Harnessing the Angiogenic Potential of Stem Cell-Derived Exosomes for Vascular Regeneration

Abstract

Mesenchymal stem cells (MSCs) are known to display important regenerative properties through the secretion of proangiogenic factors. Recent evidence pointed at the key role played by exosomes released from MSCs in this paracrine mechanism. Exosomes are key mediators of intercellular communication and contain a cargo that includes a modifiable content of microRNA (miRNA), mRNA, and proteins. Since the biogenesis of the MSCs-derived exosomes is regulated by the cross talk between MSCs and their niche, the content of the exosomes and consequently their biological function are dependent on the cell of origin and the physiologic or pathologic status of their microenvironment. Recent preclinical studies revealed that MSCs-derived exosomes have a critical implication in the angiogenic process since the use of exosomes-depleted conditioned medium impaired the MSCs angiogenesis response. In this review, we discuss the current knowledge related to the angiogenic potential of MSCs-exosomes and methods to enhance their biological activities for improved vascular regeneration. The current gain of insight in exosomes studies highlights the power of combining cell based therapies and their secreted products in therapeutic angiogenesis.

Figure 1

Different possible strategies to enhance the angiogenic potential of exosomes released by stem cells. (a) Stem cells cultured under normal culture condition constitutively produce exosomes with a basal angiogenic potential. (b) Specific in vitro stress conditions mimicking organ injury situations, such as hypoxia, irradiation, or drug treatments, induce changes in exosomal RNA and protein repertoire. These alterations of exosomal composition are thought to facilitate angiogenesis and tissue repair through an enhanced level of growth factors and cytokines. (c) The transfection of exosomes producer cells with protein or DNA encoding therapeutically active angiogenic compounds which are then released within the released exosomes constitutes another approach. Since overexpression of a specific factor does not ensure a similar increase of its representation in the exosome cargo, another strategy is to directly load the exosomes after release with proangiogenic factors such as the recombinant VEGF protein or the vector encoding its expression. Hence, boosting the exosome with proangiogenic factors can be achieved directly or indirectly, and each approach has its advantages and limitations and may be dictated by the type of the encapsulated molecule (molecular weight, posttranslational modifications) and conditions suitable for a specific type of exosome-encapsulated cargo.