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HIF-MSC Exosomes: An Efficient and Effective Strategy to Promote Angiogenesis?



Review of “Hypoxia Inducible Factor-1α Potentiates Jagged 1-Mediated Angiogenesis by Mesenchymal Stem Cell-Derived Exosomes” from STEM CELLS by Stuart P. Atkinson

Other than their potent immunomodulatory effects, mesenchymal stem cells (MSCs) also promote the formation of blood vessels (angiogenesis) and, therefore, represent a potentially exciting treatment strategy for ischemic tissue-related disease (e.g. myocardial infarction). However, the modest results of clinical trials necessitate improvements in the pro-angiogenic nature of MSCs employing strategies including hypoxic conditioning [1] or the overexpression of Hypoxia inducible factor-1α (HIF-1α) [2].

Researchers from the team of Pilar Sepúlveda (Instituto de Investigación Sanitaria La Fe, Valencia, Spain) have recently sought to explore just how hypoxic signaling amplifies angiogenic potential in engineered MSCs. In their new STEM CELLS study, Gonzalez-King et al. now correlate angiogenic capabilities of MSCs with heightened levels of exosomes carrying elevated levels of Jagged1, a Notch ligand [3]. 

Has this new study unlocked the key to improved MSC-based cell-free angiogenic therapies?

Primary analysis of dental pulp MSCs overexpressing HIF-1α (HIF-MSCs) [2] indicated that hypoxic signaling enhanced exosome secretion and trafficking to human endothelial cells (HUVECs) in co-culture experiments and also significantly altered exosome protein and microRNA content. These alterations pointed towards the involvement of the Notch signaling pathway, which regulates tissue homeostasis, stem cell maintenance, vasculature development, and angiogenesis [4-6]. Indeed, subsequent assessments of Notch ligands demonstrated a specific and significant upregulation in Jagged1 protein and mRNA in HIF1-MSC exosomes.

Encouragingly, the HIF-1α-mediated changes to exosomes also appeared to boost their therapeutic capacity, as exosomes could induce the expression of Notch target genes in human endothelial cells and enhanced angiogenesis both in an in vitro model of capillary-like tube formation and in vivo in a Matrigel plug assay in athymic nude mice when compared to unmodified MSCs.

Overall, this fascinating new study suggests that HIF-1α modified MSC exosomes carry Jagged1 can effectively promote angiogenesis in vivo and in vitro and may represent an effective and efficient cell-free means to promote vessel growth and treat ischemic tissue-related disease. Furthermore, the authors note that their study also uncovers a novel mechanism of Jagged/Notch signal regulation that does not require classical cell–cell contact.

Exciting news! Keep the Stem Cells Portal bookmarked to discover more about modifying MSCs and improving the treatment of ischemic tissue-related disease!


  1. Rosova I, Dao M, Capoccia B, et al. Hypoxic preconditioning results in increased motility and improved therapeutic potential of human mesenchymal stem cells. Stem Cells 2008;26:2173-2182.
  2. Cerrada I, Ruiz-Sauri A, Carrero R, et al. Hypoxia-inducible factor 1 alpha contributes to cardiac healing in mesenchymal stem cells-mediated cardiac repair. Stem Cells Dev 2013;22:501-511.
  3. Gonzalez-King H, García NA, Ontoria-Oviedo I, et al. Hypoxia Inducible Factor-1α Potentiates Jagged 1-Mediated Angiogenesis by Mesenchymal Stem Cell-Derived Exosomes. STEM CELLS 2017;35:1747-1759.
  4. Artavanis-Tsakonas S, Rand MD, and Lake RJ. Notch signaling: cell fate control and signal integration in development. Science 1999;284:770-776.
  5. Gridley T. Human Genetics. Notch, stroke and dementia. Nature 1996;383:673.
  6. Limbourg FP, Takeshita K, Radtke F, et al. Essential role of endothelial Notch1 in angiogenesis. Circulation 2005;111:1826-1832.