Oct-4 Enhanced the Therapeutic Effects of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Acute Kidney Injury

Background/Aims: Acute kidney injury (AKI) is a common clinical condition that can lead to chronic kidney failure. Although mesenchymal stem cell-derived extracellular vesicles (MSC EVs) are regarded as a potent AKI treatment, the mechanisms underlying their beneficial effects remain unclear. Oct-4 may play an important role in tissue injury repair. We thus hypothesized that oct-4 overexpression might enhance the therapeutic effects of MSC EVs in AKI treatment. Methods: Renal tubular epithelial cells were cultured in a low oxygen environment, then cocultured with MSC EVs or control medium for 48 h. BrdU and transferase-mediated dUTP nick-end labeling (TUNEL) staining were used to assess cell proliferation and apoptosis. Mice subjected to ischemia reperfusion were randomly divided into 4 groups, then injected with either phosphate-buffered saline (vehicle), EVs, EVs overexpressing oct-4 (EVs+Oct-4), and EVs not expressing Oct-4 (EVs–Oct-4). Blood creatinine (CREA) and urine nitrone levels were assessed 48 h and 2 weeks after injection. After ischemia reperfusion, renal tissues from each group were stained with TUNEL and proliferating cell nuclear antigen (PCNA) to determine the degree of apoptosis and proliferation. Masson trichrome staining was used to evaluate renal fibrosis progression. Snail gene expression was assessed using polymerase chain reaction (PCR). Results: At 48 h after hypoxic treatment, TUNEL and BrdU staining indicated that the EVs+Oct-4 group had the least apoptosis and the most proliferation, respectively. Treatment with EVs overexpressing Oct-4 significantly decreased serum Crea and blood urea nitrogen levels and rescued kidney fibrosis, as indicated by the low proportion of Masson staining, high number of PCNA-positive cells, and low number of TUNEL-positive cells. PCR analysis indicated that Snail was most upregulated in the vehicle group and least upregulated in the EVs+Oct-4 group. Conclusions: MSC EVs had a pronounced therapeutic effect on ischemic reperfusion injury-related AKI, and Oct-4 overexpression enhanced these therapeutic effects. Our results may inspire a new direction for AKI treatment with MSC EVs.

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Adipose tissue derived mesenchymal stem cell transplantation in the treatment of ischemia/reperfusion induced acute kidney injury in rats. Application route and therapeutic window

Acta Cirurgica Brasileira ◽

10.1590/s0102-865020180110000008 ◽

2018 ◽

Vol 33 (11) ◽

pp. 1016-1026 ◽

Cited By ~ 4

Author(s):

Betânia Souza Monteiro ◽

Bianka Souza dos Santos ◽

Bruna Lopes de Almeida ◽

Emy Hiura ◽

Wagner Alexey Back Fiorio ◽

...

Keyword(s):

Acute Kidney Injury ◽

Adipose Tissue ◽

Stem Cell ◽

Mesenchymal Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Therapeutic Window ◽

Mesenchymal Stem Cell Transplantation

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Exploring Mesenchymal Stem Cell-Derived Extracellular Vesicles in Acute Kidney Injury

Methods in Molecular Biology - Animal Models for Stem Cell Therapy ◽

10.1007/978-1-4939-1453-1_12 ◽

2014 ◽

pp. 139-145 ◽

Cited By ~ 7

Author(s):

Stefania Bruno ◽

Giovanni Camussi

Keyword(s):

Acute Kidney Injury ◽

Stem Cell ◽

Mesenchymal Stem Cell ◽

Extracellular Vesicles ◽

Kidney Injury

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Biodistribution of mesenchymal stem cell-derived extracellular vesicles in a model of acute kidney injury monitored by optical imaging

International Journal of Molecular Medicine ◽

10.3892/ijmm.2014.1663 ◽

2014 ◽

Vol 33 (5) ◽

pp. 1055-1063 ◽

Cited By ~ 129

Author(s):

CRISTINA GRANGE ◽

MARTA TAPPARO ◽

STEFANIA BRUNO ◽

DEVASIS CHATTERJEE ◽

PETER J. QUESENBERRY ◽

...

Keyword(s):

Acute Kidney Injury ◽

Stem Cell ◽

Mesenchymal Stem Cell ◽

Optical Imaging ◽

Extracellular Vesicles ◽

Kidney Injury

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Effect and mechanism of erythropoietin on mesenchymal stem cell proliferation in vitro under the acute kidney injury microenvironment

Experimental Biology and Medicine ◽

10.1258/ebm.2011.011001 ◽

2011 ◽

Vol 236 (9) ◽

pp. 1093-1099 ◽

Cited By ~ 20

Author(s):

Nanmei Liu ◽

Jun Tian ◽

Weiwei Wang ◽

Jin Cheng ◽

Dayong Hu ◽

...

Keyword(s):

Cell Proliferation ◽

Acute Kidney Injury ◽

Stem Cell ◽

Mesenchymal Stem Cell ◽

Kidney Injury ◽

Stem Cell Proliferation ◽

Proliferation In Vitro

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Mesenchymal Stem Cell-Derived Extracellular Vesicles: A Potential Therapeutic Strategy for Acute Kidney Injury

Frontiers in Immunology ◽

10.3389/fimmu.2021.684496 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jia-Kun Li ◽

Cheng Yang ◽

Ying Su ◽

Jing-Chao Luo ◽

Ming-Hao Luo ◽

...

Keyword(s):

Acute Kidney Injury ◽

Extracellular Vesicles ◽

Cellular Therapy ◽

Supportive Therapy ◽

Kidney Injury ◽

Therapeutic Effects ◽

Life Threatening ◽

Stage Renal Disease ◽

End Stage

Acute kidney injury (AKI) is a common and potential life-threatening disease in patients admitted to hospital, affecting 10%–15% of all hospitalizations and around 50% of patients in the intensive care unit. Severe, recurrent, and uncontrolled AKI may progress to chronic kidney disease or end-stage renal disease. AKI thus requires more efficient, specific therapies, rather than just supportive therapy. Mesenchymal stem cells (MSCs) are considered to be promising cells for cellular therapy because of their ease of harvesting, low immunogenicity, and ability to expand in vitro. Recent research indicated that the main therapeutic effects of MSCs were mediated by MSC-derived extracellular vesicles (MSC-EVs). Furthermore, compared with MSCs, MSC-EVs have lower immunogenicity, easier storage, no tumorigenesis, and the potential to be artificially modified. We reviewed the therapeutic mechanism of MSCs and MSC-EVs in AKI, and considered recent research on how to improve the efficacy of MSC-EVs in AKI. We also summarized and analyzed the potential and limitations of EVs for the treatment of AKI to provide ideas for future clinical trials and the clinical application of MSC-EVs in AKI.

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Mesenchymal Stem Cell-Derived Exosomes and Other Extracellular Vesicles as New Remedies in the Therapy of Inflammatory Diseases

Cells ◽

10.3390/cells8121605 ◽

2019 ◽

Vol 8 (12) ◽

pp. 1605 ◽

Cited By ~ 40

Author(s):

Carl Randall Harrell ◽

Nemanja Jovicic ◽

Valentin Djonov ◽

Nebojsa Arsenijevic ◽

Vladislav Volarevic

Keyword(s):

Stem Cell ◽

Mesenchymal Stem Cell ◽

Extracellular Vesicles ◽

Immune Cells ◽

Messenger Rna ◽

Molecular Mechanisms ◽

Inflammatory Diseases ◽

Experimental Studies ◽

Bioactive Molecules ◽

Therapeutic Effects

There is growing evidence that mesenchymal stem cell (MSC)-based immunosuppression was mainly attributed to the effects of MSC-derived extracellular vesicles (MSC-EVs). MSC-EVs are enriched with MSC-sourced bioactive molecules (messenger RNA (mRNA), microRNAs (miRNAs), cytokines, chemokines, immunomodulatory factors) that regulate phenotype, function and homing of immune cells. In this review article we emphasized current knowledge regarding molecular mechanisms responsible for the therapeutic effects of MSC-EVs in attenuation of autoimmune and inflammatory diseases. We described the disease-specific cellular targets of MSC-EVs and defined MSC-sourced molecules, which were responsible for MSC-EV-based immunosuppression. Results obtained in a large number of experimental studies revealed that both local and systemic administration of MSC-EVs efficiently suppressed detrimental immune response in inflamed tissues and promoted survival and regeneration of injured parenchymal cells. MSC-EVs-based anti-inflammatory effects were relied on the delivery of immunoregulatory miRNAs and immunomodulatory proteins in inflammatory immune cells (M1 macrophages, dendritic cells (DCs), CD4+Th1 and Th17 cells), enabling their phenotypic conversion into immunosuppressive M2 macrophages, tolerogenic DCs and T regulatory cells. Additionally, through the delivery of mRNAs and miRNAs, MSC-EVs activated autophagy and/or inhibited apoptosis, necrosis and oxidative stress in injured hepatocytes, neurons, retinal cells, lung, gut and renal epithelial cells, promoting their survival and regeneration.

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Embryonic stem cell-derived extracellular vesicles promote the recovery of kidney injury

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02460-0 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Lu Yu ◽

Siying Liu ◽

Chen Wang ◽

Chuanyu Zhang ◽

Yajie Wen ◽

...

Keyword(s):

Stem Cell ◽

Embryonic Stem Cell ◽

Extracellular Vesicles ◽

Therapeutic Potential ◽

Es Cells ◽

Ischemia Reperfusion ◽

Embryonic Stem ◽

Kidney Injury ◽

Structure And Function ◽

And Function

Abstract Background Embryonic stem cell-derived extracellular vesicles (ESC-EVs) possess therapeutic potential for a variety of diseases and are considered as an alternative of ES cells. Acute kidney injury (AKI) is a common acute and severe disease in clinical practice, which seriously threatens human life and health. However, the roles and mechanisms of ESC-EVs on AKI remain unclear. Methods In this study, we evaluated the effects of ESC-EVs on physiological repair and pathological repair using murine ischemia-reperfusion injury-induced AKI model, the potential mechanisms of which were next investigated. EVs were isolated from ESCs and EVs derived from mouse fibroblasts as therapeutic controls. We then investigated whether ESC-EVs can restore the structure and function of the damaged kidney by promoting physiological repair and inhibiting the pathological repair process after AKI in vivo and in vitro. Results We found that ESC-EVs significantly promoted the recovery of the structure and function of the damaged kidney. ESC-EVs increased the proliferation of renal tubular epithelial cells, facilitated renal angiogenesis, inhibited the progression of renal fibrosis, and rescued DNA damage caused by ischemia and reperfusion after AKI. Finally, we found that ESC-EVs play a therapeutic effect by activating Sox9+ cells. Conclusions ESC-EVs significantly promote the physiological repair and inhibit the pathological repair after AKI, enabling restoration of the structure and function of the damaged kidney. This strategy might emerge as a novel therapeutic strategy for ESC clinical application.

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