New breakthrough in hereditary polycystic kidney disease!
Posted: Sep 19, 2022
The emergence of stem cells has brought to reality a scenario that once could only be found in science fiction. Especially for some difficult diseases, the development of stem cell-based organ technology has brought more possibilities.
In a recent study published in Cell Stem Cell, scientists have used organoids that hold the promise of a new breakthrough in the treatment of hereditary polycystic kidney disease.
The genetic condition known as polycystic kidney disease, which also goes by the names of autosomal dominant polycystic kidney disease and autosomal recessive polycystic kidney disease, typically results in large fluid-filled cysts in so many kidney regions, impairing kidney function and posing a serious risk to the liver, pancreas, and heart. In addition to being a hereditary cystic condition, polycystic kidney disease has very few clinically effective treatment options, which are still limited to dialysis and kidney transplantation and are all but incurable.
To accelerate the search for new therapies for polycystic kidney, scientists from the University of Southern California have used human pluripotent stem cells (hPSC) to develop, characterize, and validate a simple and easily scalable, cost-effective kidney "organoid" platform that can be used to model polycystic kidney disease to study the mechanisms of cyst formation and to find new drugs that block cystogenesis and inhibit cyst expansion.
Polycystic kidney disease is primarily due to mutations in the PKD1, PKD2, and PKHD1 genes, and clinical treatment options are limited. Tolvaptan is the only FDA-approved drug for polycystic kidney, but it can only slow but not stop disease progression, and is only indicated for a subset of cysts consisting of specific kidney cell types.
In this study, researchers employed human pluripotent stem cells to create kidney-like organ systems in which human pluripotent stem cells develop into organized 3D structures, including a range of possible ureteral epithelial collecting systems and renal units of various renal cell types.
Scientists demonstrated that these organoids contain many of the cellular precursors and genetic features needed to build the kidney during embryonic development. When implanted in mice, the organoid's kidney unit-like structures began to develop a vascular system and reached even a limited capacity to filter waste—one of the kidney's most important functions.
To make these organoids useful for studying polycystic kidneys, scientists used CRISPR/Cas9 gene editing to inactivate PKD1 or PKD2. As expected, the gene-edited organoids began to form cysts that eventually separated and grew to a diameter of centimeters.
The scientists then conducted a first screen using gene-edited human-like organs to identify potential therapeutic agents for polycystic kidney, and they focused on a range of enzyme inhibitors to gain a broad understanding of the cellular mechanisms that control cyst formation.
After testing 247 enzyme inhibitor compounds on the organoid, the scientists identified nine compounds that inhibit the growth of the cyst without hindering the overall growth of the organoid. This also proves that the organoid is useful for further research on therapeutic candidates for polycystic kidney.
Today, with the advancement of stem cell regenerative medicine technology, stem cell organoid technology is becoming increasingly sophisticated in biology and tissue engineering excellence. The technology of culturing physiologically functional organoids in the lab is anticipated to give humans on-demand production of tissues and microorgans for the pharmaceutical industry and medical research, without being constrained by donors.
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