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.
- 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
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
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
- Cellular extrusion bioprinting improves kidney organoid reproducibility and conformation. 2021
- An In Vitro Differentiation Protocol for Human Embryonic Bipotential Gonad and Testis Cell Development. 2020
- Multivariate patterning of human pluripotent cells under perfusion reveals critical roles of induced paracrine factors in kidney organoid development. 2020
- Plasticity of distal nephron epithelia from human kidney organoids enables the induction of ureteric tip and stalk. 2020
- A Toolbox to Characterize Human Induced Pluripotent Stem Cell-Derived Kidney Cell Types and Organoids. 2019
- Direct reprogramming to human nephron progenitor-like cells using inducible piggyBac transposon expression of SNAI2-EYA1-SIX1. 2019
- DNA Methyltransferase 1 Controls Nephron Progenitor Cell Renewal and Differentiation. 2019
- Evaluation of variability in human kidney organoids. 2019
- Generating Kidney from Stem Cells. 2019
- Introducing a Spectrum of Long-Range Genomic Deletions in Human Embryonic Stem Cells Using Type I CRISPR-Cas. 2019
- Kidney micro-organoids in suspension culture as a scalable source of human pluripotent stem cell-derived kidney cells. 2019
- Lin28 and let-7 regulate the timing of cessation of murine nephrogenesis. 2019
- Nephron progenitor commitment is a stochastic process influenced by cell migration. 2019
- Outcomes Following Treatment of Maternal Hypercalcemia Due to CYP24A1 Pathogenic Variants. 2019
- Overexpression of IL-11 promotes premalignant gastric epithelial hyperplasia in isolation from germline gp130-JAK-STAT driver mutations. 2019
- Reporter-based fate mapping in human kidney organoids confirms nephron lineage relationships and reveals synchronous nephron formation. 2019
- Single cell analysis of the developing mouse kidney provides deeper insight into marker gene expression and ligand-receptor crosstalk. 2019
- Single-cell analysis reveals congruence between kidney organoids and human fetal kidney. 2019
- Vascular bioengineering of scaffolds derived from human discarded transplant kidneys using human pluripotent stem cell-derived endothelium. 2019
- 3D organoid-derived human glomeruli for personalised podocyte disease modelling and drug screening. 2018
- A Novel Approach to Single Cell RNA-Sequence Analysis Facilitates In Silico Gene Reporting of Human Pluripotent Stem Cell-Derived Retinal Cell Types. 2018
- Advances in predictive in vitro models of drug-induced nephrotoxicity. 2018
- Bayesian inference of agent-based models: a tool for studying kidney branching morphogenesis. 2018
- Branching morphogenesis in the developing kidney is not impacted by nephron formation or integration. 2018
- Choosing an easier path or following your passion. 2018
- Crim1 is required for maintenance of the ocular lens epithelium. 2018
- Development of the Human Fetal Kidney from Mid to Late Gestation in Male and Female Infants. 2018
- Functional Assessment of Patient-Derived Retinal Pigment Epithelial Cells Edited by CRISPR/Cas9. 2018
- Hamartin regulates cessation of mouse nephrogenesis independently of Mtor. 2018
- Haploinsufficiency for the Six2 gene increases nephron progenitor proliferation promoting branching and nephron number. 2018
- Identification of an Immortalised Human Airway Epithelial Cell Line with Dyskinetic Cilia. 2018
- Meeting report of the 2017 KidGen Renal Genetics Symposium. 2018
- Patient-iPSC-Derived Kidney Organoids Show Functional Validation of a Ciliopathic Renal Phenotype and Reveal Underlying Pathogenetic Mechanisms. 2018
- Pneumococcal haemolytic uraemic syndrome in the postvaccine era. 2018
- Prolonged prenatal hypoxia selectively disrupts collecting duct patterning and postnatal function in male mouse offspring. 2018
- Renal Subcapsular Transplantation of PSC-Derived Kidney Organoids Induces Neo-vasculogenesis and Significant Glomerular and Tubular Maturation In Vivo. 2018
- Reproducibility and staging of 3D human retinal organoids across multiple pluripotent stem cell lines. 2018
- Restricted cell cycle is essential for clonal evolution and therapeutic resistance of pre-leukemic stem cells. 2018
- Simultaneous reprogramming and gene editing of human fibroblasts. 2018
- Wnt11 directs nephron progenitor polarity and motile behavior ultimately determining nephron endowment. 2018
- (Re)Building a Kidney. 2017
- Clinical-Grade Isolated Human Kidney Perivascular Stromal Cells as an Organotypic Cell Source for Kidney Regenerative Medicine. 2017
- Does Renal Repair Recapitulate Kidney Development? 2017
- Long-term remission with eculizumab in atypical haemolytic uraemic syndrome. 2017
- Making a Kidney Organoid Using the Directed Differentiation of Human Pluripotent Stem Cells. 2017
- Massively parallel sequencing and targeted exomes in familial kidney disease can diagnose underlying genetic disorders. 2017
- Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease. 2017
- Optimizing Outcomes in Pediatric Renal Transplantation Through the Australian Paired Kidney Exchange Program. 2017
- Prenatal hypoxia leads to hypertension, renal renin-angiotensin system activation and exacerbates salt-induced pathology in a sex-specific manner. 2017
- Self-organisation after embryonic kidney dissociation is driven via selective adhesion of ureteric epithelial cells. 2017
- A Cas9 Variant for Efficient Generation of Indel-Free Knockin or Gene-Corrected Human Pluripotent Stem Cells. 2016
- A strategy for generating kidney organoids: Recapitulating the development in human pluripotent stem cells. 2016
- Analysed cap mesenchyme track data from live imaging of mouse kidney development. 2016
- Cap mesenchyme cell swarming during kidney development is influenced by attraction, repulsion, and adhesion to the ureteric tip. 2016
- Clinical-Grade Isolated Human Kidney Perivascular Stromal Cells as an Organotypic Cell Source for Kidney Regenerative Medicine. 2016
- Crim1 has cell-autonomous and paracrine roles during embryonic heart development. 2016
- Cystatin C Based Equation Accurately Estimates Glomerular Filtration Rate in Children With Solid and Central Nervous System Tumours: Enough Evidence to Change Practice? 2016
- GAPTrap: A Simple Expression System for Pluripotent Stem Cells and Their Derivatives. 2016
- Generating kidney tissue from pluripotent stem cells. 2016
- Generation of kidney organoids from human pluripotent stem cells. 2016
- Neonatal vascularization and oxygen tension regulate appropriate perinatal renal medulla/papilla maturation. 2016
- Understanding kidney morphogenesis to guide renal tissue regeneration. 2016
- A protocol for the identification and validation of novel genetic causes of kidney disease. 2015
- A spatially-averaged mathematical model of kidney branching morphogenesis. 2015
- Direct transcriptional reprogramming to nephron progenitors. 2015
- Generating a self-organizing kidney from pluripotent cells. 2015
- Improving our resolution of kidney morphogenesis across time and space. 2015
- Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. 2015
- Paediatric nephrology: the last 50 years. 2015
- Renal developmental defects resulting from in utero hypoxia are associated with suppression of ureteric ß-catenin signaling. 2015
- ROBO2 restricts the nephrogenic field and regulates Wolffian duct-nephrogenic cord separation. 2015
- Simultaneous Reprogramming and Gene Correction of Patient Fibroblasts. 2015
- The origin of the mammalian kidney: implications for recreating the kidney in vitro. 2015
- Xenogeneic antibodies with apparent public idiotypic specificity for anti-Ia.7 antibodies are directed in part against V kappa 21D and E subgroup marker. 1986