Kidney Development, Disease and Regeneration

The kidneys are essential organs that maintain fluid balance, blood volume and electrolyte balance. This is achieved by the 1,000,000 individual nephrons present in each adult kidney, all of which are formed before birth. In humans, the stem cells that give rise to each nephron are lost before birth, hence any disease or damage after that time results in nephron loss and reduced kidney function. Each year, more than 4000 Australians will be diagnosed with chronic kidney disease with treatment costing in excess of $1 billion per annum. With this rate increasing at 6% per annum there is an urgent need to develop novel therapies for kidney disease.

Around 10-20% of kidney disease is inherited. In children with kidney disease, this is closer to 50% although in many instances, the disease-causing mutation is unknown, therefore limiting treatment options. In our research group, we investigate the genes required for normal kidney development and what happens as a result of genetic or environmental damage during development. This knowledge is used to try to recreate kidney stem cells. We have developed methods for generating mini-kidneys from human stem cells that represent models of the human organ. We hope to use these mini-kidneys to screen drugs for kidney toxicity, as models with which to understand kidney disease, to generate cells for the treatment of kidney disease and eventually to bioengineer replacement organs.

Group Leaders: 
Group Members: 
Dr Sara Howden
Role: 
Research Officer
Dr Jessica Vanslambrouck
Role: 
Research Officer
Dr Lorna Hale
Role: 
Research Officer
Dr Kynan Lawlor
Role: 
Research Officer
Dr Santhosh Kumar
Role: 
Research Officer
Dr David Yen
Role: 
Research Officer
Dr Belinda Phipson
Role: 
Research Officer
Pei Xuan Er
Role: 
Research Assistant
Dr Gemma Martinez
Role: 
Research Assistant
Irene Ghobrial
Role: 
Research Assistant
Sean Wilson
Role: 
Research Assistant
Pamela Kairath Oliva
Role: 
PhD Student
Tom Forbes
Role: 
PhD Student
Joanne Soo
Role: 
PhD Student
Asha Serpless
Role: 
Personal Assistant to Prof Melissa Little
Trish Barber
Role: 
Stem Cells Project Manager
Dr Andrew Mallett
Role: 
Honorary Fellow Manager off-site
Louise Wardrop
Role: 
KidGen Program Manager
Ella Wilkins
Role: 
Associate Genetic Counsellor
  • Rebuilding the kidney using human pluripotent stem cells
  • Directing stem cells to form mini-kidneys for drug screening
  • Modelling kidney disease in a dish using patient-derived stem cells
  • Examining the genes that regulate kidney development
  • 3D modelling of kidney development across time
  • Understanding how nephron stem cells are maintained
  • Characterizing stem cells in the adult kidney

Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis.

Nature (2015) 526(7574):564-568

Recent kidney repair and regeneration publications

Li et al, Collecting Duct-Derived Cells Display Mesenchymal Stem Cell Properties and Retain Selective In Vitro and In Vivo Epithelial Capacity JASN (2014) In press

Takasato et al, Directing human embryonic stem cell differentiation towards a renal lineage generates a self-organising kidney. Nature Cell Biology (2013) Dec 15

Hendry et al, Direct transcriptional reprogramming of adult cells to embryonic nephron progenitors. J Am Soc Nephrol (2013) 24(9):1424-34

Pelekanos et al, Comprehensive transcriptome and immunophenotype analysis of renal and cardiac MSC-like populations supports strong congruence with bone marrow MSC despite maintenance of distinct identities. (2012) Stem Cell Research 8(1):58-73

Recent 3D modeling publications

Short et al, Global quantification of tissue dynamics in the developing mouse kidney. Developmental Cell (2014) 29: 1–15

Packard et al, Luminal mitosis drives epithelial cell dispersal within the branching ureteric bud. Developmental Cell (2013) 27(3):319-30

Lefevre et al, Modeling cell turnover in a complex tissue during development. Journal of Theoretical Biology (2013) 338:66-79

Rumballe et al, Nephron formation adopts a novel spatial topology at cessation of nephrogenesis. (2011) Dev Biol 360(1):110-122

Georgas et al, 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) Developmental Biology 332(2):273-86 (Front cover)

 
Recent animal models of renal disease and repair publications

Phua et al, Distinct sites of renal fibrosis in Crim1 mutant mice arise from multiple cellular origins. Journal of Pathology (2013) 229(5):685-96

Wilkinson et al, Association between congenital defects in papillary outgrowth and functional obstruction in Crim1 mutant mice. Journal of Pathology Apr 4. doi: 10.1002/path.4036

Rae et al, Proximal tubule overexpression of a locally acting IGF isoform, Igf-1Ea, increases inflammation after ischemic injury. (2012) Growth Horm & IGF Res 22(1):6-16

Chiu et al, Production of a mouse line with a conditional Crim1 mutant allele. (2012) Genesis 50(9):711-6

Pennisi et al, Crim1 has an essential role in glycogen trophoblast cell and sinusoidal-trophoblast giant cell development in the placenta. (2012) Placenta 33(3):175-82

Funding: 

The team’s current work has been supported by the following organisations and individuals:

  • National Health & Medical Research Council of Australia
  • EU-NHMRC
  • Australian Research Council
  • Kidney Health Australia
Collaborations: 

Institute for Molecular Bioscience, University of Queensland

  • Dr. Nicholas Hamilton
  • Dr. James LeFevre
  • Dr. Cas Simons

Australian Institute for Bioengineering and Nanotechnology

  • Prof. Ernst Wolvetang
  • Prof. Justin Cooper-White

Royal Brisbane and Women’s Hospital

  • Dr. Andrew Mallett
  • Dr. Helen Healy

The Royal Children’s Hospital, Melbourne

  • Dr. Amanda Walker
  • Dr. Cathy Quinlan

Westmead Children’s Hospital

  • Dr. Steven Alexander

Monash University

  • A/Prof. Ian Smyth
  • Prof. John Bertram

Leiden University Medical Center, The Netherlands

  • Prof. Anton J Rabelink

University of Southern California, USA

  • Professor Andrew McMahon

Cincinnatti Children’s Hospital

  • Prof. Raphael Kopan

Vanderbilt University, Nashville, USA

Prof. Matthew Wilson