Treament Of Kidney Diseases: Mesenchymal Stem Cells And Extracellular Vesicles
Mar 23, 2022
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PART Ⅱ:Mesenchymal stem cells and extracellular vesicles in therapy against kidney diseases
Yuling Huang and Lina Yang
Abstract
Kidney diseases pose a threat to human health due to their rising incidence and fatality rate. In preclinical and clinical studies, it has been acknowledged that mesenchymal stem cells(MSCs) are effective and safe when used to treat kidney diseases. MSCs(mesenchymal stem cells) play their role mainly by secreting trophic factors and delivering extracellular vesicles (EVs). The genetic materials and proteins contained in the MSC-derived EVs(extracellular vesicles) (MSC-EVs), as an important means of cellular communication, have become a research focus for targeted therapy of kidney diseases. At present, MSC-EVs(extracellular vesicles) have shown evident therapeutic effects on acute kidney injury (AKI), chronic kidney disease(CKD), diabetic nephropathy (DN), and atherosclerotic renovascular disease (ARVD); however, their roles in the transplanted kidney remain controversial. This review summarises the mechanisms by which MSC-EVs(extracellular vesicles) treat these diseases in animal models and proposes certain problems, expecting to facilitate corresponding future clinical practice.
Keywords: Kidney diseases, Mesenchymal stem cells, Extracellular vesicles
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MSC-EVs and kidney diseases
MSC-EVs(extracellular vesicles) and AKl
AKI is prevalent in critically ill patients, even the mortality of those AKI patients not in intensive care units is as high as 10-20%[45]. There is still a lack of specific and effective therapies for AKI, while stem cell transplantation is promising. Numerous experiments have confirmed the benefits of MSCs(mesenchymal stem cells) in treating AKI, and many methods of enhancing the effect of MSCs(mesenchymal stem cells) have emerged in recent years. For example, I-17A is found able to increase the percentage of Treg via the COX-2/PGE2 path-way and simulate the immunosuppression function of MSCs(mesenchymal stem cells) [46]; by coating MSCs(mesenchymal stem cells) with antibodies directed against kidney injury molecule-1, the retention of MSCs(mesenchymal stem cells) in the ischaemic kidney is prolonged [47]; in the mouse model of cisplatin-induced AKI, MSCs(mesenchymal stem cells) are injected directly to the aorta using a minimally invasive technique, which improves the effective rate of utilization of MSCs(mesenchymal stem cells) [48].
As the research progresses, evidence shows that MSC-EVs(extracellular vesicles) play a major role in treating AKI. MSC-EVs(extracellular vesicles) can relieve AKI by inhibiting oxidation, apoptosis, and inflammation and regulating angiogenesis, cell cycle, regeneration, autophagy, and proliferation [49-54](Fig. 2). However, for AKs with different pathogeneses, the signal substances transferred from MSC.EVs(extracellular vesicles) to the target cells exhibit their unique characteristics. The main pathogeneses of AKI include renal toxicity of drugs, ischaemic-reperfusion injury (IRI) caused by transplantation, and sepsis. Correspondingly, experimental AKI models are mainly induced by cisplatin, gentamicin, paraquat, ischemia-reperfusion (I/R) by occlusion of the unilateral or bilateral renal arteries, and sepsis caused by caecal ligation and puncture(CLP). The mechanisms of MSC-EVs in different AKI models in this review are summarised in Table 1.
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I/R-induced kidney injury
I/R is the common pathogenesis of AK. In animal trials, I/R models are generally established by occluding the unilateral or bilateral renal arteries and veins and then providing oxygen supply. Previous research indicated that huMSC-EVs(extracellular vesicles) can alleviate renal IRI in rats independent of the effect of promoting angiogenesis induced by the hypoxia-inducible factor-1 [49]. MSC-EVs(extracellular vesicles) can also inhibit macrophages in the I/R model via various pathways to relieve AKI. In the experiments performed by Zou et al, MVs derived from human Wharton's jelly MSCs(mesenchymal stem cells)(hWJMSCs)suppress the expression of the renal chemokine CX3CL1 by miR-15a/15b/16 and reduce the number of CD68+ macrophages [55]. Shen et al. found that the C-C chemokine receptor-2 expressed on BMMSC-Exos inhibits the recruitment and activation of CCL2 for macrophages by acting as a decoy to bind lig-and CL2 [56].
Apoptosis is closely related to IRI. Gu et al. verified, through in vivo and in vitro experiments, that EVs(extracellular vesicles) derived from hWJMSCs(mesenchymal stem cells) (hWJMSC-EVs(extracellular vesicles)) decrease the apoptosis of renal tubular epithelial cells(TECs)by inhibiting mitochondria fission using miR-30 [57]. Moreover, Li et al. stated that MSC-Exo slowed the progression of IRI by inhibiting expressions of inflammatory factors(IL-6, TNF-α, NF-kappa B, and IFN-y) and apoptosis-related factors (caspase-9, cleaved caspase-3, Bax, and Bcl-2)[50].
Antioxidation is an effective measure to alleviate I/R. Zhang et al. revealed that hWJMSC-EVs(extracellular vesicles) play their anti-oxidative effect by activating the nuclear factor-erythroid 2-related factor Nrf2/ARE [57]. Thereafter, experiments by Cao et al. demonstrated that BMMSC-EVs(extracellular vesicles) activate the Keapl-Nrf2 signaling pathway in the TECs by transferring miRNA-200a-3p, thus modulating the mitochondria to play an antioxidative role [51].
Models of AKI induced by drugs are generally established through the induction of cisplatin. Using the cisplatin-induced AKI model, Bruno et al. found that BMMSC-MVs protect the kidney by inducing expressions of anti-apoptotic genes(Bcl-XL, Bcl2, and BIRC8)in TECs and inhibiting expressions of pro-apoptotic genes (Caspl, Casp8, and LTA)[58]. Zhou et al. concluded that huMSC-Exos can stimulate proliferation of nephrocytes in vivo and in vitro by inducing the phosphorylation and activation of extracellular regulated kinase (ERK) 1/2 pathway [52].de Almeida et al. highlighted the function of ADMSC-MVs in regulating injured cells and the specific miRNA-mRNA network. For example, miR-141 targets Uk2 to regulate autophagy, and miR-377 targets Cull to modulate the cell cycle [53]. Wang et al. discovered that huMSC-Exo pre-processing can prevent cisplatin-induced renal toxicity in vivo and in vitro by activating autophagy [59]. Jia et al. conducted two studies and identified 14-3-3 as a new mechanism of autophagy activated by huMSC-Exos: 14-3-3 acts on ATG16L, which activates autophagy and therefore prevents cisplatin-induced AKI [60, 61]. Ullah et al. recently proposed that BMMSC-EVs(extracellular vesicles) and pulsed focused ultrasound both alleviate cisplatin-induced cell injury by inhibiting hsp70-mediated NLRP3 inflammasomes [62].
Fig. 2 Functional pathways of MSC-EVs(extracellular vesicles) in different AKI models. MSC-EVs(extracellular vesicles) can relieve AKI by inhibiting oxidation, apoptosis, and inflammation and regulating angiogenesis, cell cycle, regeneration, autophagy, and proliferation. MSCs(mesenchymal stem cells), mesenchymal stem cells; EVs, extracellular vesicles; AKI, acute kidney injury; I/R, ischaemia-reperfusion; CLP, caecal ligation, and punctureCisplatin-induced AKI model
AKI model due to myolysis induced by glycerinum
In recent years, the AKI model due to myolysis induced by glycerinum also has received much attention. In such a model, Bruno et al. found that BMMSC-EVs(extracellular vesicles) (mainly Exos) are enriched in specific mRNA (CCNB1, CDK8, and CDC6), which influence the onset and progression of cell cycles. The enriched miRNAs promote proliferation by growth factors(HGF and IGF-1) and therefore relieve AKI [63]. Through bioengineering, Tapparo et al. in-creased specific miRNAs(hsa-miR-10a-5p, hsa-miR-29a-3p, hsa-miR-127-3p, and hsa-miR-486-5p)in BMMSC-EVs(extracellular vesicles) to simulate the pro-regenerative effect thereof and alleviate the kidney injury induced by glycerinum [54].
CLP
The AKI model prepared by CLP simulates the sepsis-related AK of critically ill patients. In mice with sepsis, Zhang et al. revealed that huMSC-Exos inhibit NF-KkB activity by upregulating miR-146b level while downregulating interleukin-1 receptor-associated kinase expression [64]. Similarly, Gao et al. stated that ADMSC-Exo can regulate NF-KB via the SIRT1 signaling pathway, thus inhibiting inflammation of sepsis-related AKI [65].
Table 1 Functional pathways of MSC-EVs(extracellular vesicles) in different AKI models
MSC-EVs(extracellular vesicles) and CKD
There is new evidence proving that, in many cases, AKI may evolve into CKD [66]. After developing AKI, the additional risks of contracting end-stage renal diseases and CKD were estimated to be increased by 0.4 and 10 cases annually in every 100 AKI patients, respectively [67]. CKD is characterized by progressive irreversible fibrosis of the renal parenchyma. Many diseases can evolve into CKD, including AKI, diabetes, atherosclerosis, and nephrotic syndromes. Numerous evidence have been obtained in relation to the treatment of CKD with MSCs(mesenchymal stem cells) in pre-and post-clinical trials. It has been found in recent research that melatonin preconditioning enhances the treatment ability of MSCs(mesenchymal stem cells) in autologous and allogeneic transplantation [68,69]. In a clinical trial involving an 18-month follow-up of seven eligible CKD patients, the single-dose autologous MSCs(mesenchymal stem cells) have been proven to be safe and tolerable in CKD patients [70]. Re-searchers then found that the conditioned medium of huMSCs relieves the fibrosis induced by unilateral ureteral obstruction (UUO)by pro-proliferation and anti-apoptosis [71]. To date, many preclinical studies have proven that MSC-EVs(extracellular vesicles) are effective in treating CKD.
In the mouse model of chronic renal toxicity due to cyclosporine, the conditioned medium depleted of EVs(extracellular vesicles), MSC-EVs(extracellular vesicles), and EVs(extracellular vesicles) can improve the prognosis of kidney diseases [72]. In the aristolochic acid nephropathy model, MSC-EVs(extracellular vesicles) significantly reduce expressions of pro-fibrogenic genes such as α-SMA, TGFβ1, and Collar [73].In the UUO model, Wang et al.found that BMMSC-Exos alleviate renal interstitial fibrosis by inhibiting TGF-β1 with miRNA-let7c [74]. Recently, some researchers found (in the mouse model) that huMSC-Exos relieve renal interstitial fibrosis by suppressing the ROS-mediated P38MAPK/ERK pathway [75]. Chen et al. proposed that the glial-derived neurotrophic factor-modified ADMSC-Exos stimulate the perivascular capillaries in tubulointerstitial fibrosis by activating the SIRT1/eNOS pathway [76]. In addition, previous research also suggested that ADMSC-Exos upregulate the expression of the transcription factor Sox9 of TECs, and the offspring of Sox9+ cells facilitate regeneration of renal tubules rather than fibrotic transformation, thus slowing the AKI-CKD transition [17,77].
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MSC-EVs(extracellular vesicles) and DN
DN is the main pathogenesis for ESRD. There are numerous investigations evincing that MSC transplantation can slow the progression of DN. A randomized controlled trial reported that it is safe and feasible to use the mesenchymal precursor cells in subjects of type 2 diabetes [78]; however, there are immune rejection problems in allogeneic transplantation and damage induced by hyperglycaemia to autologous MSCs(mesenchymal stem cells). To solve these problems, Nagaishi et al. innovatively used Wharton's jelly extract supernatant to improve the morphologies, proliferation capacity, and cellular mobilization capacity of diabetes-derived BMMSCs, which enables effective autologous transplantation [79]. Recently, some researchers also attempted to co-culture MSCs(mesenchymal stem cells) with peritoneal macrophages [80] and to modify MSCs(mesenchymal stem cells) with angiotensin-converting enzyme 2 [81] to improve the treatment capacity of MSCs(mesenchymal stem cells) for DN.
The mechanism of MSC-EVs(extracellular vesicles), as a new means for treating DN, is under constant exploration. Gallo et al. found that MSC/human liver stem cell (HLSC)-EVs(extracellular vesicles) can protect mesangial cells from damages induced by hyperglycemia through the transfer of miR-222 [82]. Also, hyperglycemia can directly induce the injury of podocytes. The pathological changes of podocytes are closely related to the progression of DN. MSC-EVs(extracellular vesicles) are able to protect podocytes and other renal cells by diverse means, including anti-apoptosis, anti-fibrosis, and pro-autophagic effects, thus treating DN(Fig. 3). Duan et al. revealed that the Exo isolated from the conditioned medium of human urine-derived stem cells inhibits the expression of VEGFA and the apoptosis of podocytes by miRNA-16-5p, thereby relieving DN [83]. It is proven by Duan et al.that ADSC-EV miRNA-26a-5p suppresses the hyperglycemia-induced apoptosis of podocytes in mice by downregulating the TLR4 and NF-KB/VEGFA signaling pathways [84]. Anti-fibrosis is also a major mechanism invoked in DN treatment with MSC-EVs(extracellular vesicles). Zhong et al. reported that MSC-MVs are capable of suppressing cell cycle inhibitors P15 and P19 in vivo and in vitro via miRNA-45la, restarting the cell cycle and thus reversing the EMT and interstitial fibrosis [85]. Grange et al. considered that EVs(extracellular vesicles) of HLSCs and MSCs(mesenchymal stem cells) can inhibit and reverse the progression of glomerular and tubule-interstitial fibrosis in the DN mouse models by downregulating fibrosis-related gene Serpiala, the FAS ligand, CCL3, TIMP1, MMP3, type I collagen, and Snail [86]. Jin et al. verified that the ADMS C-Exo weakens the EMT of podocytes by suppressing the genetic transcription of ZEB2 by miRNA-215-5p [87]. Autophagy has also been recently considered as a mechanism to delay DN. Ebrahim et al.confirmed that MSC-Exos enhance autophagy and then slow the progression of DN via the mTOR signaling pathway [88]. Jin et al. further showed that the ADMSC-Exo can inhibit the Smadl/mTOR signaling pathway by miRNA-486, which pro-motes autophagy and inhibits apoptosis in podocytes, thus ameliorating the symptoms of DN [89]. Details of the aforementioned trials are summarised in Table 2.
MSC-EVs(extracellular vesicles) and atherosclerotic renovascular diseases
Atherosclerosis is the primary cause of renal artery stenosis. Atherosclerotic renovascular disease(ARVD)can induce chronic renal ischemia and further lead to fibrosis, which develops ESRD. Percutaneous transluminal renal angioplasty is a common surgery for treating ARVD; however, it is difficult to restore functions of the atrophic kidney. Animal experiments have confirmed that the combination of MSCs(mesenchymal stem cells) with ARVD to treat atherosclerotic renal artery stenosis helps to restore functions of the kidney [90]. Thereafter, several clinical trials have evinced the safety of infusing autologous ADMSCs(mesenchymal stem cells) in the treatment of ARVD [91-93]. Following this, ADMSC-EVs(extracellular vesicles) has also become the focus of recent research. In the model of unilateral renovascular disease complicating metabolic syndrome(MetS), Eirin et al. proved that the autologous ADMSC-EVs(extracellular vesicles) improve the renal microvascular system in pigs with metabolic renal vascular diseases [94]. Besides this, Simeoni et al. further identified the miRNA in MSC-EVs(extracellular vesicles) as an important target for ARVD [95].In addition, MSC-EVs(extracellular vesicles) were also found to enhance the advantages of Treg by TGF-β therein and therefore improve the functions of the kidney with renal artery stenosis in the MetS+RAS model [96]. Autologous ADMSC-EVs(extracellular vesicles) can also prompt the transformation of phenotypes of macrophages from M1 to M2 via IL-10, so as to relieve renal artery stenosis [97].
At the same time, some researchers proposed that MSC-Exos can only partially relieve aging kidneys induced by renal artery stenosis [98]. MetS are able to change the amount of loading of miRNA on EVs(extracellular vesicles), upregulate aging-related miRNA in EVs(extracellular vesicles), and even limit the use of EVs(extracellular vesicles) in exogenous regenerative therapy through abnormal transcription [99-101]. Zhao et al.found that autologous ADMSCs(mesenchymal stem cells) can better preserve microcirculation through comparative studies, while ADMSC-EVs(extracellular vesicles) perform better in retaining the intactness of nephrocytes and reducing necrosis [102].In summary, the application value of MSC-EVs(extracellular vesicles) in the treatment of ARVD remains in dispute, and further research is warranted to reveal their efficacy.
Fig. 3 Functional pathways of MSC-EVs(extracellular vesicles) in DN. MSC-EVs(extracellular vesicles) are able to protect podocytes and other cells by diverse means, including anti-apoptosis, anti-fibrosis, and pro-autophagic effects, thus treating DN. MSCs(mesenchymal stem cells), mesenchymal stem cells; EVs(extracellular vesicles), extracellular vesicles; DN, diabetic nephropathy
MSC-EVs(extracellular vesicles) and kidney transplantation
Kidney transplantation is the preferred treatment method for end-stage renal failure patients. The shortage of donor organs and the half-life of the transplant limit the therapy [4]. In addition, ischemia-induced AKI is widely seen in kidney transplantation due to the time available for the development of ischemia given the delay between the accession of the kidney from the donor to renal ischemia-reperfusion in receptors [103].
This is also a major cause of the delayed functions of the transplant. To solve these problems, static cold storage, hypothermic machine perfusion (HMP), and several new drug candidates targeting ischemia and reperfusion are under study [104]. The work of del Rio et al. verified that HMP and normothermic regional perfusion are preferable to static cold storage [105]. Also, researchers are devoted to finding other effective ways to complement the current techniques.
A trial involving 105 Chinese kidney transplantation subjects who received autologous MSCs(mesenchymal stem cells) in the reperfusion of the transplanted kidney suggests that it is feasible and safe to use MSCs(mesenchymal stem cells) in kidney transplantation [106]; however, a similar trial conducted by another research team recently found that the post-operative complications of renal transplantation, infectious complications, kidney functions, rejection frequency, and survival time all do not show statistical differences with the control in the 1-year follow-up[107]. Therefore, the protective effect of MSC-EVs(extracellular vesicles) in transplanted kidneys remains a matter of dispute. Gregorini et al.proved that adding MSCs(mesenchymal stem cells)/EVs(extracellular vesicles) to the Belzer solution in the HMP period can protect the kidney from ischaemic injury by preserving the enzymatic mechanism essential to cell viability [108]. Experiments by Koch et al.indicated that MSC-EVs(extracellular vesicles) regu-late the immunoreaction to allogeneic kidney transplants to some extent[109]. Significantly different from this, by establishing a rat model of heterotopic kidney trans-plantation, Jose Ramirez-Bajo et al. found that autologous MSCs(mesenchymal stem cells) prolong the survival time of transplants and subjects in the rat model of renal rejection, while EVs(extracellular vesicles) do not [110]. This topic is rarely studied, and further research is required before a conclusion can be drawn.
Table 2 Functional pathways of MSC-EVs(extracellular vesicles) in DN models
Problems and prospects
In previous research, MSCs(mesenchymal stem cells) have been found to play positive roles in treating various kidney diseases. For example, MSC-CM relieves the experimental anti-glomerular basement membrane glomerulonephritis by virtue of the M2 macrophage-mediated anti-inflammatory action[111]. In systemic lupus erythematosus (SLE), allogeneic MSC transplantation mitigates kidney injury [112]. Clinical trials also show that it is both safe and feasible to treat SLE patients with allogeneic MSCs(mesenchymal stem cells) from healthy donors [113].In the model of nephrotic syndrome induced by Adriamycin, MSCs(mesenchymal stem cells) mainly play their role in kidney repair by regulating inflammation [114]. Moreover, healthy donors and idiopathic nephrotic syndrome (INS)patients do not exhibit obvious differences in the functions and morphologies of MSCs(mesenchymal stem cells), which indicates that MSCs(mesenchymal stem cells) can be used for treating INS with autologous cells [115]. MSC treatment exerts beneficial effects on gAN by the mechanism of paracrine that modulates the balance of the Th1/Th2 cytokine [116]. In the rat model of anti-Thyl.1-induced glomerulonephritis, hypoxic-preconditioned MSCs(mesenchymal stem cells) decrease glomerular apoptosis, autophagy, and inflammation through signal transduction of HIFla/VEGF/Nrf2 [117]. MSCs(mesenchymal stem cells) relieve renal hypertension and improve kidney function in the 2-kidney,1-clip model [118]. No adverse events and severe adverse events were observed clinically when treating anti-body against antineutrophil cytoplasmic antibody-associated vasculitis [119] and autosomal dominant polycystic kidney disease [120] with autologous mesenchymal stromal cells. Existing research also proposes that MSCs(mesenchymal stem cells) possibly relieve focal segmental glomerulosclerosis via IL-22 [121].
In conclusion, both animal models and clinical trials provided much evidence of the potential of MSCs(mesenchymal stem cells) in the treatment of kidney diseases; however, there is little research into the treatment of the aforementioned diseases with MSC-EVs(extracellular vesicles), which remains to be explored. This is possible because the separation, purification, and mass production of EVs(extracellular vesicles) remain a challenge; moreover, the mechanism by which MSC-EVs treat kidney diseases has not been elucidated. In addition, in consideration of optimal source, appropriate dosage, and appropriate route of administration of EVs(extracellular vesicles), further research needs to be undertaken to assess the efficacy of the application of MSC-EVs to the clinical treatment of kidney diseases.
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Conclusion
In this review, we summarised the recent advances of complex and critical effects of MSC(mesenchymal stem cells)-EVs(extracellular vesicles) in kidney diseases, including AKI, CKD, DN, ARVD, and kidney transplantation. A large number of articles support that most kidney diseases can benefit from MSC(mesenchymal stem cells)-EVs(extracellular vesicles); however, the effects of kidney transplantation are still controversial. Although MSC(mesenchymal stem cells)-EVs(extracellular vesicles) isolated from different sources show great promise as therapeutic agents for kidney diseases in animal studies and preclinical trials, further studies are necessary since only a few clinical works have been described at the moment.
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