Brigid L.M. Hogan, Ph.D., FRS (Cambridge, UK)
Professor and Chair, Department of Cell Biology
University Program in Genetics
University Program in Cell & Molecular Biology
Graduate Program in Cancer Biology
Developmental Biology Training Program
388 Nanaline Duke Bldg., Box 3709
Duke University Medical Center
Durham, NC 27710
The Hogan lab studies the cellular and genetic mechanisms underlying the development, maintenance and repair of organs derived from embryonic foregut endoderm. We focus on the lung, using the mouse as a model organism. We are particularly interested in the stem cells that play an essential role in the development of the lung and its repair after injury. We are driven by both curiosity and by practical considerations. We believe that in the long run knowledge about the cells, signaling pathways and genetic programs required for the growth, development and regeneration of the lung will translate into new approaches to clinical problems. These include promoting lung maturation in premature babies and repair of lung epithelium after damage by harmful agents, inhibiting pulmonary fibrosis, and blocking the growth of tumors.
We focus on the lung for several reasons. First, its development depends on a fundamental developmental process known as "branching morphogenesis" shared by other organs such as the kidney and mammary glands. These organs initiate as small buds of epithelial and mesenchymal cells that undergo repeated rounds of outgrowth and branching. We have contributed to knowledge about branching morphogenesis by identifying signaling factors and pathways active in discrete populations of cells that direct the temporal and spatial pattern of airway branching. Second, pulmonary disorders affect millions of people world wide and many disorders such as lung cancer, COPD and fibrosis remain essentially intractable to therapy. While exciting progress has been made in understanding how tissue stem cells contribute to the growth and repair of other adult organ systems, still relatively little is known about their contributions in the lung. Our goal is to address this deficiency.
One hallmark of our work is the generation of mouse lines in which genes can be conditionally manipulated in specific cells in the lung. This allows us to test the function of genes and to trace the fate of cells in the intact organ. We have used lineage tracing to identify a population of multipotent progenitor cells in the tips of the rapidly growing lung buds that give rise to all the specialized epithelial cell types of the adult organ. We and others have identified a set of genes preferentially expressed in these cells (including Sox9 shown in the figure below). We have also generated several new lines of mice to test the role of candidate stem cells resident in the adult lung, including Trp63+ Krt5+ basal cells in the trachea and larger airways, secretory (Clara) cells in the conducting airways, and Type II cells in the alveoli.
We are particularly interested in the basal stem cells of the mouse trachea because they provide an important model for basal cells in the small airways of the human lung that often become damaged or occluded in disease. We have developed methods for isolating basal cells, growing them in culture and manipulating genes in them, all techniques being exploited to test specific hypotheses about their role in airway maintenance, barrier function, remodeling and repair. Most recently, we have used lineage tracing to show that mature Type II cells do not undergo epithelial-to-mesenchymal transition during experimental fibrosis. Rather, we find that multiple mesenchymal cell types, including pericytes, likely contribute to the fibrotic lesions. Our overall hypothesis is that failure of the alveolar epithelial cells to proliferate and differentiate after damage can promote the development and persistence of fibrosis. We are testing this idea using a variety of genetic approaches.
Gao X, Bali AS, Randell SH, Hogan BL. (2015) GRHL2 coordinates regeneration of a polarized mucociliary epithelium from basal stem cells. J Cell Biol 211(3):669-82.
Jain R, Barkauskas CE, Takeda N, Bowie EJ, Aghajanian H, Wang Q, Padmanabhan A, Manderfield LJ, Gupta M, Li D, Li L, Trivedi CM, Hogan BL, Epstein JA. (2015) Plasticity of Hopx(+) type I alveolar cells to regenerate type II cells in the lung. Nat Commun. 6:6727.
Alder JK, Barkauskas CE, Limjunyawong N, Stanley SE, Kembou F, Tuder RM, Hogan BL, Mitzner W, Armanios M. (2015) Telomere dysfunction causes alveolar stem cell failure. Proc Natl Acad Sci U S A. 112(16):5099-104.
Xu X, Huang L, Futtner C, Schwab B, Rampersad RR, Lu Y, Sporn TA, Hogan BL, Onaitis MW. (2014) The cell of origin and subtype of K-Ras-induced lung tumors are modified by Notch and Sox2. Genes Dev. 28(17):1929-39.
Tadokoro T, Wang Y, Barak LS, Bai Y, Randell SH, Hogan BL. (2014) IL-6/STAT3 promotes regeneration of airway ciliated cells from basal stem cells. Proc Natl Acad Sci U S A. 111(35):E3641-9.
Hogan BL, Barkauskas CE, Chapman HA, Epstein JA, Jain R, Hsia CC, Niklason L, Calle E, Le A, Randell SH, Rock J, Snitow M, Krummel M, Stripp BR, Vu T, White ES, Whitsett JA, Morrisey EE. (2014) Repair and regeneration of the respiratory system: complexity, plasticity, and mechanisms of lung stem cell function. Cell Stem Cell. 15(2):123-38.
Wansleeben, C., Bowie, E., Hotten, DF, Yu, YR, and Hogan, BL (2014) Age-related changes in the cellular composition and epithelial organization of the mouse trachea PLoS One 9(3):e93496
Barkauskas, C.E., Cronce, M.J., Rackley, C.R., Bowie, E.J., Keene, D.R., Stripp, B.R., Randell, S.H., Nobel, P.W. and Hogan, B.L. (2013) Type 2 alveolar cells are stem cells in adult lung J Clin Invest 7: 3025-36.
Wansleeben, C., Barkauskas, C.E. and Hogan, B.L. (2013) Stem cells of the adult lung: their development and role in homeostasis, regeneration, and disease Wiley Interdiscip Rev Dev Biol 1: 131-48.
O'Koren, E.G., Hogan, B.L., and Gunn, M.D. (2013) Loss of Basal Cells Precedes Bronchiolitis Obliterans-Like Pathological Changes in a Murine Model of Chlorine Gas Inhalation Am J Respir Cell Mol Biol [Epub ahead of print].
Gao, X., Vockley, C.M., Pauli, F., Newberry, K.M., Xue, Y., Randell, S.H., Reddy, T.E., Hogan, B.L. (2013) Evidence for multiple roles for grainyheadlike 2 in the establishment and maintenance of human mucociliary airway epithelium Proc Natl Acad Sci USA 23: 9356-61.
Huang, F., Zhang, H., Wu, M., Yang, H., Kudo, M., Peters, C.J., Woodruff, P.G., Solberg, O.D., Donne, M.L., Huang, X., Sheppard, D., Fahy, J.V., Wolters, P.J., Hogan, B.L., Finkbeiner, W.E., Li, M., Jan, Y.N., Jan, L.Y., and Rock, J.R. (2012) Calcuium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction Proc Natl Acad Sci USA 40:165354-9.
Xu, X. Rock, J.R., Lu, Y., Futtner, C., Schwab, B., Guinney, J., Hogan, B.L., and Onaitis, M.W. (2012) Evidence for type II cells as cells of origin of K-Ras-induced distal lung adenocarcinoma Proc Natl Acad Sci USA 13: 4910-5.