Module 2: Determining the Location, Origin and Normal Function of Endogenous Renal MSCs and their Relative Capacity to Elicit Renal Repair

Module Leader	Professor Melissa Little
Host Organisation	University of Queensland

Module description

Chronic renal failure costs $US25 billion per annum in the US ($AU1billion in Australia) and the incidence is rising at 8% per annum. Hence, the development of potential alternative therapies is of great importance. Bone marrow derived mesenchymal stem cells (BM-MSCs) have been shown to ameliorate renal damage incurred from a variety of models of acute renal damage in mice. The mode of action has been proposed to be humoral, with the BM-MSCs providing pro-proliferative and anti-inflammatory growth factors.

However, there is evidence that the long term outcome of MSCs is maldifferentiation. In our currently funded ASCC project, we have isolated a clonal, self-renewing MSC-like population of cells from the postnatal murine kidney. As for other MSC, these cells display multipotentiality and immunoregulatory capacity. However, they also show distinct gene expression and immunophenotype and have a capacity to epithelialise in vitro and in vivo. Hence, we hypothesise that i) renal MSCs can play an important reparative role in response to renal damage and ii) renal MSC will provide a more effective and safer renal reparative activity when delivered to damaged kidneys as compared to other sources of MSC.

Aims

In this modules previously funded ASCC project, they isolated a clonal, self-renewing MSC-like population of cells from the postnatal murine kidney. As for other MSCs, these cells display multipotentiality and immunoregulatory capacity. However, they also show distinct gene expression and immunophenotype and have a capacity to epithelialize in vitro and in vivo. For these reasons, we hypothesise that renal MSCs can play an important reparative role in response to renal damage.

To this end, this module will further characterise the origin and properties of endogenous renal MSCs and assess their role in responding to renal damage under the following aims:

1. Investigate the heterogeneity of the endogenous renal MSC population by quantifying clonogenicity, self renewal and potential from CFU-F of different sizes.
2. Determine the regional localisation of endogenous renal MSCs within the kidney and examine whether ER-MSCs from different regions show different phenotypes.
3. Examine the embryological origin of the cells that give rise to renal MSCs so as to better understand their potential functional properties.
4. Examine how these cells normally respond to renal damage.
5. Determine whether there is an equivalent population in the human kidney.

Module Leader biography

Professor Melissa Little is Group Leader of the Renal Development and Disease Laboratory at the Institute for Molecular Bioscience (IMB), The University of Queensland (UQ). Her research focuses on the molecular genetics of kidney development and the causes of renal disease, with the aim of developing stem cell technology for use in kidney regeneration. She has published over 80 articles in this area. Professor Little established the Renal Regeneration Consortium, a panel of national experts that works towards developing novel strategies for kidney regeneration. A direct outcome of this initiative was the incorporation of Nephrogenix Pty Ltd, which is developing cell-based therapies for renal disease.

Throughout her career, Professor Little’s achievements have been recognised by awards such as the Australian Academy of Sciences Gottschalk Medal in Medical Sciences (2004), the GlaxoSmithKline Award for Research Excellence (2005), and the Smart State Smart Women Award (2006). In 2006, she was awarded a prestigious Eisenhower Fellowship, which recognised her contribution to both the commercial and academic sectors.

Contact details

E-mail	m.little@imb.uq.edu.au
Phone	+61 7 3346 2054
Web	www.imb.uq.edu.au/index.html?page=14032&pid=0

Selected publications

1. Bickmore, W.A., Oghene, K., Little, M.H., Seawright, A., Van Heyningen, V., Hastie, N.D. Modulation of DNA binding specificity by alternative splicing of the Wilms tumor wt1 gene transcript. Science  (1992) 257,235-237
2. Little, M.H., Prosser, J., Condie, A., Smith, P.J., Van Heyningen, V., Hastie, N.D. Zinc finger point mutations within the WT1 gene in Wilms' tumor patients. Proc. Natl. Acad. Sci. USA.  (1992) 89, 4791-4795
3. Little, M.H., Williamson, K.A., Mannens, M., Kelsey, A., Gosden, C., Hastie, N.D., van Heyningen, V. Evidence that WT1 mutations in Denys-Drash syndrome patients may act in a dominant-negative fashion. Human Molecular Genetics  (1993)  2(3),259-264
4. Kennedy, D., Ramsdale, T., Mattick, J. and Little, M. An RNA recognition motif in WT1 revealed by structural modelling. Nature Genetics  (1996) 12(3),329-332
5. Patek, C.E.,  Little, M.H., Fleming, S., Miles, C., Charlieu, J-P., Clarke, A.R., Miyagawa, K., Christie, S., Doig, J., Harrison, D.J., A.J., Porteous, D., Brookes,  Hooper, M.L. & Hastie, N.D. A zinc finger truncation of murine WT1 results in the characteristic urogenital abnormalities of Denys-Drash syndrome. Proc. Natl. Acad. Sci. USA  (1999) 96(6),2931-2936
6. Challen, GA, Martinez, G, Davis, M, Teasdale, R, Grimmond, S and Little, MH. Identifying the molecular phenotype of renal progenitor cells. (2004) J Am Soc Nephrol.  15(9):2344-57
7. Challen G, Gardiner B, Caruana G., Martinez G., Davis M., Crowe M., Taylor D., Bertram J, Teasdale RD., Little MH, Grimmond SM. Temporal and spatial transcriptional programs in murine metanephric development. (2005) Physiological Genomics. 23(2):159-71
8. Challen GA, Ivan Bertoncello I, Deane J, Ricardo S & Little MH. Kidney side population cells represent a non-haematopoietic but heterogeneous population with multilineage and renal potential. (2006) J. Amer. Society Nephrol. 17(7):1896-912.
9. Brunskill E, Aronow B, Georgas K, Rumballe B, Valerius MT, Aronow J, Kaimal V, Jegga AG, Grimmond S, McMahon AP, Patterson LT, Little MH, Potter S. Atlas of gene expression in the developing kidney at microanatomic resolution. (2008) Dev Cell 15(5):781-91
10. Georgas, KM, Rumballe, BA, Valerius, MT, Chiu, HS, Thiagarajan, RD, Lesieur, E, Aronow, BJ, Brunskill, EW, Combes, AN, Tang, D, Taylor, D, Grimmond, SM, Potter, SS, McMahon, AP, Little, MH. Analysis of early nephron patterning reveals a role for distal RV proliferation in fusion to the ureteric tip via a cap mesenchyme-derived connecting segment. (2009) Dev. Biol (In  press, accepted May 29 2009)