Nonvenous Origin of Dermal Lymphatic Vasculature

Abstract

Rationale: The formation of the blood vasculature is achieved via 2 fundamentally different mechanisms, de novo formation of vessels from endothelial progenitors (vasculogenesis) and sprouting of vessels from pre-existing ones (angiogenesis). In contrast, mammalian lymphatic vasculature is thought to form exclusively by sprouting from embryonic veins (lymphangiogenesis). Alternative nonvenous sources of lymphatic endothelial cells have been suggested in chicken and Xenopus, but it is unclear whether they exist in mammals. Objective: We aimed to clarify the origin of the murine dermal lymphatic vasculature. Methods and Results: We performed lineage tracing experiments and analyzed mutants lacking the Prox1 transcription factor, a master regulator of lymphatic endothelial cell identity, in Tie2 lineage venous–derived lymphatic endothelial cells. We show that, contrary to current dogma, a significant part of the dermal lymphatic vasculature forms independently of sprouting from veins. Although lymphatic vessels of cervical and thoracic skin develop via sprouting from venous-derived lymph sacs, vessels of lumbar and dorsal midline skin form via assembly of non– Tie2 -lineage cells into clusters and vessels through a process defined as lymphvasculogenesis. Conclusions: Our results demonstrate a significant contribution of nonvenous-derived cells to the dermal lymphatic vasculature. Demonstration of a previously unknown lymphatic endothelial cell progenitor population will now allow further characterization of their origin, identity, and functions during normal lymphatic development and in pathology, as well as their potential therapeutic use for lymphatic regeneration.

Hyperplasia, de novo lymphangiogenesis, and lymphatic regression in mice with tissue-specific, inducible overexpression of murine VEGF-D

“…Rapid lymphangiectasia of the collecting vessels in the lung and kidney would suggest the response to be from the existing endothelium. In adipose tissue, the appearance of de novo lymphatic structures requires at least 1 mo (we assessed at 10 days and 2 mo) and suggests a lymphvasculogenesis or lymphagioblast-like mechanism, as has been previously reported in other systems examining postnatal and adult lymphatic expansion and regrowth (17,21,26,36,45). A return to basal VEGF-D expression resulted in a regression of the new lymphatic structures in adipose tissue, similar to the regression observed in the skin and cornea during the resolu- …”

Evidence Supporting a Lymphatic Endothelium Origin for Angiomyolipoma, a TSC2− Tumor Related to Lymphangioleiomyomatosis

“…It is now well established that LECs originate from the embryonic cardinal veins, 49,50 from circulating VEC/LEC precursors, characterized by their expression of the LEC/VEC precursor markers CD34 and CD133, 51e54 and from other less defined sources. 55,56 The best studied process of lymphangiogenesis is that undergone by LECs originated from the cardinal veins. In the latter, the first molecular indicator of LEC competence is the expression of the SOX family transcription factor SOX18 in the dorsolateral wall.…”

Meet Me in the Middle

“…However, full comprehension into the intricacies of LEC biology is still being developed. The work of Martinez-Corral et al, 8 based on lineage-tracing analyses of genetic mouse models, now provides first insights into an unexpected complexity of LEC origins in mammals.…”

“…Intriguingly, such isolated LECs were most numerous in the lumbar region of the embryo. To tease out the origin of these cells, Martinez-Corral et al 8 analyzed crosses of endothelial/hematopoietic-specific Tie2-Cre and mTmG reporter strains, which should express GFP in all cells derived from Tie2-expressing precursors. As observed before, 13 LECs from the jugular region had transdifferentiated from blood endothelial cells as they were positive for GFP.…”