Xin Sun

Research

The building of an organ starts from an amorphous cluster of cells, and proceeds following an elaborate blueprint of coordinated proliferation, morphogenesis and differentiation. Organ function relies on the harmonization with other tissues, the infusion by blood and immune cells, and the wiring by the nervous system. We employ cutting-edge technologies, including single-cell transcriptomics and epigenomics, genome editing, whole-organ clearing and imaging, to delineate the robustness that dictates normal organ function, and uncover the imperfections that initiate pathogenesis.

At the center of our investigation is the lung, an organ that is vital at first breath. It is the setting for many fetal, pediatric and adult diseases with unknown cause and no cure. We use disease modeling as a starting point for fundamental discoveries in developmental biology, stem cell biology and the neural-immune-physiology interface.

Consider the lung as a sensory organ

A mouse airway outlined by an epithelial marker for club cells (green), annotated by clusters of pulmonary neuroendocrine cells (magenta) which perform sensory function

A mouse airway outlined by an epithelial marker for club cells (green), annotated by clusters of pulmonary neuroendocrine cells (magenta) which act as airway sensors.

At resting, an average person inhales/exhales 5-8 litters of air. This air may vary in oxygen content, carry allergen, pollutants or pathogens. Each of these signals would trigger a specific set of responses. For example, allergen causes asthma while intermittent hypoxia causes pulmonary hypertension. How this exquisite specificity is established is poorly understood.

We recently found that pulmonary neuroendocrine cells, which represents less than 1% of epithelial cells in the lung, function as sensors on the airway wall (Branchfield et al., Science, 2016) . These cells are neuronally innervated, and act through secreting potent neuropeptides, neurotransmitters and amines. We found that overactivation of these cells leads to heightened baseline immune responses. Furthermore, they form neural-immune niches with residential immune cells such as innate lymphoid group 2 cells (Sui et al., Science, 2018). Together, these niches are essential for mediating allergen-induced asthmatic responses. Study of the pulmonary neuroendocrine cells have also led us to investigate the molecular nature of the neural circuit that controls lung function. We are teaming up with neurobiologists, genomicists and physiologists to map the neural circuit that originates from and returns to the lung. Our goals are to understand which aspects of lung function is controlled by the neural circuit, what underlie the specificity between inputs and outputs, and how to manipulate the circuit to restore lung function in disease settings.

Mechanisms and long-term outcomes of prematurity

In a normal adult, the gas-exchange surface area is estimated to be ~1,000ft2, equivalent to half of a tennis court. This surface is packed into our chest in the form of ~480 millions of gas-exchange units called alveoli. Approximately 95% of the gas-exchange surface area is built in the early periods after birth in a process called alveologenesis. Disruption of the final steps of lung development results in alveoli simplification, as is seen in a large proportion of premature infants diagnosed with bronchopulmonary dysplasia (BPD). BPD is often associated with lifelong breathing deficiencies, pulmonary hypertension and accelerated decline in respiratory capacity later in life.

To date, a majority of studies of alveologenesis rely on two-dimensional (2D) analysis of tissue sections. Given that an overarching theme of alveologenesis is thinning and extension of the epithelium and mesenchyme to facilitate gas exchange, often only a small portion of a cell or a cellular structure is represented in a single 2D plane. We have used a three-dimensional (3D) approach to examine the structural architecture and cellular composition of myofibroblasts, lipofibroblasts, alveolar type 2 cells and elastin extracellular matrix in normal as well as BPD-like mouse lungs (Branchfield et al., Dev Biol, 2015) . The insights revealed by 3D reconstruction of the alveoli set the foundation for future investigations of the mechanisms driving alveologenesis, as well as causes of alveolar simplification in BPD. We have also used a genetic approach to investigate the role of signaling pathways in this process (Li et al, Development, 2017; Li et al., Elife, 2018) .

Ongoing work in this research direction interrogates how different elements of prematurity impacts long-term lung function. We are interested in why some BPD patients develop pulmonary hypertension while others do not, and why BPD patients are more susceptible to viral infections later in life.

Genetic modeling of lung diseases

As whole-genome sequencing of patients becomes routine, we have established fruitful collaborations with human geneticists, and are using advanced technologies such as CRISPR/Cas9 genome editing to interrogate causal relationships between patient-specific genomic variants and phenotypes and disease phenotypes. Towards this goal, we started with rare congenital disorders, and are also extending our effort to study common and complex diseases.

In the past few years, among lung-related congenital disorders, we have studied tracheo-esophageal fistula (Domyan et al., Development 2011) , tracheobronchomalacia (Hines et al., PNAS 2013) , and congenital diaphragmatic hernia (CDH) (Domyan et al., Dev Cell, 2013; Branchfield et al., Science, 2016, McCulley et al., JCI, 2018) . Using CDH as an example, we have established a pipeline to first determine candidate gene expression in the developing lung (Herriges et al., Dev Dynamics, 2012) , and then use CRISPR/Cas9genome editing and other genetic approaches to recapitulate the mutations in mice, and determine which variants may be causal to phenotypes

As a demonstration of the effectiveness of this approach, we have uncovered distinct mechanisms from different genetic models of CDH (Domyan et al., Dev Cell, 2013; Branchfield et al., Science, 2016, McCulley et al., JCI, 2018) . These findings provide an explanation for why standard treatment works in some, but not other patients. More importantly, each of the mechanism makes prediction of personalized treatments based on patient genotype. Ongoing work in this research direction aims to expand to additional genes and diseases.

Select Publications

  • Pulmonary neuroendocrine cells amplify allergic asthma responses. Sui P, Wiesner DL, Xu J, Zhang Y, Lee J, Van Dyken S, Lashua A, Yu C, Klein BS, Locksley RM, Deutsch G, Sun X. Science . 2018 8;360(6393). pii: eaan8546.
  • Lats inactivation reveals hippo function in alveolar type I cell differentiation during lung transition to air breathing. Nantie LB, Young RE, Paltzer WG, Zhang Y, Johnson RL, Verheyden JM, Sun X. Development . 2018 Oct 10. pii:dev.163105. doi: 10.1242/dev.163105.
  • Pdgfra marks a cellular lineage with distinct contributions to myofibroblasts in lung maturation and injury response. Li R, Bernau K, Sandbo N, Gu J, Preissl S, Sun X. Elife . 2018 Sep 4;7. pii: e36865. doi: 10.7554/eLife.36865.
  • PBX transcription factor drive pulmonary vascular adaptation to birth. McCulley DJ, Wienhold MD, Hines EA, Hacker TA, Rogers A, Pewowaruk RJ, Zewdu R, Chesler NC, Selleri L, Sun X. Journal of Clinical Investigation , 2018 128(2): 655-667.
  • FGF receptors control alveolar elastogenesis. Li R, Herriges JC, Chen L, Mecham RP, Sun X. Development . 2017, 144(24):4563-4572.
  • TET-mediated DNA demethylation controls gastrulation by regulating Lefty-Nodal signalling.Dai HQ, Wang BA,Chapman DL, Fuchou Tang FC, Sun X*, Xu GL*. Nature , 2016 Oct 538(7626):528-532. *Co-corresponding authors.
  • E3 ubiquitin ligase RFWD2 controls lung branching through protein-level regulation of ETV transcription factors.Zhang Y, Yokoyama S, Herriges JC, Zhang Z, Verheyden JM, Young RE, Sun X. PNAS . 2016 Jul 113(27):7557-62.
  • Pulmonary neuroendocrine cells function as airway sensors to control lung immune response.Branchfield K, Nantie L, Verheyden JM, Sui P, Wienhold MD, Sun X. Science . 2016 Feb, 351:707-10. Perspective of this study was published in Science here.
  • A three-dimensional study of alveologenesis in mouse lung Branchfield K, Li R, Lungova V, Verheyden JM, McCulley D, Sun X. Dev Biol . 2016 Jan 409:429-41. Developmental Biology top outstanding paper award for 2016.
  • FGF-Regulated ETV Transcription Factors Control FGF-SHH Feedback Loop in Lung Branching Herriges JC, Verheyden JM, Zhang Z, Sui P, Zhang Y, Anderson MJ, Swing DA, Zhang Y, Lewandoski M, Sun X. Dev Cell . 2015 Nov 9;35(3):322-32.
  • Establishment of smooth muscle and cartilage juxtaposition in the developing mouse upper airways. Hines, E., Jones, M., Verheyden, J., Harvey, J. and Sun, X. PNAS . 2013 Nov 110(48):19444-9.
  • Roundabout receptors are critical for foregut separation from the body wall Domyan, E.T., Branchfield, K., Gibson, G.A., Naiche, L.A., Lewandoski, M., Tessier-Lavigne, M., Ma, L. and Sun, X. Dev Cell , 2013 Jan 24(1):52-63. Selected as featured article of the issue.
  • Genome-scale study of transcription factor expression in the branching mouse lung Herriges J.C., Yi L., Hines E.A., Harvey J.F., Xu G., Gray P.A., Ma Q., Sun X. Dev Dyn . 2012 Sep 241(9):1432-1453.
  • The microRNA-processing enzyme Dicer is dispensable for somite segmentation but essential for limb bud positioning Zhang Z, O'Rourke JR, McManus MT, Lewandoski M, Harfe BD and Sun X. Dev Dyn . 2011 Mar 351(2), 254-265.
  • Signaling through BMP receptors promotes respiratory identity in the foregut via repression of Sox2 Domyan, E.T., Ferretti, E.,ockmorton, K., Mishina, Y., Nicolis, S.K. and Sun, X. Development . 2011 Mar 138(5): 971-981.
  • Preaxial polydactyly: interactions among ETV, TWIST1 and HAND2 control anterior-posterior patterning of the limb Zhang, Z., Sui, P., Dong, A., Hassell, J., Cserjesi, P., Chen, Y.T., Behringer, R.R. and Sun, X. Development . 2010 Oct 137(20), 3417-3426.
  • Beta-Catenin promotes respiratory progenitor identity in mouse foregut Harris-Johnson, K.S., Domyan, E.T., Vezina, C.M. and Sun, X. PNAS . 2009 Sep 106(38), 16287-92.
  • FGF-regulated Etv genes are essential for repressing Shh expression in mouse limb buds Zhang, Z., Verheyden, J.M. and Sun, X. Dev Cell . 2009 Apr 16(4): 607-613.
  • An Fgf/Gremlin inhibitory feedback loop triggers termination of limb bud outgrowthVerheyden, J.M. and Sun, X. Nature . 2008 Jul 454(7204): 638-641.
  • Dicer function is essential for lung epithelium morphogenesis Harris, K.S., Zhang, Z., McManus, M.T., Harfe, B.D. and Sun, X. PNAS . 2006 Feb 103 (7), 2208-2213.

Biography

Xin Sun received her Ph.D. from the Department of Biology at Yale University and postdoctoral training with Dr. Gail Martin at UCSF. She was on the faculty in the Genetics Department at University of Wisconsin-Madison from 2002 to 2016, when she joined the UCSD faculty. Dr. Sun was the recipient of a Burroughs-Wellcome career award, a March of Dimes Basil O’Conner award, and Romnes Faculty Fellowship by Wisconsin Alumni Research Foundation.