Senior Principal Scientist, BioScience Renal, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D
Senior Director, Head of Biosciences Renal, BioPharmaceuticals R&D
Chronic kidney disease (CKD) is a serious, progressive condition and under-recognised public health problem, affecting nearly 840 million people worldwide.1 More than 9 million people living with CKD have progressed to kidney failure, requiring dialysis or a kidney transplant, and by 2040, CKD is expected to become the world’s 5th leading cause of mortality.2,3,4
By observing the intricacies of a complete physiological system, we can gain a better understanding of dysfunction in disease. Kidneys are composed of approximately 20-40 different cell types, arranged within a complex architectural matrix. CKD is characterised by the engagement of multiple molecular pathways, connections, and complex pathophysiology, all of which contribute to the challenge of developing new therapies for this condition. Previously, researchers would use static, one or two cell models, add investigational compounds and then examine any potential interaction. However, these standard, non-fluidic 2D cell-based models have not been able to reflect the 3D complexity of the kidney environment (including microfluid flow, shear stress and cell signalling). As such, results are not always a faithful representation of what happens in the body. A 3D culture system (e.g., kidney microphysiological systems or kidney-on-chips) offers a more realistic ‘real time’ window into what goes on in CKD. Kidney microphysiological systems (MPS) allow different cell types to be co-cultured, enabling cellular interactions and signalling to be investigated in both healthy and diseased kidneys. This opens up the possibility of greater precision in terms of identifying and reaching relevant therapeutic targets, as well as testing investigational compound behaviour and carrying out drug screening.
Recently we have presented two types of kidney-on-chip models, both with high conformity to kidney physiology and structure, at the American Society of Nephrology Annual Meeting 2021. Their fidelity could help reveal the inner pathophysiology of the kidney and potentially assess the effects of renal therapies.
Kidney MPS often culture a single type of cell, sometimes adjacent to a second cell type, on a 3D platform to mimic physiological conditions. For the first time, in collaboration with Emulate, Inc., the growth and interaction of three different cell types (glomerular endothelial cells [GECs], induced pluripotent stem cell [hiPSC]-derived podocytes and mesangial cells [MCs]) which reflect the filtration barrier of the kidney was studied using our glomerulus-on-a-chip technology.5 Analysis was performed using both transcriptomics and high content imaging to shed light on the impact of each cell type on its neighbours.
Initial findings showed that all three cell types demonstrated cross-talk with each other within the micro-fluidic environment, demonstrating that our tri-culture model was a highly physiologically relevant tool to study healthy glomerular function. We hope it will enable greater understanding of the mechanisms underlying glomerulopathies and improved qualification of new therapies.
The second system (tubule-on-a-chip) was designed to study the phenotype of proximal tubule epithelial cells (PTECs) and glomerular endothelial cells (HGECs) grown in a 3D vascularised tubule model versus those grown in a static coated/noncoated model. Groups of tubes lined with either endothelial or epithelial cells were grown together in a 3D channel, reproducing the microenvironment of a kidney tubule and its functions of reabsorption and secretion. When grown on this 3D matrix, both cell types displayed characteristics of typical healthy in vivo kidney cells – this is in comparison to 2D systems where cells typically behave in a diseased fashion.6
Tubule-on-a-chip comprised of tubes lined with either endothelial or epithelial cells grown together in a 3D channel
In situ vascular endothelial cells (left) and tubular epithelial cells (right), stained for: Nucleus (blue), VeCAD (yellow), NA/K ATPase (green), Actin (red)
Biosensors can also be introduced into MPS models, to continuously measure genetic and proteomic signatures in response to specific stimuli. As MPS platforms permit many cell types and parameters to be analysed in ‘real time’ this allows increased throughput in terms of data generation, and provides results that are more translatable and relevant to patients than those obtained from previous 2D models.
As of today, there are no reports of in vitro cellular models adequately mimicking kidney function. Patient-derived primary cells are desirable for modelling disease states in a laboratory setting and for testing potential drug candidates. However, these cells present challenges to scientists, including limited availability, loss of their physiological characteristics when in culture, and the fact that it is difficult to expand them to the scale needed for in vitro assays.
Many researchers are interested in replicating organ function using organoids which comprise at least 11 different cell types that are needed for the full organ to function normally. Although the replicated structure is not identical to the actual organ, the mixture of cells creates interactions which are similar to the situation seen in vivo. Eventually, we hope that multiple kidney component-on-a-chip devices may be linked together to produce a whole organ-on-a-chip. This would create a translatable system with high fidelity to the whole human kidney.
Kidney-on-chip technology has the potential to enhance and accelerate our ability to translate science into innovative medicines for patients with CKD. We are committed to revolutionising CKD therapies. By creating greater opportunities for sharing of expertise between different scientific and clinical disciplines – including engineering, biophysics, and biology – we will enhance our understanding of CKD and advance new approaches and technologies for treating kidney disease.