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Boosting Angiogenesis via MSC-Derived Exosomes

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Review of “Comprehensive Proteomic Analysis of Mesenchymal Stem Cell Exosomes Reveals Modulation of Angiogenesis via NFkB Signaling” from Stem Cells by Stuart P. Atkinson

Mesenchymal stem cells (MSCs) have potent pro-angiogenic properties due to their secretion of both specific proteins and lipid bound vesicles which transport protein and RNA known as exosomes [1]. Knowledge of the protein content of MSCs and exosomes may aid the construction of novel cell-free treatments for ischemic disorders such as peripheral arterial disease (PAD) [2], which has led researchers from the laboratory of Johnathon D. Anderson (University of California Davis Medical Center, USA) to employed a mass spectroscopy approach to achieve this goal [3]. Their findings suggest that the PDGF, EGF, FGF and, most notably, NFkB signaling pathway proteins are highly important exosome-derived pro-angiogenic factors [4].

To investigate important pro-angiogenic proteins, the authors first compared the protein content of MSCs grown under normoxic, high serum expansion conditions (EX), and PAD-like serum-free low oxygen conditions. Their unbiased mass-spectroscopic proteome analysis found a large difference in overall protein content, including the attenuation of networks controlling cell cycle initiation and glycolysis in MSCs exposed to PAD-like conditions. They also highlighted a PAD-mediated increase in angiogenic signaling (via platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and fibroblast growth factor (FGF)) and cholesterol/lipid biosynthesis. This increase in cholesterol/lipid formation led the authors to assess any MSC-derived extracellular vesicles such as microvesicles and exosomes (See Figure for a Transmission electron micrograph image of these structures). Interestingly, while PAD-like conditions mediated a decrease in microvesicle secretion, the secretion of exosomes containing angiogenic-signaling proteins (PDGF, EGF, and FGF) in fact increased, so mirroring the protein-expression pattern found in MSCs themselves.

Finally, the authors treated human umbilical vein endothelial cells (HUVEC) with MSC-exosomes collected under PAD-like conditions to assess their angiogenic capability via their ability to induce tubule formation. Low concentrations of exosomes (1-10 μg/mL) significantly enhanced tubule formation, although the application of a specific inhibitor of NFkB signaling inhibited this enhancement, suggesting NFkB to be a vitally important angiogenic pathway controlled by exosomally-derived proteins.

This robust proteomic characterization of MSCs and exosomes has highlighted the influence of numerous signaling pathways which can influence angiogenesis in an ischemic microenvironment, and so may provide us with the means to construct more effective therapeutic options in the future. Such options include precision-engineered MSCs primed with pro-angiogenic capability or the production of a cell-free strategy, such as MSC-derived exosomes, which has been used to treat graft versus host disease [5], or via synthetically derived exosomal formulations.

Discussion Points

  • Can exosomes become an important clinical strategy for multiple diseases/disorders?
  • Are exosomes a safer strategy than treatment with MSCs?
  • How can we engineer MSCs/Exosomes to promote angiogenesis?

References

  1. S ELA, Mager I, Breakefield XO, et al. Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov 2013;12:347-357.
  2. Liew A and O'Brien T Therapeutic potential for mesenchymal stem cell transplantation in critical limb ischemia. Stem Cell Res Ther 2012;3:28.
  3. Branca RM, Orre LM, Johansson HJ, et al. HiRIEF LC-MS enables deep proteome coverage and unbiased proteogenomics. Nat Methods 2014;11:59-62.
  4. Anderson JD, Johansson HJ, Graham CS, et al. Comprehensive Proteomic Analysis of Mesenchymal Stem Cell Exosomes Reveals Modulation of Angiogenesis via Nuclear Factor-KappaB Signaling. STEM CELLS 2016;34:601-613.
  5. Kordelas L, Rebmann V, Ludwig AK, et al. MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease. Leukemia 2014;28:970-973.