Page 56 - Mesenchymal Stem Cell-Derived Exosomes as an Emerging Paradigm for Regenerative Therapy and Nano-Medicine

Yin et al. Biomarker Research (2019) 7:8 Page 3 of 8

body weight ratio and hepatocyte proliferation. BIRC8 and down-regulated genes that have a central
MSC-CM upregulated hepatic gene expression of cyto- role in the execution-phase of cell apoptosis such as
kines and growth factors relevant for cell proliferation, Casp1, Casp8 and LTA [37]. Intravenous injection of
angiogenesis, and anti-inflammatory responses, treat- EVs isolated from the conditioned medium of human
ment with MSC-derived factors can promote hepatocyte umbilical cord MSCs after unilateral renal ischemia pre-
proliferation and regenerative responses in the early served kidney function and decreased serum levels of
phase after surgical resection [32]. Transplantation of the AKI marker neutrophil gelatinase-associated lipoca-
exosomes released from adipose derived-MSCs lin [38]. Human bone marrow MSCs-derived exosomes
(AD-MSC) can significantly reduce the elevated serum contain insulin-like growth factor-1 receptor (IGF-1R)
levels of alanine aminotransferase and aspartate amino- mRNA. Exosomal transfer of IGF-1R mRNA to damaged
transferase, liver inflammation and necrosis in concanav- renal tubular cells promoted their proliferation and re-
alin A (Con A)-induced hepatitis in C57BL/6 mice as pair and this effect was significantly reduced when
well as the serum levels of proinflammatory cytokines, IGF-1R transcription in donor cells was silenced [39].
including tumor necrosis factor-α (TNF-α), interferon-γ
(IFN-γ), IL-6, IL-18 and IL-1β, and the inflammasome Cardiovascular disease
activation in mouse liver [33]. There are preclinical studies in which MSC-derived
exosomes are used for treating cardiovascular diseases
Kidney disease (CVDs) such as AMI, stroke, pulmonary hypertension,
Mesenchymal stem/stromal cells (MSCs) have shown and septic cardiomyopathy [40]. Cui et al. demon-
promising results in experimental acute kidney injury strated adipose-derived MSC (AdMSC)-derived exo-
(AKI) and chronic kidney disease (CKD). Systemic somes led to a markedly increase in cell viability of
administration of human umbilical cord-derived MSCs H9C2 cells under hypoxia/reoxygenation (H/R) in
(huMSCs)-derived EVs in rats with renal vitro, and administration of AdMSC-derived exosomes
Ischemia-reperfusion injury (IRI) increased renal capil- protected ischemic myocardium from myocardial
lary density and reduced fibrosis by direct transfer of the ischemia-reperfusion (MI/R) injury via activation of
proangiogenic factor vascular endothelial growth factor Wnt/β-catenin signaling in vivo [41]. Furthermore,
(VEGF) and mRNAs involved in this process [34]. A sin- Wang et al. showed superior cardioprotective effects
gle intrarenal administration of adipose tissue-derived of endometrium-derived MSCs (EmMSC) in a rat
autologous MSCs-derived EVs in pigs with renal artery myocardial infarction (MI) model as compared to
stenosis attenuated renal inflammation, disclosed by de- BMSCs and AdMSCs. These differences may be
creased renal vein levels of several pro-inflammatory cy- caused by certain miRNAs particularly miR-21 enrich-
tokines, including TNF-α, IL-6, and IL-1-β. Contrarily, ment in exosomes secreted from EmMSCs, which
renal vein levels of IL-10 increased in EV-treated pigs, exerted effects on cell survival and angiogenesis by
associated with a shift from pro-inflammatory to repara- targeting PTEN [42]. HuES9.E1 derived MSCs-derived
tive macrophages populating the stenotic kidney, under- exosomes treatment increased levels of ATP and
scoring the immunomodulatory potential of EVs [35]. NADH, decreased oxidative stress, increased
Microvesicles derived from human bone marrow MSCs phosphorylated-Akt and phosphorylated-GSK-3β,re-
stimulated proliferation in vitro and conferred resistance duced phosphorylated-c-JNK in ischemic/reperfused
of tubular epithelial cells to apoptosis. In vivo, microve- hearts to enhance myocardial viability and prevented
sicles accelerated the morphologic and functional recov- adverse remodeling after myocardial ischemia/reperfu-
ery of glycerol-induced acute kidney injury (AKI) in sion injury [43]. Feng et al. determined that miR-22 is
SCID mice by inducing proliferation of tubular cells. highly enriched in exosomes secreted by mouse bone
Microarray analysis and quantitative real time PCR of marrow-derived MSCs after ischemic preconditioning,
microvesicle-RNA extracts indicate that microvesicles and administration of these exosomes significantly re-
shuttle a specific subset of cellular mRNA, such as duced infarct size and cardiac fibrosis by targeting
mRNAs associated with the mesenchymal phenotype methyl-CpG-binding protein 2 (Mecp2) in a mouse
and with control of transcription, proliferation, and im- myocardial infarction (MI) model [44]. Both bone
munoregulation [36]. The effects of bone marrow marrow MSCs and their derived exosomes are cardio-
MSCs-derived MVs in SCID mice survival in lethal protective against myocardial infarction in animal
cisplatin-induced acute renal injury (AKI) was to exert a models. However, anti-miR-125b treatment of exo-
pro-survival effect on renal cells in vitro and in vivo somes significantly attenuated their protective effect
mainly ascribed to an anti-apoptotic effect of MVs. MVs [45]. MiR-21-5p plays a key role in hMSC-exo–medi-
up-regulated in cisplatin-treated human tubular epithe- ated effects on cardiac contractility and calcium hand-
lial cells anti-apoptotic genes, such as Bcl-xL, Bcl2 and ling, likely via PI3K signaling [46]. In a rat myocardial