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IDRM researchers uncover a direct route from mesenchymal progenitors to lymphatic endothelial cells
A new study from the Stone Group at the IDRM has overturned a century-old view of how lymphatic vessels form.
Published in Nature Cardiovascular Research, the research reveals that lymphatic endothelial cells (LECs) can arise directly from a pool of mesenchymal progenitors, bypassing the venous endothelium altogether.
We spoke to postdoctoral scientist Dr David Grainger, one of the paper's authors and a member of IDRM's Stone Group, about the journey to this discovery and what it means for the future of vascular biology.
What was the biggest surprise in this study?
“The biggest surprise was that lymphatic endothelial cells (LECs) can arise directly from a specialised pool of mesenchymal progenitors (known as angioblasts), without needing to transition through a venous endothelial state.
This challenges the long-held belief that LECs mainly transdifferentiate from venous endothelium.”
Why has this question—where LECs come from—been debated for so long?
“The developmental origins of LECs have been debated for over a century, with early studies suggesting they form through budding from large veins. Later studies in mice indicated LECs mainly transdifferentiate from venous endothelium.
However, other research using different model systems revealed alternative, non-venous sources of LECs. This discrepancy in findings across various studies has fuelled the debate.”
What made it possible to finally get a clear answer?
“The discovery was made possible through a combination of single-cell genomics, inducible lineage tracing, and high-resolution imaging. Single-cell RNA sequencing helped define cells state transitions during LEC differentiation, including the identification of mesenchymal progenitors co-expressing endothelial progenitor markers (Etv2) and the master regulator of LEC fate specification (Prox1). Meanwhile, lineage-tracing experiments revealed the transient, LEC-restricted fate of these progenitors.”
What do these findings mean beyond just understanding development?
“This discovery has broad implications for our understanding of vascular development. It suggests that different subtypes of endothelial cells may originate from distinct, molecularly heterogeneous progenitor sources.
This understanding changes how we think about the origin of vascular heterogeneity and how we may recapitulate these processes in vitro. In particular, an improved understanding of the natural history of LECs serves as a blueprint for recapitulating human LEC development from pluripotent stem cells.”
Could this help with engineering lymphatic or blood vessels in the lab?
“Our ongoing work will follow up on this study in two exciting ways.
Firstly, we are studying the cellular and molecular context in which the first lymphatic progenitors are specified to inform our in vitro differentiation cultures.
Secondly, to understand whether the principle of distinct developmental origins contribute to heterogeneity in endothelial cells we are developing research tools to isolate, trace and manipulate other spatially and molecularly distinct endothelial progenitors.”
As the field of regenerative medicine continues to evolve, this study by the Stone group marks a small but important step forward in our ability to understand, and potentially find future therapies for diseases that affect the human cardiovascular system.