A blood capillary plexus-derived population of progenitor cells contributes to genesis of the dermal lymphatic vasculature during embryonic development

Abstract

Despite the essential role of the lymphatic vasculature in tissue homeostasis and disease, knowledge of the organ-specific origins of lymphatic endothelial progenitor cells remains limited. The assumption that most murine embryonic lymphatic endothelial cells (LECs) are venous derived has recently been challenged. Here, we show that the embryonic dermal blood capillary plexus constitutes an additional, local source of LECs that contributes to the formation of the dermal lymphatic vascular network. We describe a novel mechanism whereby rare PROX1-positive endothelial cells exit the capillary plexus in a -dependent manner to establish discrete LEC clusters. As development proceeds, these clusters expand and further contribute to the growing lymphatic system. Lineage tracing and analyses of-deficient mice confirmed that these clusters are endothelial in origin. Furthermore, ectopic expression of in the vasculature increased the number of PROX1-positive progenitors within the capillary bed. Our work reveals a novel source of lymphatic endothelial progenitors employed during construction of the dermal lymphatic vasculature and demonstrates that the blood vasculature is likely to remain an ongoing source of LECs during organogenesis, raising the question of whether a similar mechanism operates during pathological lymphangiogenesis.

Zebrafish facial lymphatics develop through sequential addition of venous and non‐venous progenitors

“…More recently, the “dual origin” theory, wherein a combination of venous and non‐venous lymphatic progenitors form the lymphatic vasculature , has been gaining popularity following a series of Cre‐LoxP lineage‐tracing experiments in mice . However, many of these studies have been contradictory , in part due to technical limitations in the genetic lineage‐tracing techniques, and direct evidence of a non‐venous lymphatic progenitor has remained elusive.…”

Cellular Origins of the Lymphatic Endothelium: Implications for Cancer Lymphangiogenesis

“…One of the first such examples was the superficial dermal lymphatic network, for which two different LEC origins were reported (Martinez-Corral et al, 2015;Pichol-Thievend et al, 2018). Martinez-Corral et al (2015) claimed that skin lymphatics in the cervical and thoracic regions of the mouse embryo, form via transdifferentiation of Tie2-expressing venous structures and subsequent sprouting from the jugular lymph sacs.…”

“…Fate mapping of these cells in mouse embryos revealed that they contribute to the formation of both CD31+ endothelial cells, and CD31-mesenchymal stromal niches in the lymph nodes. During postnatal development though, Nestin expression becomes predominant in the endothelial compartment including the capillaries, high endothelial venules (Huntington and McClure, 1910) Jugular sacs Mouse embryo Tie2+ (Wigle and Oliver, 1999;Wigle, 2002;Srinivasan et al, 2007) Parachordal cells Zebrafish embryo fli1a+ PCV (Yaniv et al, 2006) flt1_9a+ angioblasts (Nicenboim et al, 2015) Facial lymphatics Zebrafish embryo lyve1b+ CCV and PHS (Okuda et al, 2012;Eng et al, 2019) VA-L (Eng et al, 2019) Dermal lymphatics Mouse embryo Tie2+ cervical/thoracic region (Martinez-Corral et al, 2015) Sox18+/Cadh5+/Tie2+ cervical/thoracic region (Pichol-Thievend et al, 2018) Tie2-/Vav-dorsal/midline/lumbar region (Martinez-Corral et al, 2015) Pax3+ thoracic/lumbar/sacral region (Stone and Stainier, 2019) Myf5+ Ear skin (Stone and Stainier, 2019) Mef2c+ cervical/thoracic region (Stone and Stainier, 2019) Cardiac lymphatics Mouse embryo Tie2+ (Klotz et al, 2015) Vav1+/Pdgfb+/Csfr1+ (Klotz et al, 2015) Apln-and Apj- (Gancz et al, 2019b) Isl1+ (Maruyama et al, 2019;Lioux et al, 2020) Pax3+ ( Zebrafish mrc1a+ meningeal lymphatics (Castranova et al, 2020) mrc1a+ mural LECs (muLECs) /flt4+/prox1a+/lyve1b+ (Bower et al, 2017;Galanternik et al, 2017;van Lessen et al, 2017) Schlemm's canal Mouse embryo Kdr+ lumbar vasculature (Kizhatil et al, 2014) and LECs (Koning et al, 2016). Nevertheless, given that Nestin expression is detected in a wide variety of cells, such as neural stem cells (Mignone et al, 2004) and stem cells from the mesenchymal lineage (Méndez-Ferrer et al, 2010) including endothelial cells (reviewed in <...>…”

Endothelial Cell Dynamics in Vascular Development: Insights From Live-Imaging in Zebrafish

“…Further studies are needed to identify the exact cell origin of these non-venous VA-As. Studies in mice have also proposed non-venous origins of cardiac, dermal and mesenteric lymphatic networks (Klotz et al, 2015;Martinez-Corral et al, 2015;Stanczuk et al, 2015;Pichol-Thievend et al, 2018;Maruyama et al, 2019;Stone and Stainier, 2019).…”