Stem cell-based kidney chip revolutionizes disease modeling and research

Organ-on-chip systems, where cell biology, tissue engineering, materials science, and developmental biology come together to provide an in vitro platform to explore organ function, human diseases, and drug discovery, provide a more suitable system for studying human biological processes than animal models. However, their performance is often limited by the non-biological material used as membranes.

In a recent study published in Science Advances, a team of scientists from the United States engineered an organ-on-chip system containing a kidney glomerulus using human-induced pluripotent stem cells and an ultrathin membrane made from electrospun silk fibroin, which mimics the basement membranes.

​​​​​​​Study: An ultrathin membrane mediates tissue-specific morphogenesis and barrier function in a human kidney chip. Image Credit: luchschenF/Shutterstock.com​​​​​​​Study: An ultrathin membrane mediates tissue-specific morphogenesis and barrier function in a human kidney chip. Image Credit: luchschenF/Shutterstock.com

Background

Organ-on-chip systems are compact in vitro platforms that consist of fluidic microchannels in which cells can be cultured for tissue formation.

The regulations of decisions that determine cell signaling, maturation, proliferation, and fate, as well as the mechanosensitive stimulation of gene expression, are achieved through the shear stress applied to the cells using dynamic fluid flow.

The applications of organ-on-chips include being used as in vitro models in research on diseases to study biological responses to therapeutics, overcoming the limitations of using animal models.

However, organ-on-chips' performance is limited by their non-biological materials, such as the ones forming the membranes that separate the fluid channels.

About the Study

In the present study, the researchers engineered an ultrathin membrane using silk fibroin protein obtained from silkworms of the species Bombyx mori.

Silk fibroin is known to be biocompatible, mechanically superior, and versatile and has been used in various materials for bioelectronics, biosensors, tissue engineering, and drug delivery.

Typical organ-on-chips use polymers such as polycarbonate or polydimethylsiloxane, which are biocompatible and can withstand mechanical stress but are non-biodegradable and significantly thicker than the basement membranes found in tissues. Furthermore, the inert nature of these polymer membranes prevents the functional remodeling of the extracellular matrix by forming a permanent barrier.

Silk fibroin, in comparison, is biodegradable and stronger than other natural protein biomaterials, such as fibril and collagen-based membranes, which tend to rupture under handling and shear stress.

Furthermore, the mechanical properties of silk fibroin can be enhanced by exposing it to methanol, which converts the randomly coiled structure of the material to β sheets that are tightly packed, stronger, and insoluble in water.

Silk fibroin has previously been used to build scaffolds on which various cell types, such as cardiomyocytes, neurons, fibroblasts, kidney cells, and lung epithelial stem cells, have been propagated and differentiated.

The researchers used silk fibroin to create an ultrathin membrane with topography resembling the extracellular matrix to produce a kidney glomerular organ-on-chip.

The silk fibroin membranes were constructed by electrospinning and immersing the material in methanol to induce conformational change and enhance the mechanical properties. This membrane was then attached to a polydimethylsiloxane chip containing microfluidic channels representing the vascular compartments.

This hybrid chip was then attached to another polydimethylsiloxane chip with microfluidic channels representing the urinary filtrate compartment.

The chips were then treated to facilitate bonding, increase hydrophilicity, and increase the extracellular matrix protein laminin-511 absorption.

Podocytes and vascular endothelial cells derived from human induced pluripotent stem cells were then used to construct the kidney glomerular chip to carry out the function of the glomerular capillary wall, the blood filtration barrier in human kidneys.

Major Findings

The study showed that kidney glomerulus organ-on-chip constructed using ultrathin silk fibroin-based membrane could reconstitute kidney glomerular function and carry out selective membrane filtration.

Furthermore, the biomimetic membrane also supported robust propagation of kidney cells, transmembrane cross-talk between cells, remodeling of the basement membrane, and size-specific molecular glomerular filtration.

The silk fibroin membranes were also found to be capable of tolerating mechanical strain similar to physiological levels through cyclic mechanical stretching.

Additionally, the researchers used the chip to model glomerular disease by administering Adriamycin, a chemotherapy drug that causes glomerular injury, to induce nephrotoxicity.

The changes in cellular phenotypes and podocyte loss confirmed the potential to use kidney glomerular chips for disease modeling and drug screening to treat nephrotoxicity.

The silk fibroin also provided a porous structure through which basement proteins secreted by endothelial cells and podocytes could integrate and form scaffolds for tissue differentiation, culturing, and maturation.

Unlike nonbiodegradable polymers, the silk fibroin polymer could also be sectioned using a microtome for transmission electron microscope analysis.

Conclusions

Overall, the findings reported that the use of electrospun silk fibroin membranes in creating kidney glomerulus chips was effective in developing a robust tissue engineering platform that carried out the glomerular function of selective filtration while being porous and biodegradable, which allowed basement membrane remodeling.

The researchers also demonstrated the utility of this technology in modeling glomerular diseases and using these for drug screening.

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