Mesenchymal stem cell derived exosomes enhance lymphangiogenesis via exosomal transfer of Ang-2/Tie2

Abstract

Mesenchymal stem cell derived exosomes (MSC-Ex) are nanosized membrane-bound extracellular vesicles found in MSC conditioned medium, that have yielded beneficial effects in several experimental models of organ injury. However, the therapeutic value and mechanism of MSC-Ex in lymphedema is poorly understood. Here we find that human umbilical cord MSCs derived exosomes (hucMSC-Ex) treatment contributed to the regeneration of LYVE-1 positive lymphatic vessels and reduction of lymphedema in a mouse model of tail lymphedema. Following uptake, exosomal lymphangiogenic factors (angiopoietin (Ang)-2 and Tie2) are taken up by HDLECs and promoted HDLECs proliferation, migration, and tube formation in vitro. We also find that exosomal Ang-2 and Tie2 exert a prolymphangiogenic effect on HDLECs through upregulating Prox1 and VEGFR3/p-Akt expression. In conclusion, our result unravel a previously unappreciated prolymphangiogenic role of hucMSC-Ex in lymphedema therapy and provide a new mechanism of Ang-2 in therapeutic lymphangiogenesis.

Microenvironmental modulation of the developing tumour: an immune‐stromal dialogue

“…Here, CAF‐secreted factors such as hyaluronan [ 256 ], FGF, HGF and VEGF‐C directly induce lymphangiogenesis [ 257 , 258 , 259 ], while tumour‐derived lysyl oxidase‐like protein 2 (LOXL2) and sonic hedgehog have been reported to stimulate CAFs to upregulate VEGF‐C and SDF‐1α to support lymphatic expansion [ 260 , 261 ]. CAF‐derived ECM components such as hyaluronan, fibronectin, collagen, laminin and osteopontin have further been identified as lymphangiogenic drivers [ 257 , 262 ], as have CAF‐derived microvesicles which are reported to exert pro‐lymphangiogenic effects via angiopoietin and Tie2 driving VEGFR3 expression on lymphatics [ 263 ]. Whether similar communications are established in the early TME to support malignant transition remains to be determined.…”