A5082009119- Renal and related cancers
- Pluripotent Stem Cells Research
- Renal cell carcinoma treatment
- Genetic and Kidney Cyst Diseases
- RNA Research and Splicing
- Genetic Neurodegenerative Diseases
- Wnt/β-catenin signaling in development and cancer
- Single-cell and spatial transcriptomics
- Skin and Cellular Biology Research
- Organ Donation and Transplantation
- Cellular Mechanics and Interactions
- Renal Diseases and Glomerulopathies
- Insect Resistance and Genetics
- Mitochondrial Function and Pathology
- Viral Infectious Diseases and Gene Expression in Insects
- Birth, Development, and Health
- Hippo pathway signaling and YAP/TAZ
- Polysaccharides and Plant Cell Walls
- 3D Printing in Biomedical Research
- Muscle Physiology and Disorders
- Tissue Engineering and Regenerative Medicine
- Epigenetics and DNA Methylation
- Environmental DNA in Biodiversity Studies
- Microbial Community Ecology and Physiology
- Protein Degradation and Inhibitors
Murdoch Children's Research Institute
2017-2022
The University of Melbourne
2022
Novo Nordisk Foundation
2022
University of Copenhagen
2022
Peter MacCallum Cancer Centre
2018
Hudson Institute of Medical Research
2015
The University of Adelaide
2011-2013
University of Pennsylvania
2013
Australian Research Council
2012
Abstract The podocytes within the glomeruli of kidney maintain filtration barrier by forming interdigitating foot processes with intervening slit diaphragms, disruption in which results proteinuria. Studies into human podocytopathies to date have employed primary or immortalised podocyte cell lines cultured 2D. Here we compare 3D sieved from induced pluripotent stem cell-derived organoids conditionally lines, revealing improved podocyte-specific gene expression, maintenance vitro polarised...
ABSTRACT Recent advances in the generation of kidney organoids and culture primary nephron progenitors from mouse human have been based on knowledge molecular basis development mice. Although gene expression during has intensely investigated, single cell profiling provides new opportunities to further subsect component types signalling networks at play. Here, we describe analysis 6732 transcriptomes fetal [embryonic day (E)18.5] 7853 sorted progenitor cells (E14.5). These datasets provide...
ABSTRACT Kidney organoids have potential uses in disease modelling, drug screening and regenerative medicine. However, novel cost-effective techniques are needed to enable scaled-up production of kidney cell types vitro. We describe here a modified suspension culture method for the generation micro-organoids from human pluripotent stem cells. Optimisation differentiation conditions allowed formation micro-organoids, each containing six ten nephrons that were surrounded by endothelial stromal...
While pluripotent stem cell-derived kidney organoids are now being used to model renal disease, the proximal nephron remains immature with limited evidence for key functional solute channels. This may reflect early mispatterning of nephrogenic mesenchyme and/or insufficient maturation. Here we show that enhanced specification metanephric progenitors results in elongated and radially aligned proximalised nephrons distinct S1 - S3 tubule cell types. Such PT-enhanced possess improved albumin...
Progenitor self-renewal and differentiation is often regulated by spatially restricted cues within a tissue microenvironment. Here, we examine how progenitor cell migration impacts regionally induced commitment the nephrogenic niche in mice. We identify subset of cells that express Wnt4, an early marker nephron commitment, but migrate back into population where they accumulate over time. Single RNA-seq computational modelling returning reveals progenitors can traverse transcriptional...
The pathogenic agent responsible for the expanded repeat diseases, a group of neurodegenerative diseases that includes Huntington's disease is not yet fully understood. Expanded polyglutamine (polyQ) thought to be toxic in certain cases, however, all genes can encode polyQ sequence. Since repeat-containing RNA intermediary common these hairpin-forming single-stranded has been investigated as potential agent. More recently, it become apparent most loci have transcription occurring from both...
Stem cell-derived organoid models hold great promise to model tissue-specific disease. To enable this, it is crucial determine how their composition compares endogenous organs. However, technologies such as spatial transcriptomics (STs) that can inform on regional molecular identity have been challenging apply organoids. Here we present the first systematic profiling of multiple organoids (brain, heart muscle,heart valve, kidney, lung, cartilage, and blood) using Stereo-seq. We describe...
Recent evidence supports a role for RNA as common pathogenic agent in both the ‘polyglutamine’ and ‘untranslated’ dominant expanded repeat disorders. One feature of all sequences currently associated with disease is their predicted ability to form hairpin secondary structure at level. In order investigate mechanisms by which hairpin-forming RNAs could induce neurodegeneration, we have looked alterations gene transcript levels hallmarks cellular response toxic RNAs. Three disease-associated...
The cellular and molecular microenvironment of epithelial stem/progenitor cells is critical for their long-term self-renewal. We demonstrate that mesenchymal stem cell-like dermal microvascular pericytes are a element the skin's influencing human skin regeneration using organotypic models. Specifically, were capable promoting homeostatic tissue renewal by conferring more planar cell divisions generating two basal within proliferative compartment epidermis, while ensuring complete maturation...
Significance Statement Missense variants of NPHS2 that cause mistrafficking the encoded protein, PODOCIN, have been associated with steroid-resistant nephrotic syndrome. However, most studies overexpressed such in 2D nonpodocyte cells. This study describes generation and characterization human kidney organoids representing an allelic series homozygous missense variants. The strategy revealed a previously unappreciated reduction variant PODOCIN variant-specific subcellular localization,...
Abstract Recent advances in the directed differentiation of human pluripotent stem cells to kidney brings with it prospect drug screening and disease modelling using patient-derived cell lines. Development such an approach for high content will require substantial quality control improvements throughput. Here we demonstrate use NovoGen MMX 3D bioprinter generation highly reproducible organoids from as few 4,000 cells. Histological immunohistochemical analyses confirmed presence renal...
Abstract Recent advances in our capacity to differentiate human pluripotent stem cells kidney tissue are moving the field closer novel approaches for renal replacement. Such protocols have relied upon current understanding of molecular basis mammalian morphogenesis. To date this has depended population based-profiling non-homogenous cellular compartments. In order improve resolution individual cell transcriptional profiles during morphogenesis, we performed 10x Chromium single RNA-seq on...
Expanded DNA repeat sequences are known to cause over 20 diseases, including Huntington's disease, several types of spinocerebellar ataxia and myotonic dystrophy type 1 2. A shared genetic basis, overlapping clinical features for some these indicate that common pathways may contribute pathology. Multiple mechanisms, mediated by both expanded homopolymeric proteins RNA, have been identified the use model systems, account The such animal models enables identification distinct their 'molecular...
Abstract We have previously reported a protocol for the directed differentiation of human induced pluripotent stem cells to kidney organoids comprised nephrons, proximal and distal epithelium, vasculature surrounding interstitial elements. The utility this applications such as disease modelling will rely implicitly on developmental accuracy model, technical robustness transferability between iPSC lines. Here we report extensive transcriptional analyses sources variation across timecourse...
While pluripotent stem cell-derived kidney organoids are now being used to model renal disease, the proximal nephron remains immature with limited evidence for key functional solute channels. This may reflect early mispatterning of nephrogenic mesenchyme and/or insufficient maturation. Here we show that enhanced specification metanephric progenitors results in elongated and radially aligned proximalised nephrons distinct S1 - S3 tubule cell types. Such PT-enhanced possess improved albumin...