“…When E14.5 kidneys were cultured within type 1 collagen, in the absence of flow, the arterial lining was lost ( Fig. 4 B), supporting the widespread hypothesis ( Homan et al, 2019 ; Ryan et al, 2021 ) that blood flow is critical for arterial maintenance. Fig.…”
Section: Resultssupporting
confidence: 63%
“…While cultured kidneys and kidney organoids do contain endothelial cells, these typically do not differentiate into arteries and veins, meaning that an organotypic vascular network never forms ( Munro et al, 2017 ; Murakami et al, 2019 ). The lack of blood flow is assumed to be a major reason for the limited maturity of blood vessels in culture ( Homan et al, 2019 ; Ryan et al, 2021 ). Therefore, we aimed to determine whether the flow provided by the host embryo in the CAM system was sufficient to induce arterial smooth muscle cell recruitment within the graft, as seen in the host CAM vasculature.…”
Section: Resultsmentioning
confidence: 99%
“…An effective filtration depends on the regulation of blood flow, which is in part provided through the myogenic response of the renal arteries ( Burke et al, 2014 ), the absence or misplacement thereof is therefore likely to affect renal function. The lack of vascular maturity is often attributed to the lack of blood flow ( Homan et al, 2019 ; Ryan et al, 2021 ). Consequently, connecting renal explants to the circulatory system of a host, thereby introducing flow through the renal capillary plexus, should promote vascular maturation.…”
Kidney explant cultures are an important tool to gain insights into developmental processes, insights that can be used to develop strategies for engineering kidneys from stem cells. However, explants are not connected to a perfused vascular system. This limits their survival and limits physiological studies, for example of blood filtration, the main function of the kidney. Previous studies have shown that grafting kidneys onto avian chorioallantoic membrane (CAM) can establish perfusion and enable glomerular vascularization, but the realism and maturity of the resultant vasculature has not been examined. Here, we show that vasculature of kidney explants grafted onto CAM is very different from natural kidney vasculature, showing excessive growth of endothelial cells, absence of a hierarchical arterio-venous network and no vascular smooth muscle cell recruitment. The model therefore has serious limits.
“…When E14.5 kidneys were cultured within type 1 collagen, in the absence of flow, the arterial lining was lost ( Fig. 4 B), supporting the widespread hypothesis ( Homan et al, 2019 ; Ryan et al, 2021 ) that blood flow is critical for arterial maintenance. Fig.…”
Section: Resultssupporting
confidence: 63%
“…While cultured kidneys and kidney organoids do contain endothelial cells, these typically do not differentiate into arteries and veins, meaning that an organotypic vascular network never forms ( Munro et al, 2017 ; Murakami et al, 2019 ). The lack of blood flow is assumed to be a major reason for the limited maturity of blood vessels in culture ( Homan et al, 2019 ; Ryan et al, 2021 ). Therefore, we aimed to determine whether the flow provided by the host embryo in the CAM system was sufficient to induce arterial smooth muscle cell recruitment within the graft, as seen in the host CAM vasculature.…”
Section: Resultsmentioning
confidence: 99%
“…An effective filtration depends on the regulation of blood flow, which is in part provided through the myogenic response of the renal arteries ( Burke et al, 2014 ), the absence or misplacement thereof is therefore likely to affect renal function. The lack of vascular maturity is often attributed to the lack of blood flow ( Homan et al, 2019 ; Ryan et al, 2021 ). Consequently, connecting renal explants to the circulatory system of a host, thereby introducing flow through the renal capillary plexus, should promote vascular maturation.…”
Kidney explant cultures are an important tool to gain insights into developmental processes, insights that can be used to develop strategies for engineering kidneys from stem cells. However, explants are not connected to a perfused vascular system. This limits their survival and limits physiological studies, for example of blood filtration, the main function of the kidney. Previous studies have shown that grafting kidneys onto avian chorioallantoic membrane (CAM) can establish perfusion and enable glomerular vascularization, but the realism and maturity of the resultant vasculature has not been examined. Here, we show that vasculature of kidney explants grafted onto CAM is very different from natural kidney vasculature, showing excessive growth of endothelial cells, absence of a hierarchical arterio-venous network and no vascular smooth muscle cell recruitment. The model therefore has serious limits.
“…In 2019, Low et al discovered a protocol to differentiate vascularized kidney organoids. This method can effectively vascularize kidney organs and also provides a new idea for the source of blood vessels in the kidneys [94,148].…”
Section: Methods To Induce Stem Cells To Give Rise To Renal Cellsmentioning
The kidneys are often involved in adverse effects and toxicity caused by exposure to foreign compounds, chemicals, and drugs. Early predictions of these influences are essential to facilitate new, safe drugs to enter the market. However, in current drug treatments, drug-induced nephrotoxicity accounts for 1/4 of reported serious adverse reactions, and 1/3 of them are attributable to antibiotics. Drug-induced nephrotoxicity is driven by multiple mechanisms, including altered glomerular hemodynamics, renal tubular cytotoxicity, inflammation, crystal nephropathy, and thrombotic microangiopathy. Although the functional proteins expressed by renal tubules that mediate drug sensitivity are well known, current in vitro 2D cell models do not faithfully replicate the morphology and intact renal tubule function, and therefore, they do not replicate in vivo nephrotoxicity. The kidney is delicate and complex, consisting of a filter unit and a tubular part, which together contain more than 20 different cell types. The tubular epithelium is highly polarized, and maintaining cellular polarity is essential for the optimal function and response to environmental signals. Cell polarity depends on the communication between cells, including paracrine and autocrine signals, as well as biomechanical and chemotaxis processes. These processes affect kidney cell proliferation, migration, and differentiation. For drug disposal research, the microenvironment is essential for predicting toxic reactions. This article reviews the mechanism of drug-induced kidney injury, the types of nephrotoxicity models (in vivo and in vitro models), and the research progress related to drug-induced nephrotoxicity in three-dimensional (3D) cellular culture models.
“…The vasculature in the kidney is highly organized, associating with nephron parenchyma and stromal tissues, which is essential for kidney function to filtrate blood to remove metabolic wastes and regulate water/ion balance in the body. In nephron organoids, endothelial cells initially form but then quickly degenerate in culture in vitro [37]. However, it was reported that long-term culture of kidney organoids may produce the vasculature in vitro [28].…”
Section: Vasculature In Kidney Organoidsmentioning
Purpose of reviewDuring embryogenesis, the kidney is mainly generated from three progenitor cells; nephron progenitors, ureteric bud progenitors and stromal progenitors. Mutual interactions of the all three progenitor populations are essential to form a functional kidney with the higher-order structure. Pluripotent stem cells have potential to differentiate into all cell types of the animal body, including the kidney. In this review, we will summarize recent advances in reconstructing kidney organoids from pluripotent stem cells.Recent findingsIn the past years, major advances were reported to induce nephron and ureteric bud progenitors from pluripotent stem cells in mice and humans, and to create kidney organoids of nephron and/or ureteric bud-derived collecting duct tissues in vitro. These kidney organoid technologies were applied to high-throughput genetic screenings and small chemical screenings to identify key factors for kidney development and disease. Furthermore, a novel method was established to induce stromal progenitors from pluripotent stem cells, leading to creation of kidney organoids with the higher-order structures completely derived from pluripotent stem cells.SummaryThese advances in kidney organoids from pluripotent stem cells should lay a foundation to establish a novel therapy for kidney disease, which ultimately eliminate the need of dialysis and kidney transplantation for patients with kidney disease in the future.
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