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Abstract: SA-OR20

Deciphering the Origins of Kidney Lymphatics

Session Information

Category: Development‚ Stem Cells‚ and Regenerative Medicine

  • 500 Development‚ Stem Cells‚ and Regenerative Medicine

Authors

  • Jafree, Daniyal J., UCL Great Ormond Street Institute of Child Health, London, United Kingdom
  • Rowan, Christopher, SickKids Research Institute, Toronto, Ontario, Canada
  • Joannou, Maria K., UCL Great Ormond Street Institute of Child Health, London, United Kingdom
  • Russell, Lauren G., UCL Great Ormond Street Institute of Child Health, London, United Kingdom
  • Siegenthaler, Julie A, University of Colorado, Denver, Colorado, United States
  • Woolf, Adrian S., The University of Manchester Faculty of Biology Medicine and Health, Manchester, Manchester, United Kingdom
  • Rosenblum, Norman D., SickKids Research Institute, Toronto, Ontario, Canada
  • Scambler, Peter, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
  • Long, David A., UCL Great Ormond Street Institute of Child Health, London, United Kingdom

Group or Team Name

  • UCL ICH Kidney Development and Disease
Background

Lymphatics clear excess tissue fluid, cells and macromolecules from organs, and are emerging as players in kidney diseases and transplant rejection. Lymphatics were thought to solely originate by sprouting from veins. More recently, we showed that kidney lymphatics can arise using a distinct cellular mechanism featuring the formation of lymphatic ‘clusters’, akin to a de novo vasculogenic process. In this study, we designed experiments to decipher where kidney lymphatics come from.

Methods

To identify kidney lymphatics origins, we utilised Cre recombinase-dependent expression of tdTomato for lineage tracing in mouse embryos. We used the following Cre lines to determine the contribution of different cell lineages to lymphatics: (i) Tie2-Cre for endothelial precursors; (ii) Osr1-CreERTR for posterior intermediate mesoderm and (iii) Six2-Cre, Tbx18-CreERT2 and Foxd1-Cre for nephron epithelial, ureteral mesenchyme and renal stroma, respectively. Intact, lineage traced kidneys were subject to wholemount immunolabelling for tdTomato and the lymphatic markers, PROX1 and PDPN, before tissue clearing and confocal microscopy. From the resulting high-resolution 3D images, we quantitatively assessed contributions from each origin to kidney lymphatics.

Results

We found 85% of kidney lymphatics to derive from endothelial precursors, as assessed by labelling Tie2+ cells and their progeny. Conversely, 15% of kidney lymphatics arose from an Osr1+ cell lineage, whereas lymphatics in the heart, skin and lung did not originate from Osr1+ progenitors. We found that kidney lymphatics did not originate from Six2+ cells, or from Tbx18+ ureteral mesenchyme, both which derive from Osr1+ cells. However, we provide evidence that the Foxd1+ renal stroma is a source of progenitor cells giving rise to kidney lymphatics. No single lineage was exclusive for lymphatic clusters.

Conclusion

Our study emphasises the early colonisation of the mammalian kidney by lymphatics. It also points to an unexpected variety of lineages giving rise to kidney lymphatics, including a novel non-endothelial origin specific to the kidney. These insights challenge the paradigm that lymphatics from different origins form through distinct cellular mechanisms. Further, they critically inform future studies of the roles of lymphatics in kidney development and disease.