Our research bridges a critical gap between animal models and human applications. The data we collected and analysed creates a knowledge-base that will accelerate stem cell-based technologies to produce mini-kidneys that accurately represent human kidneys for biomedical screening and replacement therapies.
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A free online kidney atlas aims to accelerate organoid research
A kidney organoid on Day 16 of differentiation. The staining depicts the segmentation of nephron-like structures in the organoid at an early developmental stage. Image courtesy of Tracy Tran/Andy McMahon Lab, USC Stem Cell.
The kidney is an essential constituent of the body regulating blood pressure, water level, acidity and removing waste products. Nephrons are the microscopic functional unit of the kidney, comprised of the renal corpuscle and tubule which filter the blood plasma, remove water and salts, reabsorb what’s needed, and excrete the remainder as urine. They are formed during foetal development, with the stem cells being exhausted before birth.
Over the past 4 years, researchers from the University of Southern California Stem Cell department and School of Engineering have investigated the molecular, cellular and genetic differences between human and mouse kidneys during foetal development. The three studies published in the Journal of the American Society of Nephrology characterise the molecular and cellular development that occurs in human kidneys in utero, states Andrew McMahon, senior study author.
Lab-grown mini organs, or ‘organoids’, allow for models of disease to be created and for new drugs to be tested within an environment that is currently as close to the real thing as we can get, allowing researchers to observe and investigate how organs develop, how genetic disease can alter this development, and how drugs interact.
The USC team examined the processes that occur to regulate, maintain, and grow kidney stem cells into fully functioning and differentiated mature cells. The models from both human and mouse are then compared, with the aim being to better connect animal models and human applications, streamlining the research process so treatments for kidney disease can be investigated and developed more efficiently. 30 million people suffer from kidney disease in the US alone, 15% of the population, highlighting the need to mitigate this huge economic and social burden.
They compared 26 human with mouse kidney anchor genes, genes which are highly specific to a particular anatomical area or developmental stage, allowing them to be used as a point of reference to determine the identity of different cell types. A good example of this is the FOXD1 gene which shows high activity in developing human and mouse kidneys. However, in mice FOXD1 is involved in the development of interstitial cells, whereas in humans, in addition to interstitial development, it is involved in the development of nephrons. Therefore, someone relying on FOXD1 as a reference point is likely to misidentify cell types in the developing human kidney, hampering progress. Three of these genes had equivalent expression between mouse and human: SLC22A6, ENTPD5 and UMOD.
If the goal is to treat human kidney disease, clearly, it's better to focus on genes that are also active in human kidneys.
The average wait for a kidney transplant is 3.6 years, with the 3 weekly 4-hour long dialysis sessions creating long-term disruption in people’s lives. Due to the difficult nature of the problem, McMahon took a multidisciplinary approach, enlisting the help of Carl Kesselman from the Information Sciences Institute from the School of Engineering. They built a piece of software called DERIVA (Discovery Environment for Relational Information and Versioned Assets) that automated many of the processes researchers perform, fast-tracking the study and generating an online, indexed and categorised library to help other researchers with their work. For example, data are automatically uploaded from microscopes, storing and sorting the information.
If you think of data as the modern version of a book, we gave the researcher tools to write the book, made the library where the book is stored and created a catalogue system so others can find the book and check it out.
"Stem-cell based technologies hold great promise for developing kidney replacement and regeneration therapies," said Nils Lindstrom, first author of the three studies. "Getting there requires detailed knowledge of how kidneys normally form so the process can be replicated in cell cultures in the lab. Our data will help us and other scientists improve current techniques to make better tiny functional kidneys."
The new, open-source data library is available at www.gudmap.org, providing the first systematic, high-resolution atlas or databank for human kidney genesis.
Learning Zones
The Learning Zones are an educational resource for healthcare professionals that provide medical information on the epidemiology, pathophysiology and burden of disease, as well as diagnostic techniques and treatment regimens.