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Collaborative Studies on Lung Stem Cell Biology and Cell Based Therapy
 
 


Jeffrey A. Whitsett, MD
Cincinnati Children’s Hospital Medical Center

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Dr. Jeffrey Whitsett is Chief of the Section of Neonatology, Perinatal and Pulmonary Biology at Cincinnati Children's Hospital Medical Center. He received his medical degree at Columbia University.

Along with his work at the University of Cincinnati College of Medicine, he is also:

  • Executive Director, Perinatal Institute
  • Professor of Pediatrics, University of Cincinnati College of Medicine

Consortium Research Title: Transcriptional Control of Respiratory Epithelial Progenitor Cells

Consortium Research Description:

This is a multi-investigator, collaborative proposal based on the concept that respiratory epithelial stem/progenitor cell proliferation and differentiation are controlled, at least in part, by transcriptional mechanisms that determine gene expression, cell fates, and functions. Cellular replacement for therapy of severe pulmonary disorders will require detailed knowledge of the transcriptional programs that govern respiratory epithelial specification and differentiation. The long-term goals of this application are to 1) identify respiratory epithelial progenitor cells (REPCs) and the transcriptional programs mediating their proliferation and differentiation, and 2) assess the ability of these transcriptional mediators to engineer/program both endogenous respiratory epithelial progenitor cells and exogenous cells (including embryonic stem cells (ES) and multipotent stem cell progenitors (MSC/Ps), to exhibit respiratory epithelial differentiation that may be useful for cell replacement for life-threatening pulmonary disease. We will use mouse cells and transgenic mouse models to identify REPCs and the transcriptional programs regulating their proliferation and differentiation, seeking to identify subsets of conducting and peripheral airway cells that exhibit stem cell/progenitor cell behavior during lung regeneration/repair. Transcriptional engineering will be used to determine the scope of cellular plasticity and proliferation of REPCs, MSC/Ps, and ES cells. The ability of non-pulmonary cells to be transcriptionally engineered to express respiratory epithelial cell selective genes and functions will be determined. The experiments are designed to test the ability of both endogenous and exogenous REPCs to engraft in the lung and to contribute to repair of the respiratory epithelium. Clinically relevant mouse models will be utilized to assess this potential, with particular focus to post-pneumonectomy lung regeneration and repair after respiratory epithelial cell specific cell ablation and Sftpc-/- mice, the latter developing severe interstitial lung disease that is similar to that seen in individuals inheriting mutations in SFTPC, a gene causing idiopathic pulmonary fibrosis (IPF) in patients. A Stem Cell Consortium will be established at CCHMC, Univ. of Cincinnati College of Medicine to develop education, training, and research bridging hematopoietic stem cell and pulmonary stem cell biology on our campus.

 

Whitsett Lab Information: 
3333 Burnet Avenue,
Cincinnati, OH 45229-3039
Phone: 513-803-2790
Fax: 513-636-7868

Administrative Assistant Contact Info
Name:
Cindy Wilson  
Phone: 513-803-2790 
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Dr. Jeffrey Whitsett's laboratory seeks to:

  • Elucidate the hierarchy of transcriptional controls and signaling cascades which determine commitment of progenitor cells that produce the differentiated epithelial cells lining the primordial and mature respiratory tract
  • Determine mechanisms controlling cell-specific gene transcription governing lung epithelial cell proliferation and differentiation that will provide insight into the pathogenesis of acute and chronic lung disorders such as respiratory distress syndrome, pulmonary fibrosis, bronchopulmonary dysplasia and other disorders of surfactant homeostasis

Transcriptional control of surfactant expression, lung morphogenesis and function are being assessed. Conditional systems for gene targeting and addition have been developed for study of lung formation, and function, as well as for identifying lung progenitor cells and their fates in the mouse. Transgenic mouse models are being utilized to understand the pathogenesis of genetic and inflammatory lung disorders and to develop gene therapy for respiratory disease. The role of surfactant in innate host defense and lung function is studied.

Recent Publications

  • Perl, A.K., Zhang, L. and Whitsett JA.: Conditional expression of genes in the respiratory epithelium in transgenic mice: cautionary notes and toward building a better mouse trap. Am. J. Respir. Cell Mol. Biol. 40:1-3, 2009.

  • Wang, I-C., Meliton, L., Ren, X., Zhang, Y., Balli, D., Snyder, J., Whitsett, J.A., Kalinichenko, V.V. and Kalin, T.V.:  Deletion of forkhead box M1 transcription factor from respiratory epithelial cells inhibits pulmonary tumorigenesis. PLoS ONE 4:e6609, 2009.

  • Lange, A.W., Keiser, A.R., Wells, J.M., Zorn, A.M. and Whitsett, J.A.:  Sox17 promotes cell cycle progression and inhibits TGF-ß/Smad3 signaling to initiate progenitor cell behavior in the respiratory epithelium.  PLoS One  4:e5711, 2009. 

  • Linnerth, N.M., Siwicky, M.D., Campbell, C.I., Watson, K.L.M., Petrik, J.J., Whitsett, J.A. and Moorehead, R.A.:  Type I insulin-like growth factor receptor induces pulmonary tumorigenesis.  Neoplasia 11, 672-682, 2009. 

  • Chen, G., Korfhagen, T.R., Xu, Y., Kitzmiller, J., Wert, S.E., Maeda, Y., Gregorieff, A., Clevers, H. and Whitsett, J.A.:  SPDEF is required for mouse pulmonary goblet cell differentiation and regulates a network of genes associated with mucus production.  J. Clin. Invest. 119:2914-2924, 2009. 

  • Xu, Y., Saegusa, C., Schehr, A., Grant, S., Whitsett, J.A. and Ikegami, M.:  C/EBPa is required for pulmonary cytoprotection during hyperoxia.  Am. J. Physiol. 297:L286-L298, 2009. 

  • Meyer, S.E., Hasenstein, J.R., Baktula, A., Velu, C.S., Xu, Y., Wan, H., Whitsett, J.A., Gilks, C.B. and Grimes, H.L.:  Krüppel-like factor 5 is not required for K-RasG12D lung tumorogenesis, but represses ABCG2 expression and is associated with better disease-specific survival.  Am. J. Pathol., in revision.

  • Tompkins, D.H., Besnard, V., Lange, A.W., Wert, S.E., Keiser, A.R., Smith, A.N., Lang, R. and Whitsett, J.A.:  Sox2 is required for maintenance and differentiation of bronchiolar Clara, ciliated, and goblet cells.  PLoS ONE 4:e8248, 2009.

  • Chen, G., Wan, H., Luo, F., Zhang, L., Xu, Y., Lewkowich, I., Wills-Karp, M. and Whitsett, J.A.:  Foxa2 programs Th2-cell mediated innate immunity in the developing lung.  J. Immunol., in press.

  • Galambos, C., Levy, H., Cannon, C.L., Vargas, S.O., Reid, L.M., Cleveland, R., Lindeman, R., deMello, D.E., Wert, S.E., Whitsett, J.A., Perez-Atayde, A.R. and Kozakewich H.:  Pulmonary pathology in thyroid transcription factor-1 deficiency syndrome.  Am. J. Respir. Crit. Care Med., in press.

  • Tompkins, D.H., Besnard, V., Lange, A.W., Keiser, A.R., Wert, S.E., Bruno, M.D. and Whitsett, J.A.:  Sox2 activates cell proliferation and differentiation in the respiratory epithelium.  Submitted for publication.

  • Castro, M., Ramirez, M.I., Gern, J.E., Cutting, G., Redding, G., Hagood, J.S., Whitsett, J., Abman, S., Raj, J.U., Barst, R., Kato, G.J., Gozal, D., Haddad, G.G., Prabhakar, N.R., Gauda, E., Martinez, F.D., Tepper, R., Wood, R.E., Accurso, F., Teague, W.G., Venegas, J., Cole, F.S. and Wright, R.J.:  Strategic plan for pediatric respiratory diseases research:  An NHLBI working group report.  Proc. Am. Thorac. Soc. 6:1-10, 2009.

  • Castro, M., Ramirez, M.I., Gern, J.E., Cutting, G., Redding, G., Hagood, J.S., Whitsett, J., Abman, S., Raj, J.U., Barst, R., Kato, G.J., Gozal, D., Haddad, G.G., Prabhakar, N.R., Gauda, E., Martinez, F.D., Tepper, R., Wood, R.E., Accurso, F., Teague, W.G., Venegas, J., Cole, F.S. and Wright, R.J.:  Strategic plan for pediatric respiratory diseases research:  An NHLBI working group report.  Abman, S., Jobe, A., Chernick, V. and Blaisdell, C. (eds.) Pediatr. Pulmonol. 44:2-13, 2009. 

  • Wert, S.E., Whitsett, J.A. and Nogee, L.M.:  Perspectives in Pediatric Pathology.  Genetic disorders of surfactant dysfunction.  Pediatr. Dev. Pathol. 12:253-274, 2009. 

  • Whitsett, J.A., Wert, S.E. and Weaver, T.E.:  Alveolar surfactant homeostasis and the pathogenesis of pulmonary disease.  Annu. Rev. Med. 61:105-119, 2010. 

  • Marcus, C.L., Smith, R.J.H., Mankarious, L.A., Arens, R., Mitchell, G.S., Elluru, R.G., Forte, V., Goudy, S., Jabs, E.W., Kane, A.A., Katz, E., Paydarfar, D., Pereira, K., Reeves, R.H., Richtsmeier, J.T., Ruiz, R.L., Thach, B.T., Tunkel, D.E., Whitsett, J.A., Wootton, D. and Blaisdell, C.J.:  Developmental Aspects of the Upper Airway: Report from an NHLBI workshop, March 5-6, 2009.  Proc. Am. Thorac. Soc. 6:513-520, 2009.