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At 48 h post-injury, kidney HGF gene and protein expression is substantially enhanced by MV administration. (A)-(D) HGF gene expression in injured kidney tissues. MV administration led to a significant up-regulation of kidney HGF gene expression. The examination of rat HGF expression in kidney tissues using species-specific primers also indicated a similar result. As negative controls, no rat HGF mRNA was identified in MVs or in the cells of origin (hUC-MSCs). RNase pretreatment abolished the effect of MVs. By contrast, EGF, IGF-1 or TGFβ1 gene expression was not altered by MV administration. Gene expression levels in sham-treated samples were regarded as the baseline levels (dotted line). The relative expression levels of each gene were calculated using the 2−ΔΔCt method. The data were collected from 6 rats for each experimental condition. *P<0.05, AKI+MVs vs. AKI+VEHICLE; #P<0.05, AKI+RNase-MVs vs. AKI+MVs. (E) Densitometric analysis of kidney HGF protein expression. At 48 h, MV administration also resulted in a prominent increase in kidney HGF protein expression. This effect was abrogated by RNase pre-treatment. The values in the graph are expressed as densitometric ratios of HGF/GAPDH as fold changes compared with the control (sham-operated samples) (dotted line). *P<0.05, AKI+MVs vs. AKI+VEHICLE; #P<0.05, AKI+RNase-MVs vs. AKI+MVs; xP<0.01, AKI+VEHICLE vs. SHAM. (F) Representative gel photograph of kidney HGF protein expression. (G) HGF staining on kidney sections. Most of the positive staining was observed in damaged tubular cells. HGF staining of injured tubular cells was remarkably intensified in MV-treated animals at 48 h post-injury. Magnification, ×40.
Source publication
During acute kidney injury (AKI), tubular cell dedifferentiation initiates cell regeneration; hepatocyte growth factor (HGF) is involved in modulating cell dedifferentiation. Mesenchymal stem cell (MSC)-derived microvesicles (MVs) deliver RNA into injured tubular cells and alter their gene expression, thus regenerating these cells. We boldly specul...
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... the role of growth factors produced by the tubular epithelium in tubular cell dedif- ferentiation and growth, we examined the effect of MVs on growth factor expression. In AKI animals, kidney HGF expression was greatly enhanced by MV administration at 48 h post- injury, as demonstrated by RT-PCR and by western blot analysis (P<0.05, Fig. 3D, 3F-G). Immunohistochemistry staining also revealed that a substantial intensification of HGF staining was observed in damaged tubular cells (P<0.05, Fig. 3H). By contrast, TGF-β1, IGF-1 or EGF expression was not significantly altered by MV administration (Fig. 3A-3C). Using species- specific (rat) primers, we also screened for rat HGF mRNA ...
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... factor expression. In AKI animals, kidney HGF expression was greatly enhanced by MV administration at 48 h post- injury, as demonstrated by RT-PCR and by western blot analysis (P<0.05, Fig. 3D, 3F-G). Immunohistochemistry staining also revealed that a substantial intensification of HGF staining was observed in damaged tubular cells (P<0.05, Fig. 3H). By contrast, TGF-β1, IGF-1 or EGF expression was not significantly altered by MV administration (Fig. 3A-3C). Using species- specific (rat) primers, we also screened for rat HGF mRNA in damaged kidney tissues. We found that MV administration also markedly induced rat HGF expression (Fig. 3E). As a nega- tive control, no rat HGF mRNA ...
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... 48 h post- injury, as demonstrated by RT-PCR and by western blot analysis (P<0.05, Fig. 3D, 3F-G). Immunohistochemistry staining also revealed that a substantial intensification of HGF staining was observed in damaged tubular cells (P<0.05, Fig. 3H). By contrast, TGF-β1, IGF-1 or EGF expression was not significantly altered by MV administration (Fig. 3A-3C). Using species- specific (rat) primers, we also screened for rat HGF mRNA in damaged kidney tissues. We found that MV administration also markedly induced rat HGF expression (Fig. 3E). As a nega- tive control, no rat HGF mRNA was detected in MVs or in their cells of origin (hUC-MSCs) (P<0.05, data not ...
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... staining was observed in damaged tubular cells (P<0.05, Fig. 3H). By contrast, TGF-β1, IGF-1 or EGF expression was not significantly altered by MV administration (Fig. 3A-3C). Using species- specific (rat) primers, we also screened for rat HGF mRNA in damaged kidney tissues. We found that MV administration also markedly induced rat HGF expression (Fig. 3E). As a nega- tive control, no rat HGF mRNA was detected in MVs or in their cells of origin (hUC-MSCs) (P<0.05, data not ...
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... expression in the cells (Fig. 4G-4H). The conditioned medium (CM) of MV-treated tubular cells also con- tained higher levels of rat HGF (P<0.05, Fig. 4F). All of these findings indicate that MVs great- ly amplify the synthesis and release of native HGF by tubular cells. RNase pretreatment inhibited the in vivo and in vitro effects of MVs (P<0.05, Fig. 3-4). Human HGF mRNA originally residing in MVs enters the injured rat tubular cells and is translated into the HGF protein After 24 or 48 h of incubation with MVs, immunocytochemistry staining detected the human HGF protein in a few rat tubular cells (Fig. 5C). Using species-specific primers (human), real- time PCR examination also ...
Citations
... Along this line, we recently isolated and characterized podocytes from patients with Alport syndrome (10), Extracellular vesicles (EVs), cell-released vesicles involved in cell-to-cell communication, are gaining attention as biological tools with regenerative potential (11). In renal pathology, EVs derived from stem cells of different sources exert anti-apoptotic, anti-in ammatory, and pro-angiogenic effects, possibly through the transfer of mRNAs, miRNAs, and proteins to renal cells (12)(13)(14)(15). We recent demonstrated the bene cial effect of mesenchymal stromal cell-derived EVs (MSC-EVs) on podocyte injury in an in vitro milli uidic model of the glomerular ltration barrier (16). ...
Background
Personalized disease models are crucial for assessing the specific response of diseased cells to drugs, particularly novel biological therapeutics. Extracellular vesicles (EVs), nanosized vesicles released by cells for intercellular communication, have gained therapeutic interest due to their ability to reprogram target cells. We here utilized urinary podocytes obtained from children affected by steroid-resistant nephrotic syndrome with characterized genetic mutations as a model to test the therapeutic potential of EVs derived from kidney progenitor cells.
Methods
EVs were isolated from kidney progenitor cells (nKPCs) derived from the urine of a preterm neonate. Three lines of urinary podocytes obtained from nephrotic patients' urine and a line of Alport patient podocytes were characterized and used to assess albumin permeability in response to various drugs or to nKPC-EVs. RNA sequencing was conducted to identify commonly modulated pathways.
Results
Podocytes appeared unresponsive to pharmacological treatments, except for a podocyte line demonstrating responsiveness, in alignment with the patient's clinical response at 48 months. At variance, treatment with the nKPC-EVs was able to significantly reduce permeability in all the steroid-resistant patients-derived podocytes as well as in the line of Alport-derived podocytes. RNA sequencing of nKPC-EV-treated podocytes revealed the common upregulation of two genes (small ubiquitin-related modifier 1 (SUMO1) and Sentrin-specific protease 2 (SENP2)) involved in the SUMOylation pathway, a process recently demonstrated to play a role in slit diaphragm stabilization. Gene ontology analysis on podocyte expression profile highlighted cell-to-cell adhesion as the primary upregulated biological activity in treated podocytes.
Conclusions
nKPCs emerge as a promising non-invasive source of EVs with potential therapeutic effects on podocyte dysfunction. Furthermore, our findings suggest the possibility of establishing a non-invasive in vitro model for screening regenerative compounds on patient-derived podocytes.
... Umbilical cord MSC-EVs (UC-MSC-EVs) have been used in various models of kidney disease. In IRI models [79][80][81][82][83][84]86,88], UC-MSC-EVs were found to mitigate renal cell apoptosis; enhance proliferation and tubular epithelial cell growth; increase capillary vessel density; decrease epithelial cell swelling, necrosis, and casts formation; and abrogate kidney fibrosis, inflammation, and oxidative stress, thus improving kidney function. UC-MSC-EVs have also shown renoprotective effects against cisplatin-induced nephrotoxicity and were able to prevent the development of AKI [78,85]. ...
... Described beneficial effects of EVs were abrogated by RNase treatment [54,80,84]. Thus, UC-MSC-EVs promoted regeneration after AKI by accelerating tubular cell dedifferentiation and growth through HGF induction and Erk1/2 signaling, while the RNase treatment abrogated all MSC-EVs effects [80]. ...
... Described beneficial effects of EVs were abrogated by RNase treatment [54,80,84]. Thus, UC-MSC-EVs promoted regeneration after AKI by accelerating tubular cell dedifferentiation and growth through HGF induction and Erk1/2 signaling, while the RNase treatment abrogated all MSC-EVs effects [80]. Additionally, the effect of MSC-EVs in alleviating AKI in the IRI model, based on inhibiting apoptosis and stimulating tubular epithelial cell proliferation, was shown to be ineffective after RNase treatment [54]. ...
Kidney disease is a growing public health problem worldwide, including both acute and chronic forms. Existing therapies for kidney disease target various pathogenic mechanisms; however, these therapies only slow down the progression of the disease rather than offering a cure. One of the potential and emerging approaches for the treatment of kidney disease is mesenchymal stromal/stem cell (MSC) therapy, shown to have beneficial effects in preclinical studies. In addition, extracellular vesicles (EVs) released by MSCs became a potent cell-free therapy option in various preclinical models of kidney disease due to their regenerative, anti-inflammatory, and immunomodulatory properties. However, there are scarce clinical data available regarding the use of MSC-EVs in kidney pathologies. This review article provides an outline of the renoprotective effects of MSC-EVs in different preclinical models of kidney disease. It offers a comprehensive analysis of possible mechanisms of action of MSC-EVs with an emphasis on kidney disease. Finally, on the journey toward the implementation of MSC-EVs into clinical practice, we highlight the need to establish standardized methods for the characterization of an EV-based product and investigate the adequate dosing, safety, and efficacy of MSC-EVs application, as well as the development of suitable potency assays.
... In addition, two AKI models on rats illustrate beneficial effects of administration of stem cell-derived extracellular vesicles on tissue regeneration and kidney function [18,19]. Other potential beneficial effects of such treatment modality include the upregulation of renal angiogenesis as shown by the increased renal capillary density, the decline in renal fibrosis and oxidative stress as demonstrated by the decline in the renal expression of nuclear factor E2-related factor-2 [20][21][22]. Preclinical data exist regarding the potential usefulness of such therapy in few other kidney diseases including drug-induced nephropathy and renovascular diseases [23]. For instance, administration of human umbilical cord stem cell-derived exosomes into models of cisplatin-induced AKI animal models have demonstrated protective effects mediated via decline in apoptosis, oxidative stress, and pro-inflammatory cytokines along with the increase in cellular proliferation [24,25]. ...
Chronic kidney disease is among the most common causes of mortality and morbidity in adult population with limited therapeutic approaches including various medications and kidney replacement therapies. Kidney transplantation is the gold standard therapeutic alternative for the management of chronic kidney disease; nonetheless, important drawbacks include the lack of adequate living or deceased donors, high rates of pre- and post-operative complications including surgical complications, infectious complications and medication-induced adverse effects. With the latest preclinical and in vitro studies demonstrating the potentiality of kidney cells obtained from diseased kidneys to convert into fully functional kidney cells lead to a novel therapeutic alternative referred as autologous selected renal cell transplantation. Even though the clinical studies investigating the efficiency and adverse effects of autologous selected renal cell transplantation are limited, it is no doubt promising. The need for future large-scale studies on chronic kidney disease patients from a diversity of etiologies is clear for the better establishment of the therapeutic potential of autologous selected renal cell transplantation. In this narrative review, our aim is to evaluate the role of renal autologous stem cell therapy in the management of chronic kidney disease.
... The ability of MSCs and EVs to promote tissue regeneration in the setting of acute or chronic renal injury has been widely studied [50][51][52][53][54], but it is not fully understood. Several studies have shown that EVs modify gene expression in target cells by releasing their cargo, which consists of lipids, proteins, and nucleic acids such as miRNAs [55,56]. ...
We propose a new organ-conditioning strategy based on mesenchymal stromal cell (MSCs)/extracellular vesicle (EVs) delivery during hypothermic perfusion. MSCs/EVs marker CD73 is present on renal proximal tubular cells, and it protects against renal ischemia-reperfusion injury by converting adenosine monophosphate into adenosine (ADO). In this study, after checking if CD73-silenced EVs (EVsi) would impact in vitro tubular-cell proliferation, we perfused kidneys of a rat model of donation after circulatory death, with Belzer solution (BS) alone, BS supplemented with MSCs, EVs, or EVsi. The ADO and ATP levels were measured in the effluents and tissues. Global renal ischemic damage score (GRS), and tubular cell proliferation index (IPT) were evaluated in the tissue. EVsi did not induce cell proliferation in vitro. Ex vivo kidneys perfused with BS or BS + EVsi showed the worst GRS and higher effluent ADO levels than the MSC- and EV-perfused kidneys. In the EV-perfused kidneys, the tissue and effluent ATP levels and IPT were the highest, but not if CD73 was silenced. Tissue ATP content was positively correlated with tissue ADO content and negatively correlated with effluent ADO level in all groups. In conclusion, kidney conditioning with EVs protects against ischemic damage by activating the CD73/ADO system.
... 70-73 Given the limitations of cost, scalability and delivery ofMSCs, there has been increasing interest in EVs as a therapeutic. In fact, EVs have already demonstrated the ability to reverse acute kidney injury, vascular injury, pulmonary hypertension and obesity.[74][75][76][77][78] ...
Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal intestinal tract and has characteristic hypertrophic adipose changes observed in the mesentery. To better understand the role of the mesentery in the pathophysiology of Crohn's disease (CD), we evaluated the immunomodulatory potential of mesenchymal stem cells (MSCs) and their secreted extracellular vesicles (EVs) derived from Crohn's patients. MSCs and EVs were isolated from the mesentery and subcutaneous tissues of CD patients and healthy individuals subcutaneous tissues, and were analysed for differentiation, cytokine expression, self‐renewal and proliferation. The varying capacity of these tissue‐derived MSCs and EVs to attenuate T‐cell activation was measured in in vitro and an in vivo murine model. RNA sequencing of inflamed Crohn's disease mesentery tissue revealed an enrichment of T‐cell activation compared to non‐inflamed subcutaneous tissue. MSCs and MSC‐derived EVs isolated from Crohn's mesentery lose their ability to attenuate DSS‐induced colitis compared to subcutaneous tissue‐derived cell or EV therapy. We found that treatment with subcutaneous isolated MSCs and their EV product compared to Crohn's mesentery MSCs or EVs, the inhibition of T‐cell proliferation and IFN‐γ, IL‐17a production increased, suggesting a non‐inflamed microenvironment allows for T‐cell inhibition by MSCs/EVs. Our results demonstrate that Crohn's patient‐derived diseased mesentery tissue MSCs lose their immunosuppressive capacity in the treatment of colitis by distinct regulation of pathogenic T‐cell responses and/or T‐cell infiltration into the colon.
... The tubes with ADSCs were placed in a thermomixer (ThermoMixer ® C, Eppendorf, Germany) for 30 min at 300 rpm room temperature. The isolation procedure of MV was described previously [18,19]. ADSCs were centrifuged 10 min at 300× g, 4 • C to discard dead cells and cell debris. ...
Intravenous adipose mesenchymal stem cells (ADSCs) attenuate renal ischemia/reperfusion (IR) injury but with major drawbacks, including the lack of a specific homing effect after systemic infusion, cell trapping in the lung, and early cell death in the damaged microenvironment. We examined whether intrarenal arterial transplantation of dexmedetomidine (DEX) preconditioning ADSC-derived microvesicles (DEX-MVs) could promote further therapeutic potential to reduce renal IR injury. We evaluated the effect of DEX-MVs on NRK-52E cells migration, hypoxia/reoxygenation (H/R)-induced cell death, and reactive oxygen species (ROS) amount and renal IR model in rats. IR was established by bilateral 45 min ischemia followed by 4 h reperfusion. Intrarenal MVs or DEX-MVs were administered prior to ischemia. Renal oxidative stress, hemodynamics and function,
western blot, immunohistochemistry, and tubular injury scores were determined. The miR-122-5p expression in kidneys was analyzed using microarrays and quantitative RT-PCR and its action target was predicted by TargetScan. DEX-MVs were more efficient than MVs to increase migration capability and to further decrease H/R-induced cell death and ROS level in NRK-52E cells. Consistently, DEX-MVs were better than MV in increasing CD44 expression, improving IR-depressed renal hemodynamics and renal erythropoietin expression, inhibiting IR-enhanced renal ROS level, tubular injury score, miR-122-5p expression, pNF-�B expression, Bax/caspase 3/poly(ADP-ribose) polymerase (PARP)-mediated apoptosis, blood urea nitrogen, and creatinine levels. The use of NRK-52E cells confirmed that miR-122-5p mimic via inhibiting erythropoietin expression exacerbated
Bax-mediated apoptosis, whereas miR-122-5p inhibitor via upregulating erythropoietin and Bcl-2 expression reduced apoptosis. In summary, intrarenal arterial DEX-MV conferred further therapeutic potential to reduce renal IR injury through the miR-122-5p/erythropoietin/apoptosis axis.
... In consistence with the previous studies, we observed therapeutic effects of EVs in AKI or renal fibrosis by showing inhibition of apoptosis and reduction of hypertension and inflammatory factor. [46][47][48][49][50][51][52][53][54] We also showed that treatment with AEVs and NEVs at 24 hours after exposure to H2O2 could prevent the progression of injury by reducing the expression of TGF-β1, collagen I, vimentin, IL-1Β, and TNF-α and increasing E cadherin and anti-inflammatory factors (IL4, IL10). According to Wang et al, treatment with EVs following induction of autophagy in kidney cells, effectively reduces the toxic effects of cisplatin. ...
Introduction
Chronic and progressive damage to the kidney by inflammatory processes, may lead to an increase in the extracellular matrix production, a condition known as renal fibrosis. The current study aims to evaluate if the extracellular vesicles (EVs) derived from autophagic adipose-derived mesenchymal stem cells (ADMSCs) can reduce the inflammation and extracellular matrix accumulation in damaged kidney tissue.
Methods
Autophagy was induced in ADMSCs using 2µM concentration curcumin and was confirmed by evaluating LC3B, ATG7, and Beclin1 using real-time polymerase chain reaction (PCR) and Western blot. An in vitro renal fibrotic model was established in HEK-293 cells exposed to H2O2 (0.8mM) for 24 and 72 hours. The fibrotic model was confirmed through evaluation of collagen I, transforming growth factor-beta 1 (TGF-β1), E-cadherin, and vimentin genes expression using real-time PCR, collagen I protein by ELISA. After induction of fibrosis for 24 and 72 hours, the HEK cells were treated with NEVs (non-autophagy EVs) (50µM) or AEVs (autophagy EVs) (50µM) at 48, 96, and 124 hours, and then the samples were collected at 72 and 148 hours. Expression of collagen I, TGF-β1, E-cadherin, and vimentin Genes was evaluated via RT-PCR, and protein levels of IL1, TNF-α, IL4, IL10 using ELISA.
Results
Induction of autophagy using curcumin (2µM) for 24 hours significantly increased LC3B, Beclin1, and ATG7 in the ADMSCs. Upregulation in anti-fibrotic (E-cadherin) and anti-inflammatory (IL4, IL10) gene expression was significantly different in the fibrotic model treated by AEVs compared to NEVs. Also, the downregulation of fibrotic (TGF-β1, vimentin, collagen I) and pro-inflammatory (IL1, TNFα) gene expression was significantly different in AEVs compared with those treated by NEVs.
Conclusion
Our findings suggest that AEVs can be considered as a therapeutic modality for renal fibrosis in the future.
... These can be models of protein drugs. In particular, BSA has a molecular weight similar to hepatocyte growth factor that is reported to be a pleiotropic factor playing a fundamental role in tubular repair and regeneration after acute renal injury [22,23]. ...
This work focuses on formulating liposomes to be used in isolated kidney dynamic machine perfusion in hypothermic conditions as drug delivery systems to improve preservation of transplantable organs. The need mainly arises from use of kidneys from marginal donors for transplantation that are more exposed to ischemic/reperfusion injury compared to those from standard donors. Two liposome preparation techniques, thin film hydration and microfluidic techniques, are explored for formulating liposomes loaded with two model proteins, myoglobin and bovine serum albumin. The protein-loaded liposomes are characterized for their size by DLS and morphology by TEM. Protein releases from the liposomes are tested in PERF-GEN perfusion fluid, 4 °C, and compared to the in vitro protein release in PBS, 37 °C. Fluorescent liposome uptake is analyzed by fluorescent microscope in vitro on epithelial tubular renal cell cultures and ex vivo on isolated pig kidney in hypothermic perfusion conditions. The results show that microfluidics are a superior technique for obtaining reproducible spherical liposomes with suitable size below 200 nm. Protein encapsulation efficiency is affected by its molecular weight and isoelectric point. Lowering incubation temperature slows down the proteins release; the perfusion fluid significantly affects the release of proteins sensitive to ionic media (such as BSA). Liposomes are taken up by epithelial tubular renal cells in two hours’ incubation time.
... The underlying mechanisms of the therapeutic action in native EVs are attributed to the cell-surface interactions between EVs and the target cells as well as the subsequent transfer of the cargos from EVs to target cells, which will trigger a series of signaling pathways. Several well-studied signaling pathways associated with EVs have been reported, including pAkt/mTOR [65], Erk1/2 [66], STAT [67], TGF-β/ Smad [68], Efna3 [69], and Hedgehog signaling [70]. These significant signaling pathways will regulate various physiological functions of the body, including mitigating or eliciting immune responses, reducing inflammation, inhibiting apoptosis, promoting angiogenesis, and minimizing oxidative stress ( Figure 5), eventually ameliorating the adverse effects of diseases and promoting regenerative functions [11]. ...
... Meanwhile, Vesna's team has proved that several growth factors including brain-derived neurotrophic factor (BDNF), fibroblast growth factor-1 (FGF-1), glial cell-derived neurotrophic factor (GDNF), insulin-like growth factor-1 (IGF-1) and nerve growth factor (NGF) within EVs derived from adipose-MSCs could increase the growth of neurite and ultimately enhance sciatic nerve regeneration both in vitro and in vivo [81]. Similarly, EVs derived from human umbilical cord-MSCs could stimulate injured tubular cells to produce a high concentration of hepatocyte growth factor (HGF), which subsequently accelerated tubular cells growth and prevented injured cell apoptosis by activating the signaling of Erk1/2 [66]. ...
In recent decades, extracellular vesicles (EVs), as bioactive cell-secreted nanoparticles which are involved in various physiological and pathological processes including cell proliferation, immune regulation, angiogenesis and tissue repair, have emerged as one of the most attractive nanotherapeutics for regenerative medicine. Herein we provide a systematic review of the latest progress of EVs for regenerative applications. Firstly, we will briefly introduce the biogenesis, function and isolation technology of EVs. Then, the underlying therapeutic mechanisms of the native unmodified EVs and engineering strategies of the modified EVs as regenerative entities will be discussed. Subsequently, the main focus will be placed on the tissue repair and regeneration applications of EVs on various organs including brain, heart, bone and cartilage, liver and kidney, as well as skin. More importantly, current clinical trials of EVs for regenerative medicine will also be briefly highlighted. Finally, the future challenges and insightful perspectives of the currently developed EV-based nanotherapeutics in biomedicine will be discussed. In short, the bioactive EV-based nanotherapeutics have opened new horizons for biologists, chemists, nanoscientists, pharmacists, as well as clinicians, making possible powerful tools and therapies for regenerative medicine.
... De-differentiation In vivo (rat) In vitro I/R-induced AKI HGF mRNA [64] Proliferation In vivo (rat) I/R-induced AKI HGF mRNA [65] Angiogenesis In vivo (rat) In vitro I/R-induced AKI and CKD miR-210 [65,66] Immunomodulation Anti-inflammation In vivo (rat) I/R and drug-induced AKI; renal artery stenosis; unilateral ureteral obstruction; 5/6 subtotal nephrectomy miR-210/-378 miR-21 miR-199a [67] Macrophage inhibition and switch from M1 to M2 anti-inflammatory phenotype ...
Current treatment of primary and secondary glomerulopathies is hampered by many limits and a significant proportion of these disorders still evolves towards end-stage renal disease. A possible answer to this unmet challenge could be represented by therapies with stem cells, which include a variety of progenitor cell types derived from embryonic or adult tissues. Stem cell self-renewal and multi-lineage differentiation ability explain their potential to protect and regenerate injured cells, including kidney tubular cells, podocytes and endothelial cells. In addition, a broad spectrum of anti-inflammatory and immunomodulatory actions appears to interfere with the pathogenic mechanisms of glomerulonephritis. Of note, mesenchymal stromal cells have been particularly investigated as therapy for Lupus Nephritis and Diabetic Nephropathy, whereas initial evidence suggest their beneficial effects in primary glomerulopathies such as IgA nephritis. Extracellular vesicles mediate a complex intercellular communication network, shuttling proteins, nucleic acids and other bioactive molecules from origin to target cells to modulate their functions. Stem cell-derived extracellular vesicles recapitulate beneficial cytoprotective, reparative and immunomodulatory properties of parental cells and are increasingly recognized as a cell-free alternative to stem cell-based therapies for different diseases including glomerulonephritis, also considering the low risk for potential adverse effects such as maldifferentiation and tumorigenesis. We herein summarize the renoprotective potential of therapies with stem cells and extracellular vesicles derived from progenitor cells in glomerulonephritis, with a focus on their different mechanisms of actions. Technological progress and growing knowledge are paving the way for wider clinical application of regenerative medicine to primary and secondary glomerulonephritis: this multi-level, pleiotropic therapy may open new scenarios overcoming the limits and side effects of traditional treatments, although the promising results of experimental models need to be confirmed in the clinical setting.
