Hematopoietic Stem Cells Contribute to Lymphatic Endothelium

Abstract

BackgroundAlthough the lymphatic system arises as an extension of venous vessels in the embryo, little is known about the role of circulating progenitors in the maintenance or development of lymphatic endothelium. Here, we investigated whether hematopoietic stem cells (HSCs) have the potential to give rise to lymphatic endothelial cells (LEC).Methodology/Principal FindingsFollowing the transfer of marked HSCs into irradiated recipients, donor-derived LEC that co-express the lymphatic endothelial markers Lyve-1 and VEGFR-3 were identified in several tissues. HSC-derived LEC persisted for more than 12 months and contributed to ∼3–4% of lymphatic vessels. Donor-derived LECs were not detected in mice transplanted with common myeloid progenitors and granulocyte/macrophage progenitors, suggesting that myeloid lineage commitment is not a requisite step in HSC contribution to lymphatic endothelium. Analysis of parabiotic mice revealed direct evidence for the existence of functional, circulating lymphatic progenitors in the absence of acute injury. Furthermore, the transplantation of HSCs into ApcMin/+ mice resulted in the incorporation of donor-derived LEC into the lymphatic vessels of spontaneously arising intestinal tumors.Conclusions/SignificanceOur results indicate that HSCs can contribute to normal and tumor associated lymphatic endothelium. These findings suggest that the modification of HSCs may be a novel approach for targeting tumor metastasis and attenuating diseases of the lymphatic system.

Myeloid Cells and Lymphangiogenesis

“…In mice subcutaneously transplanted with B16F1 melanoma and Lewis lung carcinoma and previously transplanted with genetically labeled bone marrow, no integration of bone marrow-derived cells into tumor-associated lymphatic vessels has been observed (He et al 2004). In contrast, contribution of bone marrow cells has been observed in subcutaneous T241 fibrosarcoma tumors and in the genetic Apc Min/þ model of intestinal adenoma (Religa et al 2005;Jiang et al 2008). In the transgenic Rip1Tag2 mouse model of pancreatic b-cell carcinogenesis and in subcutaneously grown TRAMP-C1 prostate adenocarcinoma, a combination of adoptive bone marrow transfer and genetic lineage tracing experiments has revealed that bone marrow-derived cells of the myeloid lineage integrate into tumorassociated lymphatic vessels ).…”

Molecular Regulation of Lymphangiogenesis in Development and Tumor Microenvironment

“…There is evidence showing that bone-marrow (BM) derived cells could participate in lymphangiogenic vessel growth after differentiation into LECs (Maruyama et al 2005;Jiang et al 2008;Zumsteg et al 2009). In tumor-associated lymphangiogenesis, the contribution of BM-derived cells in lymphatic vessels was reported to be approximately 3 % (Jiang et al 2008;Zumsteg et al 2009). However, we showed previously that most tumor lymphatics were within 1 mm from tumor margin in an animal tumor model.…”

À la recherche d’une définition moléculaire plus que descriptive pour les cellules souches

“…Quant à la réalité d'une transdifférenciation des CSH, elle avait été contestée à l'époque et on avait attribué les observations à l'existence d'un processus de fusion cellulaire (entre par exemple monocytes et hépatocytes) suivi d'une reprogrammation des cellules. Pourtant, l'analyse de cellules individuelles semblerait confirmer la transdifférenciation de CSH en fibroblastes et myofibroblastes [28] et leur production de cellules hépatiques [29] et de l'endothélium lymphatique [30]. ment pour qu'un retour spontané vers un état de pluripotence se produise ; les cellules seraient arrêtées à des étapes diverses, aboutissant à des phénotypes de mono-ou bi-ou tri-potentialité.…”