Non-Venous Origin of Dermal Lymphatic Vasculature
Rationale: The formation of the blood vasculature is achieved via two 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 non-venous sources of lymphatic endothelial cells (LECs) have been suggested in chicken and Xenopus, but it is unclear if 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 LEC identity, in Tie2 lineage venous-derived LECs. We show that, contrary to current dogma, a significant part of the dermal lymphatic vasculature forms independently of sprouting from veins. While 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 non-venous derived cells to the dermal lymphatic vasculature. Demonstration of a previously unknown LEC 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.
- lineage tracing
- lymphatic capillary
- endothelial cell
- endothelial progenitor cells
- vascular biology
- developmental biology
- Received February 5, 2015.
- Revision received February 23, 2015.
- Accepted March 2, 2015.