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Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_998_Библиотеки_им_академика_М_И_Перельмана

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R. Schäfer et al.
skeletal degenerations, are measuring up to immunomodulation therapy of graft-versus-host disease (GvHD) [9].
Despite promises and hopes for successful treatment of severe conditions by MSCs, there are substantial challenges to overcome before MSC therapies can be sustainably implemented in clinical medicine. Particularly, MSCs’ hetero­geneity [2] and lack of deep understanding their mechanisms of action are hampering rapid prog­ress. What we know so far is that MSCs produce various growth factors and cytokines suggesting that both their regenerative and immunomodula­tory functions are mediated by such secreted and/ or released proteins interacting with local effec­tor cells [9, 15]. Specically, extracellular vesi­cles (EVs) are regarded as a relevant means for factor trafcking between MSCs and other cell types [16], and, as proof-of-principle, MSC­derived EVs have been already successfully applied in the clinic [17].
In the following, the concept of MSC-EVs, as well as approaches to enhance their release and to improve their therapeutic potential, will be discussed.
10.2 Extracellular Vesicles
All eukaryotic cells and even prokaryotes release nano-sized, membranous vesicles, termed EVs [18]. Initially believed to take part only in waste management [19], it has mean­while become clear that EVs are involved in many biological processes and diseases, and that they may have great potential as biomarkers
and possibly also for therapy development in regenerative medicine [
20, 21]. According to
their origin and size, the following particle types are subsumed under the EV concept: exosomes (about 30–150nm, released by exocytosis from multivesicular bodies), microvesicles (ca. 100– 1000nm, shed from the plasma membrane), and apoptotic bodies (about 400–5000nm, released by blebbing of apoptotic cells) (Table 10.1) [22]. According to our current understanding, exosomes are primarily described as mediators of short- and long- range communication, while they, together with microvesicles and apoptotic bodies, take also part in waste disposal and recycling [
23–26]. EVs’ cargo can consist of
proteins, cytokines, lipids, RNA [e.g., mRNA, ncRNA], and DNA (e.g., mitochondrial DNA) (Fig.10.1) [22, 27, 28]. EV-mediated changes in cellular activity in both healthy and diseased conditions can be affected by exosomes carry­ing MHC complexes [29], anti-inammatory noncoding RNA [30], factors promoting angio­genesis (e.g., PDGF, EGF, VEGF, NF-κB path­way proteins) [31], or wound healing [32]. Key in isolation of EVs and EV subpopulations are reproducible, affordable, and efcient technolo­gies. Current methods can only enrich but not selectively purify EV subpopulations, and pro­tein-RNA-complex contaminations are still an issue [33–35]. Therefore, it is of no surprise that EV studies suffer from inconsistencies of repro­ducibility [36]. However, the number of studies dealing with EVs has continuously increased in the past decade and therefore many efforts to standardize isolation and characterization are made. Current techniques for EVs isolation are
Table 10.1 Extracellular vesicles: characterization by size, markers, and contents [21, 22]
Type Origin Size Markers Contents Exosomes Multivesicular bodies
Microvesicles Plasma membrane budding 100–
Apoptotic bodies
(endosomal pathway), internal budding, exocytosis
Cell fragmentation/blebbing 400–
30– 150nm
1000nm
5000nm
Tetraspanins, ESCRT components, PDCD6IP, TSG101, otillin, MFGE8
Integrins, selectins, CD40 ligand
Phosphatidylserines Proteins, lipids,
Proteins, lipids, coding and noncoding RNA, cytosol
Like exosomes
DNA, rRNA, organelles and cytosol
s
Prostaglandins Cholestero Ceramide Sphingo
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cholesterol LBPA PS
MHC class I
LPC Flotillin-1
lipid raft
ncRNA
microRNA
– Let7 – miR200 – miR105 – miR494 – miR34a
103
MHC class II
l
myelin
Tetraspanins
CD9 CD63 CD81
Fig. 10.1 Overview of characteristic extracellular vesicle (EV) contents. LBPA lysobisphosphatidic acid, PS phospha- tidylserine, LPC lysophosphatidylcholine, ncRNA noncoding RNA
precipitation, differential ultracentrifugation, density gradient enrichment, size-exclusion chromatography, and immune- afnity capture
mRNA
Lipids
Virus
Proteins
DNA
Receptors
Integrins
Transcription factor
– HIF1a – VEGF – TGFb – MMP2 – EGFR
Enzymes Heat shock proteins
10.3 Preconditioning Regimens toEnhance MSCs Regenerative Potential
technology. Differential ultracentrifugation is widely used but without further purication steps (such as sucrose density gradient ultracen­trifugation) contaminating proteins are often present in the EV preparations [20]. Also, ultra­centrifugation produces aggregates of EVs and non-vesicular macromolecules [37] and intro­duces many, likely uncontrollable parameters, like g-force, rotor-type, and angle [36]. In com­parison, immune-afnity purication holds promise for more pure isolates [22].Currently, there are more and more supporters for size­exclusion chromatography [34, 38], especially in combination with preceding concentration steps [39], as it delivers better preserved bioac­tive vesicles compared to other isolation tech­niques [40].
Cell-based therapies have been widely used in experimental and clinical studies as a new thera­peutic approach for several diseases. The protec­tive effects of MSCs, their conditioned medium (CM), or EVs derived from MSCs have been shown to promote regeneration after various organ and tissue injuries. The mechanisms by which MSCs enhance regeneration and ease inammation and injury are not completely understood, but multiple pathways might mediate the release of soluble mediators, EVs, organelle transfer, and cell-to-cell contacts [41]. Comprehensive proling of the factors secreted by MSCs revealed that their secretome consists of various cytokines, chemokines, growth fac­tors, extracellular matrix proteins, and molecules
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of vascularization and hematopoiesis pathways. Factors that limit the regenerative capacity and the therapeutic efcacy of transplanted MSCs are their poor migration and survival in the target tis­sue. Transplantation of MSCs or application of their CM including EVs or even puried EVs requires MSCs with maximum regenerative capacity. Therefore, the rationale should be pri­marily to develop new strategies for improve­ment of the regenerative efciency of MSCs and the vesicles released by MSCs (Table 10.2). In vitro pretreatment (“preconditioning”) strategies have been shown to enhance survival, engraft­ment, and paracrine properties of MSCs and, therefore, optimize their reparative and regenera­tive capacity [9].
Recent data indicate that the regenerative potential of MSCs could be boosted by pretreat­ment with environmental or pharmacological stimuli, enhancing their therapeutic efcacy. The factors and vesicles released by preconditioned MSCs are manifold and exert immunomodula­tory, anti-apoptotic, pro-angiogenic, and trophic effects [42]. Currently used MSCs precondition­ing regimens include their culture in a hypoxic or anoxic atmosphere, incubation with trophic fac­tors (growth factors, cytokines, or hormones), application of lipopolysaccharides or pharmaco­logical agents, as well as overexpression of spe­cic factors by genetic modication of the cells [43–46]. Nevertheless, genetic modications such as overexpression of genes involved in
migration, apoptosis, or survival can be complex to translate into clinical-grade protocols. Therefore, alternative preconditioning regimens without active manipulation in the genome might be considered.
Hypoxic preconditioning has been shown to enhance cell survival, proliferation, and also the angiogenic potential of MSCs [47–50]. Also, hypoxic preconditioning protects MSCs by acti­vation of anti-apoptotic signaling mechanisms and enhances their angiogenic potential by induction of the expression of proangiogenic genes invitro [51]. Furthermore, preincubation under hypoxia leads to metabolic changes result­ing in higher invivo cell survival after transplan­tation [48], and also induces the expression of genes that are involved in migration and homing (e.g., CXCR4 and SDF-1) [52]. The downstream signaling pathway during hypoxic pretreatment is the induction and translocation of HIF1α to the cell nucleus with the activation of gene expression (e.g., VEGF), and also the generation of reactive oxygen species (ROS) [50]. The nd­ings of Lee and coworkers showed that hypoxic preconditioning of MSCs promotes proliferation and angiogenic cytokine secretion via the HIF1α- GRP78- Akt signal pathway, and improves the survival of the cells in an invivo model of hind limb ischemia [53]. MSCs treat­ment by anoxia also enhances their survival and promotes their regenerative capacity [54]. As underlying mechanism of these benecial effects
Table 10.2 Characteristics of extracellular vesicles derived from MSCs (Modied from [95])
Type [Human] Protein content RNA content Adipose- derived MSCs CD105, CD90 miR29c, miR150 Wharton- Jelly MSCs CD9, CD44, CD63, CD73 miR15a,-15b,-16 Bone marrow MSCs
Embryonic MSCs OCT4, WNT3 [isoform A and B] OCT4, NANOG, GATA4, SOX2, KLF4,
MSCs from induced pluripotent stem cells
Liver- derived MSCs
CD44, CD29, α4- α5-integrins, CD73, TIA, TIAR, HuR, STAU1, STAU2, AGO2
CD9, CD24, CD63, CD81, integrins, glycoproteins
CD29, α4- integrin, CD44
POLR2E, SENP2/SUMO1, RBL1, CXCR7, LTA4H, CLOCK, IRF6, CRLF1, IL1RN, miR-24, -103-1, -140, -143-5p, -340, -223,
-451, -564
LIN28, miR-292, -294, -295 OCT4, NANOG, SOX2, miR- 302/367
cluster miRNAs MATK, MRE11A, CHECK2, MYH11,
VASP, CDK2, STAU2, miR-451, -223, -24,
-125b, -31, -122
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anoxia induced increased phosphorylation of cell survival factors such as Akt and endothelial nitric oxide synthase [55].
ROS and reactive nitrogen species are biologi­cally active oxidants and are regarded as impor­tant physiological signaling molecules. Various reports indicate the role of ROS as second mes­sengers in the O2 sensing [56, 57]. Preconditioning by ROS has been shown to enhance the proangio­genic properties of MSCs [57]. ROS generation increased MSCs secretion of the proangiogenic and anti-apoptotic factors VEGF and HGF, but did not affect MSCs ability to differentiate into cells with endothelial phenotype in vitro [57]. Applying a pharmacological preconditioning strategy with the mitochondrial inhibitors to modulate ROS generation in MSCs, Carriere etal. [57] described a strongly improved revascu­larization and increased number of CD31positive cells in the ischemic area of their invivo model.
In vitro pretreatment with pharmacological or chemical agents is an alternative precondi­tioning concept to boost MSCs regenerative potential. For example, preincubation with sildenal (or a silencing vector to phosphodies­terase-5) signicantly improved viability and decreased necrosis and apoptosis of MSCs. It increased the release of growth factors in MSCs, and enhanced their regenerative poten­tial in an invivo model of myocardial infarction [58]. Incubation of MSCs with deferoxamine, an iron chelating drug, has been shown to stabi­lize HIF-1α under normoxic conditions as well as the activity of two metalloproteases [59]. The stabilization of HIF-1α resulted in its increased translocation to the nucleus and in increased transcription of genes involved in cell migration [60]. In addition, deferoxamine pre­conditioning prior to transplantation increased homing of MSCs through modulating the expression of chemokine receptors as well as metalloproteases [59]. Other pharmacological approaches include the pretreatment with atorv­astatin [61], diazoxide [62], or curcumin [63]. For example, curcumin has been reported to cause potent antioxidant and anti- inammatory properties, and free radical- scavenging activity
[63]. Consequentially, pretreatment of MSCs with curcumin improved tolerance to oxidative stress injury and resulted in enhancement of their therapeutic potential in myocardial repair after myocardial infarction [63].
Another promising approach to enhance MSCs therapeutic potential is the preincubation with growth factors or other small molecules via the culture medium (reviewed in [9]). In this regard, the growth factors EGF, GDNF, and IGF­1, the pro-inammatory cytokine TNFα, the che­mokine SDF-1 (CXCL12), or hormones such as angiotensin-II have been shown to enhance regenerative capacity or the paracrine functions of MSCs [64–72]. EGF promoted invitro expan­sion of MSCs without altering their multipotency [71–73] and enhanced MSCs motility and migra­tion [72–74], and also the release of factors like VEGF, HGF, HB-EGF, and interleukin (IL)-6 and -11 [71, 75]. Others have shown that pretreat­ment with TGF-β increased VEGF production of MSCs in vitro [66]. TNF-α pretreated MSCs increased the release of cytokines, chemokines, and proteases compared to untreated MSCs. In this study, the enhanced secretion of 118 proteins into the culture medium upon TNF-α incubation was identied [76], specically, many of them known to be critically involved in inammatory processes (e.g., IL-6, IL-8, and MCP-1). Inammation is a key response to organ and tis­sue injury, with cytokines and chemokines also being associated with regeneration processes. Enhanced expression of IL-6, IL-8, or MCP-1 goes along with enhanced migration of mono­cytes to the site of injury, hereby promoting apro­inammatory response.
Taken together, enhancement of the regenera­tive capacities of MSCs by preceding invitro pre­conditioning regimens is a promising strategy for regenerative therapies, which may also decrease the amount of cells for transplantation and, there­fore, possibly reduces the risk of side effects. Due to the proposed main mechanistic concept by paracrine activation, the application of CM (including regenerative factors and EVs) or EVs might be an alternative or complement of the cell therapy.
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10.4 Current Approaches toEnhance theRelease andPotential ofMSC-EVs
Although there are a substantial number of stud­ies showing the highly promising effects of pre­conditioning strategies on the therapeutic potential of MSCs or their CM, only few studies have been published to date focussing on the spe­cic involvement of isolated EVs in this context. Increasing amounts of experimental data have revealed that MSC-derived EVs can stimulate angiogenesis, modulate the immune status, and exert paracrine effects that improve organ or tis­sue regeneration following injury. EVs were shown to carry variety of biomolecules such as growth factors, receptors, enzymes, transcription factors, signaling and immunomodulatory mole­cules, DNA, RNA transcripts, and noncoding RNA including retrotransposons, vault RNA, long noncoding RNAs, and microRNAs (Fig.10.1) [77, 78], and are major communica­tion mediators between cells [79–81]. EVs are taken up by cells and can alter gene expression or activate intracellular signal cascades. Hypoxic or anoxic microenvironment or oxidative stress can increase the amount and concentration of EVs in culture [82–84]. In this context, invitro precondi­tioning regimens of MSCs prior to EV isolation and their transplantation in an in vivo injury model seem to be promising approaches to enhance the regenerative potential of EVs.
It has been shown that hypoxic precondition­ing not only stimulates the secretion of growth factors, cytokines, and other proteins, but also the release of exosomes and microvesicles from MSCs. EVs from hypoxia-preconditioned cells had better therapeutic effects in organ injury through specic cargoes compared to EVs from non-preconditioned cells [85]. A recent study by Cui and coworkers examined whether exosomes derived from hypoxia-preconditioned MSCs (hypEx) and non-preconditioned MSCs (npEx) could prevent memory decits in Alzheimer dis­ease (AD) [86]. The results showed that neuro­logic conditions were signicantly improved, plaque deposition and Aβ levels were lower, and expression of many effector proteins was differ-
ent in the hypEx group compared to the npEx group. Furthermore, hypEx increased the level of miR-21in the brain of AD mice [ induce a positive effect during pathophysiologi­cal processes in the brain [87]. Others investi­gated whether hypEx were superior for myocardial repair, compared to exosomes from normoxia-treated MSCs [88]. The study showed that infusion of hypEx resulted in signicantly higher survival, smaller scar size, and better car­diac functions recovery. In addition, signicantly higher levels of miRNA-210 were detected in hypEx. Hypoxia treatment of MSCs increased the expression of neutral sphingomyelinase 2 (nSMase2) which is crucial for exosome secre­tion. Blocking the activity of nSMase2 resulted in reduced miR-210 secretion and abrogated the benecial effects of hypEx. The authors therefore concluded that hypoxia augments miR-210 and nSMase2 activities, which is responsible at least in part for the enhanced cardioprotective poten­tial of hypEx [ exosomes enriched with miR-22 were secreted by MSCs following ischemic preconditioning (repeated cycles of anoxia with intermittent reox­ygenation). These miR-22 enriched exosomes reduced apoptosis of cardiomyocytes in vitro, and reduced cardiac brosis in an invivo model.
Another recent study investigated the inu­ence of an in vitro preconditioning stimulus, i.e., hypoxia or isourane, on EV concentration and composition of cardiomyocytes, broblasts, and a myoblast cell line [90]. Whereas the authors found no signicant inuence of the preconditioning regimen on secretion of EVs and their morphology, the protein and miRNA (e.g., miR- 761) load was affected by the invitro pretreatment. Also, EV markers (e.g., CD63, heat shock protein 70) were signicantly upreg­ulated. In another study, pretreatment of cardio­myocytes with hypoxia resulted in the upregulation and enrichment of miR-30a in their exosomes [91].
The main downstream signaling pathway dur­ing hypoxic pretreatment is the induction and translocation of HIF1α to the cell nucleus. In this context, it has been shown that overexpression of HIF-1α in MSCs enhanced their exosome secretion
88]. Feng etal. [89] showed that
86], which may
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and improved therapeutic potential by inducing angiogenesis in transplanted tissues [92].
Lu etal. [93] showed that the trophic functions of adipose-derived MSCs for their use in bone tis­sue regeneration were further potentiated when cells were preconditioned with tumor necrosis factor-alpha (TNF-α). This effect was mainly mediated by their EVs, as the removal of EVs from the medium largely diminished their effects on proliferation and osteogenic differentiation of primary osteoblasts. The study further showed that the cellular content of Wnt-3a was elevated in MSC-EVs after preconditioning with TNF- α, and inhibition of Wnt signaling decreased the effect of MSC-EVs on osteoblasts [93]. Interestingly, pre­conditioning with interferon-γ, another proinam­matory cytokine, abrogated the protective effects of MSC-EVs in an animal model of ischemic acute kidney injury [94]. Specically, EVs from untreated control MSCs ameliorated kidney dys­function and acute tubular necrosis, whereas EVs from preconditioned MSCs did not inuence the development of kidney injury [94]. Also, this study demonstrated that interferon-γ pretreatment leads to the production of EVs, which originate from distinct internal vesicle routes. EVs from untreated and preconditioned cells contained different and unique proteins, and had different therapeutic potential.
Although not nally proven, it appears that the regenerative potential of EVs is promising and may be even greater by preconditioning. Nevertheless, recent preconditioning regimens mainly focus on hypoxic or anoxic microenvi­ronment. The results from these studies that show the potential of pretreatment regimens on MSC preparations demonstrate the urgent need to further investigate the mechanistic inuence and involvement of MSC-derived EVs in organ and tissue regeneration, and the enhancement of these processes by preconditioning regimens. Elucidating the multiple functions of EVs will eventually contribute to further understanding the complex self-regeneration mechanisms of the organism and the therapeutic capacities of MSCs, hereby optimizing their clinical applica­tion to support organ or tissue regeneration in the future.
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