cKit Lineage Hemogenic Endothelium-Derived Cells Contribute to Mesenteric Lymphatic Vessels.

Pathological lymphatic diseases mostly affect vessels in specific tissues, yet little is known about organ-specific regulation of the lymphatic vasculature. Here, we show that the vascular endothelial growth factor receptor 3 (VEGFR-3)/p110α PI3-kinase signaling pathway is selectively required for the formation of mesenteric lymphatic vasculature. Using genetic lineage tracing, we demonstrate that part of the mesenteric lymphatic vasculature develops from cKit lineage cells of hemogenic endothelial origin through a process we define as lymphvasculogenesis. This is contrary to the current dogma that all mammalian lymphatic vessels form by sprouting from veins. Our results reveal vascular-bed-specific differences in the origin and mechanisms of vessel formation, which may critically underlie organ-specific manifestation of lymphatic dysfunction in disease. The progenitor cells identified in this study may be exploited to restore lymphatic function following cancer surgery, lymphedema, or tissue trauma.We thank Bart Vanhaesebroeck (UCL Cancer Institute, London) for p110 alphaflox and p110 alphaD933A mice, Dimitris Kioussis (National Institute for Medical Research, London) for Vav-Cre mice, Erwin Wagner for Vegfr2flox mice, Ian Roswell and the transgenic services at the LRI for help with establishing mouse lines, Henrik Ortsater for assistance with experiments, and staff at the LRI and Uppsala University animal units for animal husbandry. We also thank the light microscopy unit at the LRI and BioVis at Uppsala University for advice and help with experiments. This study was supported by Cancer Research UK (L.S., I.M.-C., and T.M.); EMBO Young Investigator Programme, the Kjell and Marta Beijer Foundation, and the Swedish Research Council (T.M.); Fundacion Alfonso Martin Escudero (I.M.-C.); Spanish Ministry of Education (FECYT grant, postdoctoral mobility contract EDU/2934/2009; B.L.); MRC G0501711 (M.F.); Deutsche Forschunsgemeinschaft (DFG SA 137/1-3; D.S.); Ministry of Science and Innovation of Spain (grants BIO2009-09488 and SAF2010-18765 to S.O. and grant SAF2010-15661 to M.G.); European Research Council (ERC-2010-AdG-268804 to K.A. and ERC-2011-AdG-294556 to C.B.); Knut and Alice Wallenberg Foundation and the Swedish Cancer Foundation (C.B.); the Leducq Foundation (11CVD03) (K.A.); and the Marie Curie ITN (Vessel, FP7-PEOPLE-2012-ITN; K.A., R.H.A., C.B., and M.G.).S