In published work, we used diphtheria toxin-induced genetic cellular ablation to understand how normal tissue architecture is restored after the loss of a single airway epithelial cell type. We discovered 4 new phenomenon not previously described (1) that a fully mature vertebrate cell can dedifferentiate into a stem cell when stem cells are ablated, (2) that the ablation of the most terminally differentiated cell type in the airway epithelium does not engender a regenerative response suggesting that there is no feedback injury signal emanating from the ciliated cell to guide stem cell-based regeneration, (3) that basal cells are not merely sources of new cells, but that they send feed-forward signals to secretory epithelial cells to actively orchestrate whole tissue behavior, and finally (4) that the basal cells are not a homogeneous population of stem cells. We further identified Notch signaling as the mechanistic basis for both the novel stem cell feed-forward signaling mechanism and as the basis of basal cell heterogeneity. In this application, we propose to continue our use of precise genetic cellular ablation studies to interrogate the regulatory circuitry of the airway epithelium, and to define how Notch signaling orchestrates the behavior of specific populations of airway epithelial cells. We now propose to directly extend our prior work examining the steady state airway epithelium, and deploy our model systems to study physiologically relevant- injury. We have three general hypotheses that we intend to verify or refute using our now well-developed tools for cellular ablation and cell type-specific Notch signaling modulation. First, we hypothesize that the basal stem cell is a central actor during the regenerative response, and that it actively makes use of Notch ligands to fundamentally regulate the process of mucous metaplasia in multiple cell types. Thus, rather than simply serving to supply new cells to replace injured ones, stem cells are hypothesized to orchestrate whole tissue behaviors. Secondly, we hypothesize that distinct components of both the Notch signal sending (Notch ligands) and receiving (Notch receptors) pathways are modulated differentially in response to differing degrees and types of injury. Thirdly we postulate that a feedback signal regulating regeneration must be present to complement the novel feed forward signaling mechanism that we have recently demonstrated. Furthermore, since this signal seems absent from ciliated cells, we hypothesize that the feedback signal must emanate from the secretory cells. This work has taken on added importance, as antibody reagents for Notch modulation are now being considered as clinical interventions.
The regeneration of the airway is essential to prevent respiratory diseases such as COPD, asthma, cystic fibrosis, recovery from bronchitis and infection, and a host of rare respiratory illnesses. Disease is often associated with failed regeneration, and this proposal aims to understand how cells within the airway communicate. If we can apply these lessons to patients, we can restore proper airways to patients who suffer from lung disease.
| Taylor, Martin S; Chivukula, Raghu R; Myers, Laura C et al. (2018) Delayed Alveolar Epithelialization: A Distinct Pathology in Diffuse Acute Lung Injury. Am J Respir Crit Care Med 197:522-524 |
| Lin, Brian; Srikanth, Priya; Castle, Alison C et al. (2018) Modulating Cell Fate as a Therapeutic Strategy. Cell Stem Cell 23:329-341 |
| Tata, Purushothama Rao; Chow, Ryan D; Saladi, Srinivas Vinod et al. (2018) Developmental History Provides a Roadmap for the Emergence of Tumor Plasticity. Dev Cell 44:679-693.e5 |
| Taylor, Martin S; Chivukula, Raghu R; Myers, Laura C et al. (2018) A Conserved Distal Lung Regenerative Pathway in Acute Lung Injury. Am J Pathol 188:1149-1160 |
| Yonker, Lael M; Pazos, Michael A; Lanter, Bernard B et al. (2017) Neutrophil-Derived Cytosolic PLA2? Contributes to Bacterial-Induced Neutrophil Transepithelial Migration. J Immunol 199:2873-2884 |
| Paksa, Azadeh; Rajagopal, Jayaraj (2017) The epigenetic basis of cellular plasticity. Curr Opin Cell Biol 49:116-122 |
| Tata, Purushothama Rao; Rajagopal, Jayaraj (2016) Cellular plasticity: 1712 to the present day. Curr Opin Cell Biol 43:46-54 |
| Tata, Purushothama Rao; Rajagopal, Jayaraj (2016) Regulatory Circuits and Bi-directional Signaling between Stem Cells and Their Progeny. Cell Stem Cell 19:686-689 |
| Mou, Hongmei; Vinarsky, Vladimir; Tata, Purushothama Rao et al. (2016) Dual SMAD Signaling Inhibition Enables Long-Term Expansion of Diverse Epithelial Basal Cells. Cell Stem Cell 19:217-231 |
| Pardo-Saganta, Ana; Tata, Purushothama Rao; Law, Brandon M et al. (2015) Parent stem cells can serve as niches for their daughter cells. Nature 523:597-601 |
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