Reconstructing the Complex Human Airway Niche: Interplay of Epithelial Progenitors, Fibroblasts, and Immune Cells

Abstract

Human organoids derived from reprogrammed and tissue stem cells offer a valuable in vitro platform for studying human development, regeneration, and disease modeling. Current platforms mainly focus on generating airway epithelial cells from human ESCs and iPSCs but do not effectively translate complex communications across various cellular and tissue niches of the human airway. Moreover, there is a lack of consensus benchmarking standards across different organoid platforms and human samples. Addressing this knowledge and technological gap, we developed an improved method to create human airway organoids containing both epithelial and stromal lineages. These organoids exhibit functional motile ciliated cells and mucin-secreting submucosal gland cells within a well-organized pseudostratified epithelium, with transcriptomic profiles displaying a high similarity to human tissues. They contain a FOXF1+ fibroblast niche conserved in both fetal human and mouse airways. We introduced a co-culture approach incorporating blood-circulating monocytes, leading to enhanced mesenchymal-epithelial crosstalk, the emergence of fetal-specific pulmonary neuroendocrine cells, and the differentiation of monocytes into self-sustaining alveolar macrophages. Our multi-lineage organoid system, incorporating mesenchymal, immune, and epithelial cells, successfully recapitulates the cellular heterogeneity and organization of the human conducting airway and provides insights into the organized cell-cell interactions in the proximal airway. By presenting an integrated analysis using published single-cell RNA-seq datasets pertinent to the proximal airway of mice, humans as well as human organoids, we address current benchmarking progress and future challenges in the field. Our analyses underscore the importance of constructing a complex signaling niche for a better understanding of human tissue regeneration, highlighting the potential of this research in translating discoveries into clinical applications.

Biography

Dr. Mu He is an Assistant Professor in the School of Biomedical Sciences, The University of Hong Kong. She graduated with a BS from Cornell University in 2007. She pursued her graduate research in the laboratory of Kathryn Anderson at the Memorial Sloan Kettering Cancer Center from 2008 to 2014. Her PhD thesis focused on the genetic and molecular connections between primary cilia and the mammalian Hedgehog signalling (PNAS 2009, Development 2010, JCB 2012, NCB 2014). To follow how embryonic forms acquire physiological functions, she pursued her postdoctoral training with Lily Jan at University of California, San Francisco from 2014 to 2020. In collaboration with Chan Zuckerberg Biohub, she constructed a comprehensive single cell atlas of the developing trachea of mice and humans to better understand the developmental programs and cellular composition that establish the airway mucosal barrier (PNAS 2017, eLife 2020, Nat Physics 2020, Nature 2020). As an independent group leader in HKU, Mu is leveraging the power of stem cell biology, live imaging, organoids, and single-cell technologies to understand how the respiratory mucosal barrier develops, repairs, and regenerates. Given the species-specific differences in airway biology between mice and humans, new approaches are needed and they are using new model systems and performing comparative studies to reveal unifying principles of regeneration. Through proactive collaboration between research and medicine, their ultimate goal is to translate basic biomedical discovery into effective therapies for patients affected by respiratory diseases, including COVID-19, asthma, COPD, and cancers.

 

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