Human Umbilical Cord Mesenchymal Stem Cell Exosomes Enhance Angiogenesis Through the Wnt4/β-Catenin Pathway

Abstract

Human umbilical cord mesenchymal stem cells (hucMSCs) and their exosomes have been considered as potential therapeutic tools for tissue regeneration; however, the underlying mechanisms are still not well understood. In this study, we isolated and characterized the exosomes from hucMSCs (hucMSC-Ex) and demonstrated that hucMSC-Ex promoted the proliferation, migration, and tube formation of endothelial cells in a dose-dependent manner. Furthermore, we demonstrated that hucMSC-Ex promoted wound healing and angiogenesis in vivo by using a rat skin burn model. We discovered that hucMSC-Ex promoted b-catenin nuclear translocation and induced the increased expression of proliferating cell nuclear antigen, cyclin D3, N-cadherin, and b-catenin and the decreased expression of E-cadherin. The activation of Wnt/b-catenin is critical in the induction of angiogenesis by hucMSC-Ex, which could be reversed by b-catenin inhibitor ICG-001. Wnt4 was delivered by hucMSC-Ex, and the knockdown of Wnt4 in hucMSC-Ex abrogated b-catenin nuclear translocation in endothelial cells. The in vivo proangiogenic effects were also inhibited by interference of Wnt4 expression in hucMSC-Ex. Taken together, these results suggest that hucMSC-Ex-mediated Wnt4 induces b-catenin activation in endothelial cells and exerts proangiogenic effects, which could be an important mechanism for cutaneous wound healing. STEM CELLS TRANSLATIONAL MEDICINE 2015; 4:513-522 SIGNIFICANCEHuman umbilical cord mesenchymal stem cells (hucMSCs) and their exosomes have been considered as potential therapeutic tools for tissue regeneration; however, the underlying mechanisms are still not well understood. In this study, it is reported that hucMSC-Ex-mediated Wnt4 induces b-catenin activation in endothelial cells and exerts proangiogenic effects, which could be one of the important mechanisms responsible for cutaneous wound healing.

Enhancing endogenous capacity to repair a stroke-damaged brain: An evolving field for stroke research

“…Bone marrow-derived MSC exosomes increase the number of mature NeuN positive cells in lesioned striatum (Doeppner et al, 2015a) and prevent post-stroke immune suppression that is a common sequela of clinical stroke. Cord blood-derived MSC exosomes are pro-angiogenic (Zhang et al, 2015) while EPC exosomes contain miR-126 and miR-296 which activates the PI3K/Akt signaling pathway in endothelial cells (Deregibus et al, 2007). The NSC cell-line, CTX0E03, produces exosomes with a myriad of miRNAs, although the most abundant was miR-1246 (Stevanato et al, 2016).…”

WNT4 mediates the autocrine effects of growth hormone in mammary carcinoma cells

“…In contrast, WNT4 has been shown to decrease cell migration of rat thyroid cells FRTL-5 suggesting that it can exert different actions depending on the cellular context (De Menna et al 2013). It was recently shown that WNT4 secretion by human umbilical cord mesenchymal stem cells stimulates their migration, and is activating angiogenesis in vivo in a rat skin burn model (Zhang et al 2015). Interestingly, exosomal release of WNT4 is responsible for mesenchymal stem cell migration (Zhang et al 2015), and similar exosome release of WNT5a induces human melanoma cancer cell migration and invasion (Ekström et al 2014).…”

“…It was recently shown that WNT4 secretion by human umbilical cord mesenchymal stem cells stimulates their migration, and is activating angiogenesis in vivo in a rat skin burn model (Zhang et al 2015). Interestingly, exosomal release of WNT4 is responsible for mesenchymal stem cell migration (Zhang et al 2015), and similar exosome release of WNT5a induces human melanoma cancer cell migration and invasion (Ekström et al 2014). Whether a similar mechanism is involved for WNT4-induced migration of normal mammary epithelial cells needs to be investigated.…”

Exosomes as a novel pathway for regulating development and diseases of the skin (Review)

“…Human umbilical cord MSC-derived exosomes (hucMSC-Exos) through the Wnt4 pathway are also involved in skin wound healing. HucMSC-Exos facilitate the function of endothelial cells; various studies have demonstrated that the hucMSC-Exo-mediated Wnt4 pathway induced β-catenin activation in endothelial cells and enhanced vascular regeneration (57,67). Furthermore, research has suggested that exosomes from the serum may accelerate wound healing in mice, predominantly due to the impact on collagen synthesis (68).…”