Great weekend celebrating @emmarose64.bsky.social's graduation with friends and family. Very proud! 😊

A huge thank you to all my co-authors, particularly Irina Lupu, Nils Kirschnick, @oliverastone.bsky.social and Friedemann Kiefer I am grateful to have been part of a project that opens so many exciting questions for the field For more details, please read our paper: doi.org/10.1038/s441...

Direct specification of lymphatic endothelium from mesenchymal progenitors - Nature Cardiovascular Research

Lupu, Grainger, Kirschnick et al. show that, contrary to prevailing belief, the initial specification of mammalian lymphatic endothelial cells primarily occurs from previously unidentified mesenchymal...

doi.org

Finally, our proposed model showing LEC differentiation through in situ specification from ETV2+PROX1+ paraxial mesoderm-derived lymphangioblasts

HCR (@hcrimaging.bsky.social) stainings suggest VEGFC/VEGFR3 signaling acts upstream of PROX1 In the absence of VEGFC/VEGFR3 signaling, specification of LECs from PXM stalls at the angioblast stage with Vegfc-/- embryos having more Etv2+Prox1- cells in the HDM.

If migrating venous ECs are the major source of LECs, a substantial increase in EC numbers would be required to maintain venous integrity. Analysis of cell cycle phase suggests angioblast-derived LECs and not venous ECs, are proliferative enough to support the rapid expansion of LECs.

Conditional lineage tracing analyses using an inducible Pax3-CreERT2 line further highlighted the transient nature of this progenitor source, and demonstrated that lymphangioblasts give rise to LECs in various tissues.

To better characterise lymphangioblast specification from PXM we performed snMultiome (RNA & ATAC) on Pax3-lineage progenitors and ECs at E9.5. SCENIC+ analysis showed GRNs formed by known (ETV2/SOX18) and novel (EBF1/2) regulators of EC/LEC specification & differentiation in lymphangioblasts

IF and HCR (@hcrimaging.bsky.social) staining of wholemount and vibratome sectioned E9.5 embryos identified lymphangioblasts as residing immediately dorsal to the cardinal vein in the Lbx1+ hypaxial dermomyotome in a pattern reminiscent of LECs migrating from the cardinal vein

Surprisingly, we identified a population of cells that express both the angioblast marker Etv2 and the master regulator of LEC fate, Prox1. We have termed these cells lymphangioblasts.

The prevailing model was that PXM-derived cells contribute to venous endothelium and then transdifferentiate to LECs Irina Lupu's postdoc in Ollie's newly established lab aimed to define molecular features that may drive PXM's LEC competence using scRNA-seq on sorted EC and progenitor populations

In 2019, @oliverastone.bsky.social and Didier Stainier identified Pax3+ paraxial mesoderm as the only lineage competent for LEC differentiation www.sciencedirect.com/science/arti...

Paraxial Mesoderm Is the Major Source of Lymphatic Endothelium

Endothelial cells (ECs), which line blood and lymphatic vessels, are generally described to come from the lateral plate mesoderm despite experimental …

sciencedirect.com

✨Excited to share our work revisiting the developmental origins of mammalian lymphatic endothelial cells.✨ A summary of our key findings using scRNA-seq, snMultiome-seq and imaging to show the direct specification of mesenchymal progenitors to LECs🧵 #blutorial #blabstract tinyurl.com/LECspec

Direct specification of lymphatic endothelium from mesenchymal progenitors - Nature Cardiovascular Research

Lupu, Grainger, Kirschnick et al. show that, contrary to prevailing belief, the initial specification of mammalian lymphatic endothelial cells primarily occurs from previously unidentified mesenchymal...

tinyurl.com

I'm not saying I spend too much time on the microscope but I can't help seeing blood vessels in christmas lights