Spatiotemporal dynamics and heterogeneity of renal lymphatics in mammalian development and cystic kidney disease
- University College London, United Kingdom
- Mayo Clinic, United States
- University of Oxford, United Kingdom
- University of Manchester, United Kingdom
Abstract
Heterogeneity of lymphatic vessels during embryogenesis is critical for organ-specific lymphatic function. Little is known about lymphatics in the developing kidney, despite their established roles in pathology of the mature organ. We performed three-dimensional imaging to characterize lymphatic vessel formation in the mammalian embryonic kidney at single-cell resolution. In mouse, we visually and quantitatively assessed the development of kidney lymphatic vessels, remodeling from a ring-like anastomosis under the nascent renal pelvis, a site of VEGF-C expression, to form a patent vascular plexus. We identified a heterogenous population of lymphatic endothelial cell clusters in mouse and human embryonic kidneys. Exogenous VEGF-C expanded the lymphatic population in explanted mouse embryonic kidneys. Finally, we characterized complex kidney lymphatic abnormalities in a genetic mouse model of polycystic kidney disease. Our study provides novel insights into the development of kidney lymphatic vasculature; a system which likely has fundamental roles in renal development, physiology and disease.
Data availability
The FIJI script used for segmenting and binarizing PROX1+/LYVE1+ cells has been provided as Source code file 1. All raw numerical data and results of statistical tests are attached as Source Data files with the appropriate figure.
Article and author information
Author details
Funding
UCL Great Ormond Street Institute of Child Health (Child Health Research Studentship)
- Daniyal J Jafree
- Peter Scambler
- David A Long
British Heart Foundation (RG/15/14/31880)
- Peter Scambler
Kidney Research UK (Paed_RP_10_2018)
- Daniyal J Jafree
- Adrian S Woolf
- David A Long
Kidney Research UK (IN_012_2019)
- Daniyal J Jafree
- David A Long
University College London MB/PhD Programme (MB/PhD Studentship)
- Daniyal J Jafree
Medical Research Council (MR/P018629/1)
- David A Long
Medical Research Council (MR/L002744/1)
- Adrian S Woolf
Medical Research Council (MR/K026739/1)
- Adrian S Woolf
British Heart Foundation (FS/19/14/34170)
- Rosa Maria Correra
Diabetes UK (15/0005283)
- David A Long
NIHR Great Ormond Street Hospital Biomedical Research Centre Award (17DD08)
- Dale Moulding
British Heart Foundation (CH/11/1/28798)
- Paul R Riley
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experiments were carried out according to a UK Home Office project license (PPL: PE52D8C09) and were compliant with the UK Animals (Scientific Procedures) Act 1986.
Human subjects: Human fetal kidneys were obtained from the Human Developmental Biology Resource (http://www.hdbr.org), which obtains written consent from donors to collect, store and distribute human fetal material between 4-20PCW.
Copyright
© 2019, Jafree et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 4,451
- views
-
- 549
- downloads
-
- 49
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Spatiotemporal dynamics and heterogeneity of renal lymphatics in mammalian development and cystic kidney disease
eLife 8:e48183.
https://doi.org/10.7554/eLife.48183
Further reading
-
- Cell Biology
- Developmental Biology
Eukaryotic cells depend on exocytosis to direct intracellularly synthesized material toward the extracellular space or the plasma membrane, so exocytosis constitutes a basic function for cellular homeostasis and communication between cells. The secretory pathway includes biogenesis of secretory granules (SGs), their maturation and fusion with the plasma membrane (exocytosis), resulting in release of SG content to the extracellular space. The larval salivary gland of Drosophila melanogaster is an excellent model for studying exocytosis. This gland synthesizes mucins that are packaged in SGs that sprout from the trans-Golgi network and then undergo a maturation process that involves homotypic fusion, condensation, and acidification. Finally, mature SGs are directed to the apical domain of the plasma membrane with which they fuse, releasing their content into the gland lumen. The exocyst is a hetero-octameric complex that participates in tethering of vesicles to the plasma membrane during constitutive exocytosis. By precise temperature-dependent gradual activation of the Gal4-UAS expression system, we have induced different levels of silencing of exocyst complex subunits, and identified three temporarily distinctive steps of the regulated exocytic pathway where the exocyst is critically required: SG biogenesis, SG maturation, and SG exocytosis. Our results shed light on previously unidentified functions of the exocyst along the exocytic pathway. We propose that the exocyst acts as a general tethering factor in various steps of this cellular process.
-
- Cell Biology
- Developmental Biology
In most murine species, spermatozoa exhibit a falciform apical hook at the head end. The function of the sperm hook is not yet clearly understood. In this study, we investigate the role of the sperm hook in the migration of spermatozoa through the female reproductive tract in Mus musculus (C57BL/6), using a deep tissue imaging custom-built two-photon microscope. Through live reproductive tract imaging, we found evidence indicating that the sperm hook aids in the attachment of spermatozoa to the epithelium and facilitates interactions between spermatozoa and the epithelium during migration in the uterus and oviduct. We also observed synchronized sperm beating, which resulted from the spontaneous unidirectional rearrangement of spermatozoa in the uterus. Based on live imaging of spermatozoa-epithelium interaction dynamics, we propose that the sperm hook plays a crucial role in successful migration through the female reproductive tract by providing anchor-like mechanical support and facilitating interactions between spermatozoa and the female reproductive tract in the house mouse.
