Accumulating evidence demonstrates important roles for metabolism in cell fate determination. However, it is a challenge to assess metabolism at a spatial resolution that acknowledges both... Show moreAccumulating evidence demonstrates important roles for metabolism in cell fate determination. However, it is a challenge to assess metabolism at a spatial resolution that acknowledges both heterogeneity and cellular dynamics in its tissue microenvironment. Using a multi-omics platform to study cell-type-specific dynamics in metabolism in complex tissues, we describe the metabolic trajectories during nephrogenesis in the devel-oping human kidney. Exploiting in situ analysis of isotopic labeling, a shift from glycolysis toward fatty acid b-oxidation was observed during the differentiation from the renal vesicle toward the S-shaped body and the proximal tubules. In addition, we show that hiPSC-derived kidney organoids are characterized by a metabolic immature phenotype that fails to use mitochondrial long-chain fatty acids for energy metabolism. Further-more, supplementation of butyrate enhances tubular epithelial differentiation and maturation in cultured kid-ney organoids. Our findings highlight the relevance of understanding metabolic trajectories to efficiently guide stem cell differentiation. Show less
Koning, M.; Dumas, S.J.; Avramut, M.C.; Koning, R.I.; Meta, E.; Lievers, E.; ... ; Rabelink, T.J. 2022
Human induced pluripotent stem cell-derived kidney organoids have potential for disease modeling and to be developed into clinically transplantable auxiliary tissue. However, they lack a functional... Show moreHuman induced pluripotent stem cell-derived kidney organoids have potential for disease modeling and to be developed into clinically transplantable auxiliary tissue. However, they lack a functional vasculature, and the sparse endogenous endothelial cells (ECs) are lost upon prolonged culture in vitro, limiting maturation and applicability. Here, we use intracoelomic transplantation in chicken embryos followed by single-cell RNA sequencing and advanced imaging platforms to induce and study vasculogenesis in kidney organoids. We show expansion of human organoid-derived ECs that reorganize into perfused capillaries and form a chimeric vascular network with host-derived blood vessels. Ligand-receptor analysis infers extensive potential interactions of human ECs with perivascular cells upon transplantation, enabling vessel wall stabilization. Perfused glomeruli display maturation and morphogenesis to capillary loop stage. Our findings demonstrate the beneficial effect of vascularization on not only epithelial cell types, but also the mesenchymal compartment, inducing the expansion of ' on target ' perivascular stromal cells, which in turn are required for further maturation and stabilization of the neo-vasculature. The here described vasculogenic capacity of kidney organoids will have to be deployed to achieve meaningful glomerular maturation and kidney morphogenesis in vitro. Show less
Geelhoed, W.J.; Boonekamp, M.; Stadt, H. van de; Badulescu, S.; Lalai, R.A.; Groeneweg, K.E.; ... ; Rotmans, J.I. 2021
The cannulation of blood vessels is one of the most basic and essential interventions in medical practice. A common adverse event of this procedure is miscannulation with infiltration of the second... Show moreThe cannulation of blood vessels is one of the most basic and essential interventions in medical practice. A common adverse event of this procedure is miscannulation with infiltration of the second part of the vessel wall, often resulting in a perivascular hematoma. In hemodialysis patients, surgically created arteriovenous conduits are cannulated 3-4 times per week to provide sufficient blood supply to the hemodialysis machine. However, the high blood flow and pressure in these vascular access sites increase the risk of complications upon miscannulation. A novel needle system that allows for rapid automatic retraction of the needle in response to contact with blood after positioning the cannula in the blood vessel was developed to reduce the risk of miscannulation. The device can easily be incorporated into existing needle designs. The mechanical functionality of the device was validated by testing prototypes in an ex vivo system. Optimization of the needle system was performed to enhance response time and piston shape. A final prototype design was manufactured and validated. The optimal membrane composition and piston shape were determined, which resulted in a needle response time of 40 ms upon contact with fluid at a pressure of 100 mmHg (arterial pressure). Here, we have successfully designed, mechanically validated, and tested a novel automated rapid needle retraction system that allows incorporation into existing needle systems. This device could notably decrease the difficulty of vessel cannulation and the prevalence of hematoma formation. Show less
How long does the average person sleep? Here, Kocevska et al. conducted a meta-analysis including over 1.1 million people to produce age- and sex-specific population reference charts for sleep... Show moreHow long does the average person sleep? Here, Kocevska et al. conducted a meta-analysis including over 1.1 million people to produce age- and sex-specific population reference charts for sleep duration and efficiency.We aimed to obtain reliable reference charts for sleep duration, estimate the prevalence of sleep complaints across the lifespan and identify risk indicators of poor sleep. Studies were identified through systematic literature search in Embase, Medline and Web of Science (9 August 2019) and through personal contacts. Eligible studies had to be published between 2000 and 2017 with data on sleep assessed with questionnaires including >= 100 participants from the general population. We assembled individual participant data from 200,358 people (aged 1-100 years, 55% female) from 36 studies from the Netherlands, 471,759 people (40-69 years, 55.5% female) from the United Kingdom and 409,617 people (>= 18 years, 55.8% female) from the United States. One in four people slept less than age-specific recommendations, but only 5.8% slept outside of the 'acceptable' sleep duration. Among teenagers, 51.5% reported total sleep times (TST) of less than the recommended 8-10 h and 18% report daytime sleepiness. In adults (>= 18 years), poor sleep quality (13.3%) and insomnia symptoms (9.6-19.4%) were more prevalent than short sleep duration (6.5% with TST < 6 h). Insomnia symptoms were most frequent in people spending >= 9 h in bed, whereas poor sleep quality was more frequent in those spending <6 h in bed. TST was similar across countries, but insomnia symptoms were 1.5-2.9 times higher in the United States. Women (>= 41 years) reported sleeping shorter times or slightly less efficiently than men, whereas with actigraphy they were estimated to sleep longer and more efficiently than man. This study provides age- and sex-specific population reference charts for sleep duration and efficiency which can help guide personalized advice on sleep length and preventive practices. Show less
Koning, M.; Berg, C.W. van den; Rabelink, T.J. 2019
Kidney organoids can be generated from human pluripotent stem cells (PSCs) using protocols that resemble the embryonic development of the kidney. The renal structures thus generated offer great... Show moreKidney organoids can be generated from human pluripotent stem cells (PSCs) using protocols that resemble the embryonic development of the kidney. The renal structures thus generated offer great potential for disease modeling, drug screening, and possibly future therapeutic application. At the same time, use of these PSC-derived organoids is hampered by lack of maturation and off-target differentiation. Here, we review the main protocols for the generation of kidney organoids from human-induced PSCs, discussing their advantages and limitations. In particular, we will focus on the vascularization of the kidney organoids, which appears to be one of the critical factors to achieve maturation and functionality of the organoids. Show less
Berg, C.W. van den; Ritsma, L.; Avramut, M.C.; Wiersma, L.E.; Berg, B.M. van den; Leuning, D.G.; ... ; Rabelink, T.J. 2018
