior and regulatory networks of adult stem cells and niche cells in the lung.

What inspired you to pursue stem cell research?

Stem cells are incredible populations. They can self-renew and generate a whole lineage of populations. What is really fascinating about it is that stem cell research is one of the fields that is really close to translational medicine. It allows us to better understand the human disease.

Do you have a scientific idol that influenced the scientific path you’ve chosen?

Every single scientist who has the passion to keep asking basic fundamental questions! I really appreciate the scientists next to me, always influencing me and encouraging me to go forward.

You mentioned that you had some young visitors from a primary school when you were in Boston. Could you describe the experience?

They were 8, maybe 10 years old. They visited our lab. We showed them the microscope and they were very impressed. My supervisor wanted me to show them the organoid culture system. Here I was thinking, “How can I explain the organoid system to these little babies?" So I asked them, “Do you know how to grow plants or flowers?" They answered yes. So I explained that the organoid culture system is similar: we place stem cells in the “pot" (plates we use for the organoid culture), add the “seeds" (stem cells), add “water" (media), and get the whole “roots, leaf, and flower" (all the lineages). Then I showed them the beautiful lung organoids that were branching in Matrigel. I was very surprised that they really asked the right questions, such as “how do the stem cells know to generate all of this?" After having this conversation with them, I realized that stem cells are really the future for us to better understand human disease and developmental biology.


The Science

What are your research interests?

Lung is an architecturally complex organ composed of a heterogeneous mixture of various epithelial cells and surrounding stromal cells. Recent studies have shown the plasticity of lung progenitor cells and mesenchymal lineage during regeneration. As a result, the information on the identity and behaviour of these cell populations is limited. Recently, we found that there are anatomically discreet stromal cells that are transcriptionally programmed to support specialized niches, for airway or alveolar lineage differentiation depending on their spatial identity. We are trying to understand the key stem-mesenchymal interactions and the precise mechanisms that maintain lung homeostasis and regeneration. Specifically, we are asking how the quiescent state is maintained and becomes activated, how cell fate is determined, and how niches develop and remodel in lung homeostasis, injury repair, and early tumorigenesis. We believe that our studies will help better understand the multi-cellular lung diseases.

How is your organoid culture system different from the conventional 3D culture system for lung organoids?

We use air-liquid interface (ALI) culture system in our lung organoid culture. Specifically, we grow the organoids inside Matrigel on top of an insert, with medium at the bottom of the insert. In this way, the organoid/Matrigel mixture is in contact with air on the top and is exposed to medium in the bottom, recapitulating in vivo lung environment. In addition, we have established an organoid co-culture system for distal lung organoid cultures, which led us to dissect the cellular interactions between certain epithelial progenitor cells and stromal cells. You can add endothelial cells, fibroblasts, or immune cells in your organoid culture to see the impact of these cells on self-renewing or differentiation properties of stem cells. We believe that this is a powerful tool to understand the complex cellular interactions in a reductionist way.

What do you consider to be the most important advances in stem cell or the lung field in the last five years?

In the stem cell field, the biggest advances are organoids and CRISPR - two different technologies that have greatly advanced the stem cell research and led to the potential for personalized medicine.

What breakthroughs would you anticipate in the lung field in the next five years?

Many pioneers in the lung biology field have focused on understanding the “nature of lung”. In particular, lineage tracing technique has greatly advanced our understanding of murine lungs including lung development and regeneration. However, recent development of organoid cultures derived from human tissues or iPSCs has allowed us to better understand human lung at the cellular and molecular levels. In addition, single cell RNA sequencing, high resolution imaging, and computational biology have helped us overcome the previous limitations of dissecting complexities of human lungs. Although we had learned a lot from mouse models, there are differences between human and mouse lung. In the next five years, I think we will put more efforts into defining functional human lung stem/progenitor cells and niche cells, and their contribution to lung regeneration and diseases. Currently, we are able to grow human adult large and small airway epithelial cells in organoid cultures, but growing alveolar cells is still challenging. Since many of the human diseases have the defects in alveolar cell populations, we wish we can define the required factors to grow and expand functional alveolar lineages in culture within a year.


The Tools

Have you tried PneumaCult™ media for your organoid cultures?

We have not tried the ALI medium (PneumaCult™-ALI) from STEMCELL with human lung organoids. We have tried PneumaCult™-Ex to expand human basal cells, and it worked well. We would love to try PneumaCult™-Ex Plus and PneumaCult™-ALI for our human lung organoid cultures.

Featured Publications

  • Lee JH*, Tammela T, Hofree M, Choi J, Marjanovic ND, Han S, Canner DA, Wu K, Paschini M, Bhang DH, Jacks T, Regev A, Kim CF* (2017) Anatomically and functionally distinct lung mesenchymal populations marked by Lgr5 and Lgr6. Cell. In press. (*, corresponding authors)
  • Choi J, Iich E, Lee JH (2016) Organogenesis of adult lung in a dish: Differentiation, disease and therapy. Dev Biol. 420(2):278-86.
  • Lee JH and Kim CF (2014) Mesenchymal progenitor panoply. Science. 346 (6211):810-1.
  • Lee JH, Bhang DH, Beede A, Huang TL, Stripp B, Bloch KD, Wagers AJ, Tseng YH, Ryeom S, Kim CF (2014) Lung stem cell differentiation in mice directed by endothelial cells via a BMP4-NFATc1-Thrombospondin-1 axis. Cell. 156(3):440-55.