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Stem Cell Exosomes: They "Wnt" to Help Angiogenesis

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Review of “Human Umbilical Cord Mesenchymal Stem Cell Exosomes Enhance Angiogenesis Through the Wnt4/β-Catenin Pathway” from Stem Cells TM by Stuart P. Atkinson

Mesenchymal stem cell (MSC) treatment is a promising therapeutic option for multiple diseases and disorders, with paracrine action rather than long term cell engraftment and transdifferentiation thought to be behind their utility. Exosomes are protein and nucleic acid containing vesicles released from cells which are thought to function in intercellular communication [1], and while studies have linked MSC-derived exosomes to the effective treatment of multiple disorders [2-4], the mechanisms behind their functions in this context are relatively unknown. Now, researchers from the laboratory of Wenrong Xu and Hui Qian (Jiangsu University, China) have studied exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-Ex) and report that these exosomes aid the repair of skin burn injuries through paracrine actions mediated through the Wnt4/β-Catenin pathway [5].  

After isolation of HucMSC-Ex, Zhang et al assessed the effect of differing doses of exosomes for differing time periods on endothelial cells (ECs), finding that exosomes promoted EC growth and migration (transwell migration and wound healing assays) and in vitro angiogenesis (endothelial tube formation assay) in a dose dependent manner. Exosomes also induced higher levels of angiogenesis, as measured by the increased presence of CD31-positive ECs, in a skin-deep second-degree burn model in rats as compared to vehicle control. 

When studying potential molecular mechanisms behind these beneficial effects, the group found that exosome treatment of ECs increased the stability and nuclear accumulation of β-Catenin, as well as an increase in PCNA and Cyclin D3 protein levels suggesting increased cell proliferation. Interestingly, artificial β-Catenin inhibition reduced any exosome-induced increase in angiogenesis in the in vivo wound healing assay. The group added to their previous finding of Wnt4-mediated cutaneous regeneration by exosomes [6] by showing that Wnt4 stabilized β-Catenin in PCs and is a vital requirement for the pro-angiogenic effect of exosome treatment. The adjoining figure demonstrates that Wnt4 inhibition by short hairpin RNA expression in the rat wound healing model reduced the pro-angiogenic properties, as signified by the loss of exosome-induced angiogenic marker CD31 expression. Finally, the study also found increased N-cadherin expression and decreased E-cadherin expression in exosome treated PCs suggesting that increased motility may be due to the alteration of these cell junction components.

This interesting new study highlights a specific paracrine mechanism through which MSCs promote angiogenesis - the Wnt/ β-Catenin pathway. But is there more? Subsequent analysis of both miRNA and mRNA may uncover further mechanistic insights, and additionally, it may be interesting to contrast and compare MSCs taken from differing sources to assess if human umbilical cord represents the best source for exosomes in this context.

References

  1. Bang C and Thum T Exosomes: new players in cell-cell communication. Int J Biochem Cell Biol 2012;44:2060-2064.
  2. Lai RC, Arslan F, Lee MM, et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem cell research 2010;4:214-222.
  3. Li T, Yan Y, Wang B, et al. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis. Stem cells and development 2013;22:845-854.
  4. Zhou Y, Xu H, Xu W, et al. Exosomes released by human umbilical cord mesenchymal stem cells protect against cisplatin-induced renal oxidative stress and apoptosis in vivo and in vitro. Stem cell research & therapy 2013;4:34.
  5. Zhang B, Wu X, Zhang X, et al. Human Umbilical Cord Mesenchymal Stem Cell Exosomes Enhance Angiogenesis Through the Wnt4/beta-Catenin Pathway. Stem Cells Translational Medicine 2015;4:513-522.
  6. Zhang B, Wang M, Gong A, et al. HucMSC-Exosome Mediated-Wnt4 Signaling Is Required for Cutaneous Wound Healing. Stem Cells 2015; In Press.