Page 78 - Mesenchymal Stem Cell-Derived Exosomes as an Emerging Paradigm for Regenerative Therapy and Nano-Medicine

C. R. Harrell et al.

proteins, lipids, DNA fragments, mRNA and exosomes (Merino-González et al. 2016;
small RNA species (Villarroya-Beltri et al. Nakamura et al. 2015). Lee and coworkers (Lee
2014; Vlassov et al. 2012). The cargo is not et al. 2013) revealed that MSC-derived exosomes
randomly distributed into exosomes: strictly enriched with miR-16 suppress tumor progres-
regulated mechanisms determine the “informa- sion and angiogenesis via down-regulation of
tion” that will be distributed from MSC to the the VEGF expression in tumor cells. Opposite
recipient cell by exosome (Villarroya-Beltri results were reported by Zhu and colleagues
et al. 2014). (Zhu et al. 2012) who showed that in vivo appli-
MSC derived exosomes carry nucleic acids cation of MSC-derived exosomes activated extra-
proteins (cytokines chemokines) and lipids. In cellular signal-regulated kinase1/2 (ERK1/2)
cargo of MSC-derived exosomes 4850 unique pathway in tumor cells that resulted with the
gene products and 4150 miRNAs have been enhanced expression of VEGF, increased
detected and identified by mass spectrometry neo-angiogenesis and accelerated tumor growth.
antibody array and microarray analysis (Lai Intravenous transplantation of MSC-derived
et al. 2012; Chen et al. 2010). Furthermore, exosomes improves neurogenesis, neurite
proteasome subunits were observed in remodeling and angiogenesis after ischemic
MSC-derived exosomes (Carayon et al. 2011). It brain injury (Xin et al. 2013). Therapy based on
has been revealed that the 20S proteasome is the delivery of MSC-derived exosomes promoted
responsible for degradation of intracellular oxida- axonal growth and significantly increased the
tive damaged proteins which may partly contrib- number of neuroblasts and ECs in ischemic and
ute to the cardioprotective activity of injured regions of central nervous system (CNS)
MSC-derived exosomes (Lai et al. 2012). (Xin et al. 2013). MSCs communicate with brain
Through the activation of phosphatidylinositol- parenchymal cells and regulate neurites
4,5-bisphosphate 3-kinase (PI3K)/Akt pathway outgrowth by transferring miR-133b in neurons
MSC-derived exosomes increased levels of aden- and astrocytes via exosomes (Xin et al. 2012)
osine triphosphate (ATP) reduced oxidative stress which could be a promising therapeutic strategy
attenuated myocardial ischemic injury and pro- in the treatment of spinal cord injury.
moted myocardial viability and cardiac function
(Lai et al. 2010; Li et al. 2013), indicating their
potential therapeutic use in the treatment of 3 Modulation of Immune
myocardial ischemia (Arslan et al. 2013) Response and Inflammation
The presence of nucleic acids inside the in the Eye by MSC-Derived
exosomes had the crucial role in altering the fate Exosomes
of recipient cells. Within the nucleic acids spec-
trum, miRNA sequences become the most inten- MSCs have capacity to synthesize and secrete a
sively investigated (Zaharie et al. 2015; Berindan- broad spectrum of exosomes, significantly more
Neagoe and Calin 2014). Several miRNAs, than other exosome producing cells of
detected in MSC-derived exosomes, including mesodermal origin (Yeo et al. 2013).
miR-191, miR-222, miR-21, miR-222, and MSC-derived exosomes are involved in impor-
miR-6087 were responsible for increased differ- tant physiological and pathological processes
entiation of ECs enabling modulation of angio- such as disposal of unwanted proteins, genetic
genesis (Merino-González et al. 2016). Similarly, exchange, modulation of immune response and
through the activity of miR-494, MSC-derived inflammation (Théry et al. 2009; Zöller 2009).
exosomes accelerate muscle regeneration and Immediately after engraftment, MSCs through
promote myogenesis and angiogenesis the release of exosomes interact with multiple cell
(Nakamura et al. 2015). types to elicit appropriate cellular responses:
MSC based modulation of vascular endothelial affect the support of stromal cells enabling main-
growth factor (VEGF)-driven angiogenesis is tenance of dynamic and homeostatic tissue micro-
mediated by miR contained within MSC-derived environment (Lai et al. 2015) and modulate