Module 4: Adult Lung Stem Cells

Module Leader	Associate Professor Ivan Bertoncello
Host Organisation	Australian Stem Cell Centre

Module description

The most significant impediment to the delivery of cell therapies for intractable respiratory diseases is the lack of knowledge about the precise identity and spatial location of regenerative stem cells in the adult lung, and the way in which lung stem and progenitor cell compartments are regulated by growth factors, stromal cells and extracellular matrix proteins which comprise their microenvironment.

Photo to right:  this image uses immunohistological staining, which demonstrates that cells within the colony secrete the mucins MUC5A (Blue) and MUC1 (green) and Surfactant Protein-C (red). The stem cells were grown in matrigel.

Aims

The broad aims of research in this module are to:

1. establish the identity and properties of regenerative stem and progenitor cells in the adult lung, and determine how they are organised
2. identify key biomatrix elements and stromal cells comprising the lung epithelial stem cell niche(s) which regulate their regenerative potential
3. develop a 'gold-standard' transplantation model and in vitro clonogenic assays which measure and predict lung stem cell regenerative potential
4. identify and characterise the human homologues of lung epithelial stem and progenitor cells identified in mouse models

The successful completion of this project will enable us to identify endogenous stem cells in the adult lung around which therapies can be constructed, and enable us to understand how their microenvironment can be manipulated to best harness their potential in the treatment of lung diseases.

Module Leader biography

A/Professor Ivan holds honorary academic appointments in the Department of Anatomy and Cell Biology, Monash University, and the Department of Pathology, University of Melbourne, and is a former Fellow of the Alexander von Humboldt Foundation (Germany).

Associate Professor Bertoncello’s pioneering work in the development of Rhodamine 123 and Hoechst 33342 dye-based cell separative strategies for haemopoietic stem cell isolation, and his laboratory’s definitive study of haemopoietic stem cell cycling and turnover has provided the field with powerful tools for the analysis of haemopoietic stem cells leading to a re-evaluation of models of haemopoietic stem cell organisation and function. He has served as president of the Australian and New Zealand Society of Cell and Developmental Biology. (1992–1994); Associate Editor of Experimental Hematology (1994–1998); Co-chair of a National Heart, Lung and Blood Institute (NIH) working group on standardisation of surrogate haematopoietic stem cell assays relevant to clinical transplantation (1998-1999); Chair of the Nominating Committee of the International Society of Hematology (2000) and Senior Advisor to the Emerging Leaders Taskforce of the International Society of Experimental Hematology (2002–2004).

Contact Details

E-mail	ivan.bertoncello@stemcellcentre.edu.au
Phone	+61 3 9271 1174

Selected publications

1. Bradford GB, Williams B, Rossi R, Bertoncello I. (1997) Quiescence, cycling and turnover in the primitive hematopoietic stem cell compartment. Exp Hematol., 25:445-453.
2. Bertoncello I, Williams B. (2004) Hematopoietic stem cell characterization by Hoechst 33342 and Rhodamine 123 staining. In " Methods in Molecular Biology Vol 263: Flow Cytometry Protocols", 2nd Edition. Eds. TS Hawley, RG Hawley (Humana Press Inc., Totowa, New Jersey), Pps. 181-200.
3. Ramsay RG, Micallef S, Lightowler S, Mucenski ML, Mantamadiotis T, Bertoncello I. (2004) c-myb heterozygous mice are hypersensitive to 5-fluorouracil and ionizing radiation. Mol Cancer Res 2:354-361.
4. Ramsay RG, Micallef SJ, Williams B, Lightowler S, Vincan E, Heath J, Mantamadiotis T, Bertoncello I. (2004) Colony-stimulating Factor 1 promotes clonogenic growth of normal murine colonic crypt epithelial cells in vitro. J Interferon Cytokine Res 24:416-427.
5. Kaur P, Li A, Redvers R, Bertoncello I. (2004) Keratinocyte stem cell assays: an evolving science. J Investig Dermatol Symp Proc 9:238-247.
6. Challen GA, Bertoncello I, Deane JA, Ricardo SD, Little MH. (2006) Kidney side population reveals multilineage potential and renal functional capacity but also cellular heterogeneity. J Am Soc Nephrol 17:1896-1912.
7. Wong SHA, Lowes KN, Bertoncello I, Cook MJ, Simmons PJ, Kornberg AJ, Kapsa RMI. (2007) Evaluation of Sca-1 and c-Kit as selective markers for muscle remodelling by non-hemopoietic bone marrow cells. Stem Cells 25:1364-1374.
8. Jokubaitis VJ, Sinka L, Driessen R, Whitty G,  Haylock DN, Bertoncello I, Smith I, Péault B, Tavian M, Simmons PJ. (2008) Angiotensin-converting enzyme (CD143) marks hematopoietic stem cells in human embryonic, fetal, adult hematopoietic tissues. Blood 111:4055-4063.
9. McQualter JL, Brouard N, Williams B, Baird BN, Sims-Lucas S, Yuen K, Nilsson SK, Simmons PJ, Bertoncello I. (2009)  Endogenous fibroblastic progenitor cells in the adult mouse lung are highly enriched in the Sca-1 positive cell fraction. Stem Cells 27: 623-633.
10. Huynh D, Dai X, Nandi S, Lightowler S, Trivett M, Chan C, Bertoncello I, Ramsay R, Stanley ER. (2009) Paneth cell development in the small intestine is CSF-1 dependent. Gastroenterology 137:136-144.