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.
Reviewing Editor
- Kari Alitalo, Wihuri Research Institute, Finland
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.
Version history
- Received: May 3, 2019
- Accepted: November 30, 2019
- Accepted Manuscript published: December 6, 2019 (version 1)
- Version of Record published: January 8, 2020 (version 2)
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
-
- 4,318
- views
-
- 538
- downloads
-
- 44
- 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
-
- Developmental Biology
Large-scale cell flow characterizes gastrulation in animal development. In amniote gastrulation, particularly in avian gastrula, a bilateral vortex-like counter-rotating cell flow, called ‘polonaise movements’, appears along the midline. Here, through experimental manipulations, we addressed relationships between the polonaise movements and morphogenesis of the primitive streak, the earliest midline structure in amniotes. Suppression of the Wnt/planar cell polarity (PCP) signaling pathway maintains the polonaise movements along a deformed primitive streak. Mitotic arrest leads to diminished extension and development of the primitive streak and maintains the early phase of the polonaise movements. Ectopically induced Vg1, an axis-inducing morphogen, generates the polonaise movements, aligned to the induced midline, but disturbs the stereotypical cell flow pattern at the authentic midline. Despite the altered cell flow, induction and extension of the primitive streak are preserved along both authentic and induced midlines. Finally, we show that ectopic axis-inducing morphogen, Vg1, is capable of initiating the polonaise movements without concomitant PS extension under mitotic arrest conditions. These results are consistent with a model wherein primitive streak morphogenesis is required for the maintenance of the polonaise movements, but the polonaise movements are not necessarily responsible for primitive streak morphogenesis. Our data describe a previously undefined relationship between the large-scale cell flow and midline morphogenesis in gastrulation.
-
- Developmental Biology
- Physics of Living Systems
Geometric criteria can be used to assess whether cell intercalation is active or passive during the convergent extension of tissue.
