Project Description

Prof. Melissa Little

Murdoch Children’s Research Institute

A view into human kidney morphogenesis using stem cells

Advanced microscopy analysis and modelling

Friday 6 July 2018

Professor Melissa Little, BSc PhD GAICD, is the Theme Director of Cell Biology at the Murdoch Children’s Research Institute in Melbourne. An NHMRC Senior Principal Research Fellow at MCRI, she is also Program Leader of Stem Cells Australia and Professor, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne. Melissa is also President of the Australasian Society for Stem Cell Research. She is internationally recognised for her work on the systems biology of kidney development. This fundamental research has underpinned her pioneering studies into potential regenerative therapies for kidney disease. As a result, her team have developed approaches for directing the differentiation of human pluripotent stem cells to human kidney organoids. Her group are applying this knowledge to disease modelling, drug screening, cell therapy and tissue engineering. A Fellow of the Australian Academy of Science and the Australian Academy of Health and Medical Sciences, Professor Little’s work has been recognised by many awards, including the GlaxoSmithKline Award for Research Excellence (2005), AAS Gottschalk Medal in Medical Sciences (2004), Eisenhower Fellowship (2006), ANZSCDB Presidents Medal (2015), Boerhaave Professorship, Leiden University (2015) and the UNSW Eureka Prize (2016).

The capacity to generate a pluripotent stem cell from any somatic cell type has revolutionalised stem cell biology. The development of protocols for the stepwise differentiation of such pluripotent cells, not only to specific cellular endpoints but complex 3D organoids representative of developing human tissues, completely changes the future prospects of stem cell medicine. It is hoped that such stem cell-derived human tissue will drive personalised disease modelling, toxicity and screening, cell therapy and even tissue bioengineering. It is also hoped that this will provide a window into human development not previously available and potentially allow the dissection of the biophysical requirements for tissue self-organisation. All this will depend upon how reliably these models mirror normal human development at the level of cellular identity, multicellular complexity and functional maturation. We have developed a protocol for the generation of kidney organoids (Takasato et al, Nature, 2015) from human pluripotent stem cells. This protocol relies upon the stepwise recapitulation of morphogenetic events previously characterised during normal kidney development in the mouse. Hence, the validity of the model remains to be investigated. Using CRISPR-Cas9 editing, we have developed a suite of reporter lines that is now allowing us to query the accuracy of patterning within the organoids, the lineage relationships during organoid formation and the transcriptional (bulk and single cell) profiles of individual cell types. We are also applying CRISPR-Cas9 gene editing to patient stem cell lines to test the capacity of organoids to model human kidney disease. Finally, the use of fluorescent reporter lines is facilitating real-time imaging after in vivo transplantation to assess the degree to which we can mature such stem cell-derived tissue for renal replacement.

No available.