Associate Professor, Department of Pulmonary Medicine - Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
My lab is interested in the normal developmental processes that build the lung and how such processes go awry during lung malformations, injury and tumorigenesis. What is unique about my lab is our effort to develop a series of three-dimensional labeling and imaging methods such as optical projection tomography. We develop these novel methods to address a major challenge in studying the lung – its complex three-dimensional architecture including the tree-like airways and honeycomb-like alveoli, making it difficult to compare structures on conventional two-dimensional sections.
Development of the alveolar type 1 cell and bronchopulmonary dysplasia
Bronchopulmonary dysplasia (BPD) is a major chronic lung disease associated with preterm birth and characterized by alveolar simplification with dysmorphic microvasculature. Current BPD research focuses on myofibroblasts, alveolar type 2 (AT2) cells and the endothelium, but seems to leave out the “elephant in the room”, the alveolar type 1 (AT1) cell, which constitutes nearly all the alveolar surface and associates intimately with the microvasculature. We have delineated a two-step AT1 cell morphogenesis process, cell flattening and cell folding, which leads to its ultrathin and yet expansive morphology. We have identified a key transcriptional regulator of this process, without which AT1 cells lose their molecular and cellular characteristics and the lung undergoes alveolar simplification as in BPD. Thus, our findings have implicated AT1 cell development and its regulator in the pathogenesis of BPD. We are dissecting the direct and indirect targets of this regulator. We are also interested in its role in AT1 cell homeostasis and injury in the adult lung.
Novel signaling roles of the alveolar type 1 cell
AT1 cells are traditionally considered a passive structural component of the alveoli while attention has been focused on AT2 cells due to their proposed stem cell function. We have found that AT1 cells, instead of AT2 cells, are the unexpected source of a key angiogenic factor VEGFA and AT1 cell-derived VEGFA is required for alveolar angiogenesis. These findings open the door to a mechanistic understanding of alveolar angiogenesis, which is proposed to occur through intussusceptive angiogenesis, but is poorly understood on the molecular and cellular level. We are studying how lung endothelial cells respond to Vegfa during intussusceptive angiogenesis and whether and how the same Vegfa signaling elicits distinct responses from those during the well-characterized retinal sprouting angiogenesis. We are also interested in the role of AT1 cell-derived VEGFA during homeostasis and tumorigenesis.
Given our demonstration of the unexpected angiogenic role of AT1 cells and their extensive surface area, we hypothesize that AT1 cells have other novel signaling roles. Through a series of transcriptome analyses, we have identified a Wnt ligand specifically expressed in AT1 cells but not AT2 cells, an expression pattern similar to that of Vegfa. We have generated conditional knockout alleles to test whether AT1 cells may also signal to mesenchymal cells such as myofibroblasts.
Maintenance of airway cell mosaicism during growth and regeneration
The lung filters the inhaled air via mucociliary clearance, the failure of which encourages microbial growth and inflammation as in asthma and COPD. The mucociliary clearance function is split between and hence requires coordination of two airway cell types, secretory and ciliated cells, where secretory cells secret mucus to trap inhaled microbes and particles while ciliated cells move the mucus layer rostrally via a conveyor belt-like action. Such functional coordination depends on secretory and ciliated cells intermingled at the proper proportion and pattern, which we call airway cell mosaicism. This airway cell mosaicism is established during embryonic development under the control of Notch signaling, but must be maintained during subsequent airway growth and reestablished during regeneration. Combining clonal analyses, whole-mount imaging and computational modeling, we have found evidence for a robust self-correcting mechanism of maintaining the airway cell mosaicism. We are developing a novel somatic CRISPR method to dissect the underlying molecular mechanisms. We are also interested in extending our analyses to the more complex trachea epithelium with a third airway cell type, basal cells.
A hierarchical gene regulatory network controlling SOX9 epithelial progenitors
We have shown that the entire lung epithelium arises from a group of SOX9 epithelial progenitors. The SOX9 progenitors emerge as the lung primordium just buds off the embryonic foregut, constitute all the tips of the rapidly-branching respiratory tree, and disappear soon after birth as the alveolar region matures. Lineage tracing shows that they differentiate into SOX2 airway cells during early development and alveolar cells during late development. Thus, the maintenance and differentiation of the SOX9 progenitors must be precisely controlled in coordination with branching morphogenesis and developmental timing. Although a number of signaling pathways have been identified to affect the SOX9 progenitors, it is unclear how different signaling pathways interact and what molecular changes they elicit in the SOX9 progenitors. We hypothesize a hierarchical gene regulatory network shapes the epigenetic landscape of the SOX9 progenitors to control their maintenance and differentiation. Using genetic epistasis analysis and genomic bioinformatics, we have assembled an initial gene regulatory network and are developing methods to assay the epigenome of purified SOX9 progenitors. We believe that perturbation or modulation of the gene network in the SOX9 progenitors underlies abnormal/sub-optimal lung development or species-specific lung branching complexity, respectively.
|2007||The Johns Hopkins University School of Medicine, Baltimore, MD, USA, PHD, Molecular Biology and Genetics|
|2007||The Johns Hopkins University School of Public Health, Baltimore, MD, USA, MHS, Bioinformatics|
|2001||Fudan University, Shanghai, CHN, BS, Biochemistry|
|2007-2011||Postdoctoral fellowship, Biochemistry, Stanford University, Stanford, CA|
Assistant Professor, Department of Pulmonary Medicine - Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 2011 - 2017
|2016||MDACC Division of Internal Medicine Cyrus Scholar Award|
|2015||March of Dimes Basil O'Connor Scholar Award|
|2015||American Lung Association Biomedical Research Grant (declined)|
|2014||MDACC R. Lee Clark Fellows Award|
|2013||UT Lung SPORE Career Development Award|
|2013||MDACC Division of Internal Medicine Distinguished Paper Award|
|2013||MDACC Division of Internal Medicine Researcher of the Year|
|2011||The University of Texas System Rising STARS award|
|2007||Jane Coffin Childs Memorial Fund for Medical Research|
|2007||Phi Beta Kappa (Ph.D.)|
|1999||Monsanto Fellowship for Distinguished Students|
|1998||Excellent Student of Fudan University|
|1998||Outstanding Student Fellowship of Fudan University|
|1998||People Scholarship of Fudan University|
|1998||Hongkong Sponsor Fellowship for distinguished students|
|1997||Tan Jiazhen Life Science Fellowship|
|1997||The Freshman Fellowship for excellent performance in the National College Entrance Examinations|
- Yang J, Hernandez BJ, Martinez Alanis D, Narvaez Del Pilar O, Vila-Ellis L, Akiyama H, Evans SE, Ostrin EJ, Chen J. Development and Plasticity of Alveolar Type 1 Cells (cover article). Development 143(1):54-65, 2016. e-Pub 2015. PMID: 26586225.
- Yang J, Chen J. Developmental Programs of Lung Epithelial Progenitors: a Balanced Progenitor Model. Wiley Interdiscip Rev Dev Biol 3(5):331-47, 2014. e-Pub 2014. PMID: 25124755.
- Alanis DM, Chang DR, Akiyama H, Krasnow MA, Chen J. Two Nested Developmental Waves Demarcate a Compartment Boundary in the Mouse Lung. Nat Commun 5:3923, 2014. e-Pub 2014. PMID: 24879355.
- Chen J, Krasnow MA. Integrin Beta 1 suppresses multilayering of a simple epithelium. PLoS One 7(12):e52886, 2012. PMID: 23285215.
- Chen J, Nathans J. Estrogen-related receptor beta/NR3B2 controls epithelial cell fate and endolymph production by the stria vascularis. Dev Cell 13(3):325-37, 2007. PMID: 17765677.
- Chen J, Nathans J. Genetic ablation of cone photoreceptors eliminates retinal folds in the retinal degeneration 7 (rd7) mouse. Invest Ophthalmol Vis Sci 48(6):2799-805, 2007. PMID: 17525215.
- Chen J, Rattner A, Nathans J. Effects of L1 retrotransposon insertion on transcript processing, localization and accumulation: lessons from the retinal degeneration 7 mouse and implications for the genomic ecology of L1 elements. Hum Mol Genet 15(13):2146-56, 2006. e-Pub 2006. PMID: 16723373.
- Chen J, Rattner A, Nathans J. The rod photoreceptor-specific nuclear receptor Nr2e3 represses transcription of multiple cone-specific genes. J Neurosci 25(1):118-29, 2005. PMID: 15634773.
- Chang DR, Martinez Alanis D, Miller RK, Ji H, Akiyama H, McCrea PD, Chen J. Lung epithelial branching program antagonizes alveolar differentiation (cover article). Proc Natl Acad Sci U S A. e-Pub 2013. PMID: 24058167.
- Chen J. Origin and regulation of a lung repair kit. Nat Cell Biol 19(8):885-886, 2017. PMID: 28752852.
|Title:||Airway tube size control|
|Funding Source:||Jane Coffin Childs Memorial Fund for Medical Research|
|Title:||3D imaging of lung development|
|Funding Source:||The University of Texas System Rising STARS award|
|Title:||Lung development and lung cancer|
|Funding Source:||The University of Texas M. D. Anderson Cancer Center Start-up Fund|
|Title:||Genetic and Cellular Mechanisms of Airway Diameter Control|
|Funding Source:||March of Dimes Basil O'Connor Scholar Award|
|Title:||Role of AT1 cells in perinatal lung maturation|
|Title:||Cyrus Scholar Award|
|Funding Source:||The Cyrus Family Foundation|
|Title:||R. Lee Clark Fellows Award|