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Hejazian SM, Hejazian SS, Mostafavi SM, Hosseiniyan SM, Montazersaheb S, Ardalan M, Zununi Vahed S, Barzegari A. Targeting cellular senescence in kidney diseases and aging: A focus on mesenchymal stem cells and their paracrine factors. Cell Commun Signal 2024; 22:609. [PMID: 39696575 DOI: 10.1186/s12964-024-01968-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Accepted: 11/28/2024] [Indexed: 12/20/2024] Open
Abstract
Cellular senescence is a phenomenon distinguished by the halting of cellular division, typically triggered by DNA injury or numerous stress-inducing factors. Cellular senescence is implicated in various pathological and physiological processes and is a hallmark of aging. The presence of accumulated senescent cells, whether transiently (acute senescence) or persistently (chronic senescence) plays a dual role in various conditions such as natural kidney aging and different kidney disorders. Elevations in senescent cells and senescence-associated secretory phenotype (SASP) levels correlate with decreased kidney function, kidney ailments, and age-related conditions. Strategies involving senotherapeutic agents like senolytics, senomorphics, and senoinflammation have been devised to specifically target senescent cells. Mesenchymal stem cells (MSCs) and their secreted factors may also offer alternative approaches for anti-senescence interventions. The MSC-derived secretome compromises significant therapeutic benefits in kidney diseases by facilitating tissue repair via anti-inflammatory, anti-fibrosis, anti-apoptotic, and pro-angiogenesis effects, thereby improving kidney function and mitigating disease progression. Moreover, by promoting the clearance of senescent cells or modulating their secretory profiles, MSCs could potentially reverse some age-related declines in kidney function.This review article intends to shed light on the present discoveries concerning the role of cellular senescence in kidney aging and diseases. Furthermore, it outlines the role of senotherapeutics utilized to alleviate kidney damage and aging. It also highlights the possible impact of MSCs secretome on mitigating kidney injury and prolonging lifespan across various models of kidney diseases as a novel senotherapy.
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Affiliation(s)
| | - Seyyed Sina Hejazian
- Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Seyyedeh Mina Mostafavi
- Ayatollah Taleghani Hospital, Research Development Unit, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Soheila Montazersaheb
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Abolfazl Barzegari
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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Zhang C, Cai L, Ma M, Xie X, Wang J, Zhang Y. Hypoxia-Treated Adipose Mesenchymal Stem Cells Derived Exosomes Enhance the Therapeutic Effects on Unilateral Ureteral Obstruction Mice. Pharmacology 2024:1-13. [PMID: 39561719 DOI: 10.1159/000542609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 11/11/2024] [Indexed: 11/21/2024]
Abstract
INTRODUCTION The exosomes from adipose-derived mesenchymal stem cells (AMSCs) had therapeutic effects. However, whether the exosomes derived from hypoxia-treated AMSCs could improve renal functions in unilateral ureteral obstruction (UUO) mice remains unclear. METHODS The exosomes were characterized using a transmission electron microscope and Western blot. Its size distribution was determined using the Zetasizer Nano ZS analysis system. The differentiation ability was assessed by alkaline phosphatase and oil red staining. Consequently, the function of exosomes in inhibiting inflammatory factors was evaluated using an enzyme-linked immunosorbent assay, and apoptosis inhibition was evaluated by Western blot. Finally, the function of exosomes to ameliorate kidney fibrosis was evaluated using quantitative reverse transcription polymerase chain reaction, Western blot, hematoxylin-eosin staining, and Masson staining. RESULTS The cultured AMSCs could differentiate into osteoblast and adipocyte. Meanwhile, the cultured AMSCs could effectively secrete the exosomes, which were characterized by around 110 nm diameter and surface marker expression. Exosomes derived from hypoxia-treated AMSCs improved renal functions in UUO mice. The mechanism exploration revealed that exosomes could decrease the TNF-α and IL-6 and inhibit cell apoptosis. Finally, the fibrosis-associated protein was reversed, and the renal dysfunctions were ameliorated in UUO mice. CONCLUSION The exosomes derived from the hypoxia-treated AMSCs have a better effect than those from normal AMSCs in ameliorating renal dysfunctions in UUO mice.
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Affiliation(s)
- Chi Zhang
- Department of Nephrology, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, China
- Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, China
| | - Longjun Cai
- Department of Urology, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, China
| | - Meimei Ma
- Department of Pathology, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, China
| | - Xiaohui Xie
- Department of Nephrology, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, China
| | - Junsheng Wang
- Department of Nephrology, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, China
| | - Yuanyuan Zhang
- Department of Nephrology, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, China
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Liu C, Li Q, Ma JX, Lu B, Criswell T, Zhang Y. Exosome-mediated renal protection: Halting the progression of fibrosis. Genes Dis 2024; 11:101117. [PMID: 39263535 PMCID: PMC11388648 DOI: 10.1016/j.gendis.2023.101117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 08/09/2023] [Accepted: 08/13/2023] [Indexed: 09/13/2024] Open
Abstract
Renal fibrosis is a complex and multifactorial process that involves inflammation, cell proliferation, collagen, and fibronectin deposition in the kidney, ultimately leading to chronic kidney disease and even end-stage renal disease. The main goal of treatment is to slow down or halt the progression of fibrosis and to improve or preserve kidney function. Despite significant progress made in understanding the underlying mechanisms of renal fibrosis, current therapies have limited renal protection as the disease progresses. Exosomes derived from stem cells are a newer area of research for the treatment of renal fibrosis. Exosomes as nano-sized extracellular vesicles carry proteins, lipids, and nucleic acids, which can be taken up by local or distant cells, serving as mediators of intercellular communication and as drug delivery vehicles. Exosomes deliver molecules that reduce inflammation, renal fibrosis and extracellular matrix protein production, and promote tissue regeneration in animal models of kidney disease. Additionally, they have several advantages over stem cells, such as being non-immunogenic, having low risk of tumor formation, and being easier to produce and store. This review describes the use of natural and engineered exosomes containing therapeutic agents capable of mediating anti-inflammatory and anti-fibrotic processes during both acute kidney injury and chronic kidney disease. Exosome-based therapies will be compared with stem cell-based treatments for tissue regeneration, with a focus on renal protection. Finally, future directions and strategies for improving the therapeutic efficacy of exosomes are discussed.
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Affiliation(s)
- Chuanqi Liu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Qingfeng Li
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Jian-Xing Ma
- Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27101, United States
| | - Baisong Lu
- Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States
| | - Tracy Criswell
- Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States
| | - Yuanyuan Zhang
- Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States
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Li B, Qi C, Zhang Y, Shi L, Zhang J, Qian H, Ji C. Frontier role of extracellular vesicles in kidney disease. J Nanobiotechnology 2024; 22:583. [PMID: 39304945 DOI: 10.1186/s12951-024-02852-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 09/11/2024] [Indexed: 09/22/2024] Open
Abstract
Kidney diseases represent a diverse range of conditions that compromise renal function and structure which characterized by a progressive deterioration of kidney function, may ultimately necessitate dialysis or kidney transplantation as end-stage treatment options. This review explores the complex landscape of kidney diseases, highlighting the limitations of existing treatments and the pressing need for innovative strategies. The paper delves into the role of extracellular vesicles (EVs) as emerging biomarkers and therapeutic agents in the context of kidney pathophysiology. Urinary extracellular vesicles (uEVs), in particular, offer a non-invasive means of assessing renal injury and monitoring disease progression. Additionally, mesenchymal stem cell-derived EVs (MSC-EVs) are examined for their immunomodulatory and tissue repair capabilities, presenting a promising avenue for novel therapeutic interventions. And discusses the potential of engineering EVs to enhance their targeting and therapeutic efficacy. This paper systematically integrates the latest research findings and aims to provide a comprehensive overview of the role of EVs in kidney disease, providing cutting-edge insights into their potential as a diagnostic and therapeutic tool.
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Affiliation(s)
- Bei Li
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Chen Qi
- Department of Clinical Laboratory, Suzhou Municipal Hospital of Anhui Province, Anhui, 234000, China
| | - Yifan Zhang
- College of Medical Imaging, Dalian Medical University, Dalian, Liaoning, 116000, China
| | - Linru Shi
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Jiahui Zhang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Hui Qian
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China.
| | - Cheng Ji
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China.
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Lu W, Guo Y, Liu H, Zhang T, Zhang M, Li X, Li Z, Shi M, Jiang Z, Zhao Z, Yang S, Li Z. The Inhibition of Fibrosis and Inflammation in Obstructive Kidney Injury via the miR-122-5p/SOX2 Axis Using USC-Exos. Biomater Res 2024; 28:0013. [PMID: 38617751 PMCID: PMC11014086 DOI: 10.34133/bmr.0013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 02/14/2024] [Indexed: 04/16/2024] Open
Abstract
Background: Fibrosis and inflammation due to ureteropelvic junction obstruction substantially contributes to poor renal function. Urine-derived stem-cell-derived exosomes (USC-Exos) have therapeutic effects through paracrine. Methods: In vitro, the effects of USC-Exos on the biological functions of HK-2 and human umbilical vein endothelial cells were tested. Cell inflammation and fibrosis were induced by transforming growth factor-β1 and interleukin-1β, and their anti-inflammatory and antifibrotic effects were observed after exogenous addition of USC-Exos. Through high-throughput sequencing of microRNA in USC-Exos, the pathways and key microRNAs were selected. Then, the antifibrotic and anti-inflammatory effects of exosomal miR-122-5p and target genes were verified. The role of the miR-122-5p/SOX2 axis in anti-inflammatory and antifibrotic effects was verified. In vivo, a rabbit model of partial unilateral ureteral obstruction (PUUO) was established. Magnetic resonance imaging recorded the volume of the renal pelvis after modeling, and renal tissue was pathologically analyzed. Results: We examined the role of USC-Exos and their miR-122-5p content in obstructive kidney injury. These Exos exhibit antifibrotic and anti-inflammatory activities. SOX2 is the hub gene in PUUO and negatively related to renal function. We confirmed the binding relationship between miR-122-5p and SOX2. The anti-inflammatory and antifibrotic effects of miR-122-5p were inhibited, indicating that miR-122-5p has anti-inflammatory and antifibrotic effects by inhibiting SOX2 expression. In vivo, the PUUO group showed typical obstructive kidney injury after modeling. After USC-Exo treatment, the shape of the renal pelvis shown a remarkable improvement, and inflammation and fibrosis decreased. Conclusions: We confirmed that miR-122-5p from USC-Exos targeting SOX2 is a new molecular target for postoperative recovery treatment of obstructive kidney injury.
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Affiliation(s)
- Wenjun Lu
- Department of Pediatric Surgery,
The Sixth Hospital Affiliated to Harbin Medical University, Harbin Medical University, No.998 Aiying Street, Harbin 150027, Heilongjiang, China
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province,
School of Life Sciences, Westlake University,Hangzhou 310024, Zhejiang, China
- Center for Infectious Disease Research,
Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang, China
- Laboratory of Systems Immunology,
Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, Zhejiang, China
| | - Yujun Guo
- Department of Pediatric Surgery,
The Sixth Hospital Affiliated to Harbin Medical University, Harbin Medical University, No.998 Aiying Street, Harbin 150027, Heilongjiang, China
| | - Hengchen Liu
- Department of General Surgery,
The Second Hospital Affiliated to Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou 310022, Zhejiang, China
| | - Tingting Zhang
- Department of Pediatric Surgery,
The Sixth Hospital Affiliated to Harbin Medical University, Harbin Medical University, No.998 Aiying Street, Harbin 150027, Heilongjiang, China
| | - Mingzhao Zhang
- Department of General Surgery,
The Second Hospital Affiliated to Anhui Medical University, No. 678 Furong Road, Hefei 230031, Anhui, China
| | - Xiangqi Li
- Department of Pediatric Surgery,
The Sixth Hospital Affiliated to Harbin Medical University, Harbin Medical University, No.998 Aiying Street, Harbin 150027, Heilongjiang, China
| | - Zhou Li
- Department of Pediatric Surgery,
The Sixth Hospital Affiliated to Harbin Medical University, Harbin Medical University, No.998 Aiying Street, Harbin 150027, Heilongjiang, China
| | - Manyu Shi
- Department of Pediatric Surgery,
The Sixth Hospital Affiliated to Harbin Medical University, Harbin Medical University, No.998 Aiying Street, Harbin 150027, Heilongjiang, China
| | - Zhitao Jiang
- Department of Pediatric Surgery,
The Sixth Hospital Affiliated to Harbin Medical University, Harbin Medical University, No.998 Aiying Street, Harbin 150027, Heilongjiang, China
| | - Zheng Zhao
- Department of Pediatric Surgery,
The Sixth Hospital Affiliated to Harbin Medical University, Harbin Medical University, No.998 Aiying Street, Harbin 150027, Heilongjiang, China
| | - Shulong Yang
- Department of Pediatric Surgery,
The Sixth Hospital Affiliated to Harbin Medical University, Harbin Medical University, No.998 Aiying Street, Harbin 150027, Heilongjiang, China
| | - Zhaozhu Li
- Department of Pediatric Surgery,
The Sixth Hospital Affiliated to Harbin Medical University, Harbin Medical University, No.998 Aiying Street, Harbin 150027, Heilongjiang, China
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Hong S, Kim H, Kim J, Kim S, Park TS, Kim TM. Extracellular vesicles from induced pluripotent stem cell-derived mesenchymal stem cells enhance the recovery of acute kidney injury. Cytotherapy 2024; 26:51-62. [PMID: 37843481 DOI: 10.1016/j.jcyt.2023.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 08/08/2023] [Accepted: 09/16/2023] [Indexed: 10/17/2023]
Abstract
BACKGROUND AIMS To investigate whether the extracellular vesicles (EVs) from mesenchymal stem cell-like cells derived from induced pluripotent stem cells (iMSC-EVs) can inhibit the progression of acute kidney injury (AKI). METHODS The characteristics of iMSC-EVs were confirmed by immunoblotting, cryo-transmission electron microscopy, nanoparticle tracking analysis, and their localization in kidneys. Using human renal epithelial cells, the potential of iMSC-EVs to stimulate the growth and survival of HK-2 cells undergoing cisplatin-induced cell death was investigated. The anti-inflammatory effects of iMSC-EVs was examined in M1-polarized THP-1 macrophages. Subsequently, the therapeutic potential of iMSC-EVs was assessed in cisplatin-induced acute kidney injury in BALB/c mice. The anti-apoptotic and anti-inflammatory effect of iMSC-EVs was evaluated using serum biochemistry, histology, immunohistochemistry, and gene expression analysis. RESULTS iMSC-EVs promoted the growth of renal epithelial cell (HK-2) and enhanced the survival of HK-2 undergoing cisplatin-induced cell death. In cisplatin-induced mice with AKI, iMSC-EVs alleviated AKI, as shown by reduced blood nitrogen urea/creatinine and increased body weight. Also, iMSC-EVs enhanced renal tissue integrity and the number of proliferating cell nuclear antigen-positive tubules. iMSC-EVs decreased the infiltration of immune cells, reduced the expression of inflammatory genes in M1-induced THP-1 cells and enhanced capillary density in the kidney of AKI mice. Real-time quantitative polymerase chain reaction analysis showed that the expression of inflammatory genes in the kidney of AKI mice was reduced compared with that received vehicle. Immunoblotting revealed that iMSC-EVs led to a decreased protein expression of key inflammatory genes. Also, iMSC-EVs reversed the activation of ERK1/2 signaling induced by AKI. Finally, iMSC-EVs inhibited the apoptosis of HK-2 cells induced by cisplatin as well as that of renal tissue of AKI mice. CONCLUSIONS Our data suggest that iMSC-EVs have potential to become a novel, cell-free therapeutic for cisplatin-induced AKI.
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Affiliation(s)
- Sungok Hong
- Institutes of Green Bio Science and Technology, Seoul National University, Pyeongchang, Gangwon-do, South Korea
| | - Hongduk Kim
- Institutes of Green Bio Science and Technology, Seoul National University, Pyeongchang, Gangwon-do, South Korea
| | - Jimin Kim
- Brexogen Research Center, Brexogen Inc., Songpa-gu, Seoul, South Korea
| | - Soo Kim
- Brexogen Research Center, Brexogen Inc., Songpa-gu, Seoul, South Korea
| | - Tae Sub Park
- Institutes of Green Bio Science and Technology, Seoul National University, Pyeongchang, Gangwon-do, South Korea; Graduate School of International Agricultural Technology, Seoul National University, Pyeongchang, Gangwon-do, South Korea
| | - Tae Min Kim
- Institutes of Green Bio Science and Technology, Seoul National University, Pyeongchang, Gangwon-do, South Korea; Graduate School of International Agricultural Technology, Seoul National University, Pyeongchang, Gangwon-do, South Korea.
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Nørregaard R, Mutsaers HAM, Frøkiær J, Kwon TH. Obstructive nephropathy and molecular pathophysiology of renal interstitial fibrosis. Physiol Rev 2023; 103:2827-2872. [PMID: 37440209 PMCID: PMC10642920 DOI: 10.1152/physrev.00027.2022] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 07/05/2023] [Accepted: 07/09/2023] [Indexed: 07/14/2023] Open
Abstract
The kidneys play a key role in maintaining total body homeostasis. The complexity of this task is reflected in the unique architecture of the organ. Ureteral obstruction greatly affects renal physiology by altering hemodynamics, changing glomerular filtration and renal metabolism, and inducing architectural malformations of the kidney parenchyma, most importantly renal fibrosis. Persisting pathological changes lead to chronic kidney disease, which currently affects ∼10% of the global population and is one of the major causes of death worldwide. Studies on the consequences of ureteral obstruction date back to the 1800s. Even today, experimental unilateral ureteral obstruction (UUO) remains the standard model for tubulointerstitial fibrosis. However, the model has certain limitations when it comes to studying tubular injury and repair, as well as a limited potential for human translation. Nevertheless, ureteral obstruction has provided the scientific community with a wealth of knowledge on renal (patho)physiology. With the introduction of advanced omics techniques, the classical UUO model has remained relevant to this day and has been instrumental in understanding renal fibrosis at the molecular, genomic, and cellular levels. This review details key concepts and recent advances in the understanding of obstructive nephropathy, highlighting the pathophysiological hallmarks responsible for the functional and architectural changes induced by ureteral obstruction, with a special emphasis on renal fibrosis.
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Affiliation(s)
- Rikke Nørregaard
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | | | - Jørgen Frøkiær
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Tae-Hwan Kwon
- Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Taegu, Korea
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Huang W, Hong S, Zhu X, Alsaeedi MH, Tang H, Krier JD, Gandhi D, Jordan KL, Saadiq IM, Jiang Y, Eirin A, Lerman LO. Obesity Blunts the Effect of Mesenchymal Stem Cell-Derived Extracellular Vesicles. Kidney Int Rep 2023; 8:1841-1851. [PMID: 37705914 PMCID: PMC10496020 DOI: 10.1016/j.ekir.2023.06.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 06/02/2023] [Accepted: 06/12/2023] [Indexed: 09/15/2023] Open
Abstract
Introduction Mesenchymal stem/stromal cell-derived extracellular vesicles (MSC-EVs) are paracrine vectors with therapeutic functions comparable to their parent cells. However, it remains unclear if donor obesity affects their therapeutic functions. We tested the hypothesis that the curative effect of human adipose tissue-derived MSC-EVs (A-MSC-EVs) is blunted by obesity. Methods MSC-EVs were isolated by ultracentrifugation from mesenchymal stem/stromal cells (MSCs) collected from abdominal subcutaneous fat of obese and lean human subjects (obese and lean-MSC-EVs, respectively) and injected into the aorta of mice 2 weeks after renal artery stenosis (RAS) induction. Magnetic resonance imaging studies were conducted 2 weeks after MSC-EVs delivery to determine renal function. The effect of MSC-EVs on tissue injury was assessed by histology and gene expression of inflammatory factors, including interleukin (IL)-1β, IL-6, monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor alpha (TNF-α). Oxidative damage, macrophage infiltration, plasma renin, and hypoxia inducible factor-1α (HIF-1α) were also assessed. Results Tracking showed that MSC-EVs localized in the kidney tissue, including glomeruli and tubules. All MSC-EVs decreased systolic blood pressure (SBP) and plasma renin and improved the poststenotic kidney (STK) volume, but obese-MSC-EVs were less effective than lean-MSC-EVs in improving medullary hypoxia, fibrosis, and tubular injury. Lean-MSC-EVs decreased inflammation, whereas obesity attenuated this effect. Only lean-MSC-EVs decreased STK cortical HIF-1α expression. Conclusion Obesity attenuates the antihypoxia, antifibrosis, antiinflammation, and tubular repair functions of human MSC-EVs in chronic ischemic kidney disease. These observations may have implications for the self-repair potency of obese subjects and for the use of autologous MSC-EVs in regenerative medicine.
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Affiliation(s)
- Weijun Huang
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Siting Hong
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
- Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiangyang Zhu
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | - Mina H. Alsaeedi
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | - Hui Tang
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | - James D. Krier
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | - Deep Gandhi
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | - Kyra L. Jordan
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | - Ishran M. Saadiq
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | - Yamei Jiang
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | - Alfonso Eirin
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | - Lilach O. Lerman
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
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Kosanović M, Milutinović B, Kutzner TJ, Mouloud Y, Bozic M. Clinical Prospect of Mesenchymal Stromal/Stem Cell-Derived Extracellular Vesicles in Kidney Disease: Challenges and the Way Forward. Pharmaceutics 2023; 15:1911. [PMID: 37514097 PMCID: PMC10384614 DOI: 10.3390/pharmaceutics15071911] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 06/23/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023] Open
Abstract
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.
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Affiliation(s)
- Maja Kosanović
- Institute for the Application of Nuclear Energy (INEP), University of Belgrade, 11 000 Belgrade, Serbia
| | - Bojana Milutinović
- Department of Neurosurgery, MD Anderson Cancer Center, University of Texas, Houston, TX 770302, USA
| | - Tanja J Kutzner
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, 45355 Essen, North Rhine-Westhpalia, Germany
| | - Yanis Mouloud
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, 45355 Essen, North Rhine-Westhpalia, Germany
| | - Milica Bozic
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, 45355 Essen, North Rhine-Westhpalia, Germany
- Vascular and Renal Translational Research Group, Biomedical Research Institute of Lleida Dr. Pifarré Foundation (IRBLLEIDA), 25196 Lleida, Spain
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10
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Ceccotti E, Saccu G, Herrera Sanchez MB, Bruno S. Naïve or Engineered Extracellular Vesicles from Different Cell Sources: Therapeutic Tools for Kidney Diseases. Pharmaceutics 2023; 15:1715. [PMID: 37376163 DOI: 10.3390/pharmaceutics15061715] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 06/09/2023] [Accepted: 06/10/2023] [Indexed: 06/29/2023] Open
Abstract
Renal pathophysiology is a multifactorial process involving different kidney structures. Acute kidney injury (AKI) is a clinical condition characterized by tubular necrosis and glomerular hyperfiltration. The maladaptive repair after AKI predisposes to the onset of chronic kidney diseases (CKD). CKD is a progressive and irreversible loss of kidney function, characterized by fibrosis that could lead to end stage renal disease. In this review we provide a comprehensive overview of the most recent scientific publications analyzing the therapeutic potential of Extracellular Vesicles (EV)-based treatments in different animal models of AKI and CKD. EVs from multiple sources act as paracrine effectors involved in cell-cell communication with pro-generative and low immunogenic properties. They represent innovative and promising natural drug delivery vehicles used to treat experimental acute and chronic kidney diseases. Differently from synthetic systems, EVs can cross biological barriers and deliver biomolecules to the recipient cells inducing a physiological response. Moreover, new methods for improving the EVs as carriers have been introduced, such as the engineering of the cargo, the modification of the proteins on the external membrane, or the pre-conditioning of the cell of origin. The new nano-medicine approaches based on bioengineered EVs are an attempt to enhance their drug delivery capacity for potential clinical applications.
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Affiliation(s)
- Elena Ceccotti
- Department of Medical Sciences, University of Torino, 10126 Torino, Italy
| | - Gabriele Saccu
- Department of Medical Sciences, University of Torino, 10126 Torino, Italy
- Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy
| | - Maria Beatriz Herrera Sanchez
- Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy
- 2i3T, Società per la Gestione dell'incubatore di Imprese e per il Trasferimento Tecnologico, University of Torino, 10126 Torino, Italy
| | - Stefania Bruno
- Department of Medical Sciences, University of Torino, 10126 Torino, Italy
- Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy
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11
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Karnas E, Dudek P, Zuba-Surma EK. Stem cell- derived extracellular vesicles as new tools in regenerative medicine - Immunomodulatory role and future perspectives. Front Immunol 2023; 14:1120175. [PMID: 36761725 PMCID: PMC9902918 DOI: 10.3389/fimmu.2023.1120175] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 01/11/2023] [Indexed: 01/25/2023] Open
Abstract
In the last few decades, the practical use of stem cells (SCs) in the clinic has attracted significant attention in the regenerative medicine due to the ability of these cells to proliferate and differentiate into other cell types. However, recent findings have demonstrated that the therapeutic capacity of SCs may also be mediated by their ability to secrete biologically active factors, including extracellular vesicles (EVs). Such submicron circular membrane-enveloped vesicles may be released from the cell surface and harbour bioactive cargo in the form of proteins, lipids, mRNA, miRNA, and other regulatory factors. Notably, growing evidence has indicated that EVs may transfer their bioactive content into recipient cells and greatly modulate their functional fate. Thus, they have been recently envisioned as a new class of paracrine factors in cell-to-cell communication. Importantly, EVs may modulate the activity of immune system, playing an important role in the regulation of inflammation, exhibiting broad spectrum of the immunomodulatory activity that promotes the transition from pro-inflammatory to pro-regenerative environment in the site of tissue injury. Consequently, growing interest is placed on attempts to utilize EVs in clinical applications of inflammatory-related dysfunctions as potential next-generation therapeutic factors, alternative to cell-based approaches. In this review we will discuss the current knowledge on the biological properties of SC-derived EVs, with special focus on their role in the regulation of inflammatory response. We will also address recent findings on the immunomodulatory and pro-regenerative activity of EVs in several disease models, including in vitro and in vivo preclinical, as well as clinical studies. Finally, we will highlight the current perspectives and future challenges of emerging EV-based therapeutic strategies of inflammation-related diseases treatment.
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12
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Torrico S, Hotter G, Játiva S. Development of Cell Therapies for Renal Disease and Regenerative Medicine. Int J Mol Sci 2022; 23:ijms232415943. [PMID: 36555585 PMCID: PMC9783572 DOI: 10.3390/ijms232415943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/12/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022] Open
Abstract
The incidence of renal disease is gradually increasing worldwide, and this condition has become a major public health problem because it is a trigger for many other chronic diseases. Cell therapies using multipotent mesenchymal stromal cells, hematopoietic stem cells, macrophages, and other cell types have been used to induce regeneration and provide a cure for acute and chronic kidney disease in experimental models. This review describes the advances in cell therapy protocols applied to acute and chronic kidney injuries and the attempts to apply these treatments in a clinical setting.
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Affiliation(s)
- Selene Torrico
- M2rlab-XCELL, 28010 Madrid, Spain
- Department of Experimental Pathology, Instituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Científicas Institut d’Investigacions Biomèdiques August Pi i Sunyer (IIBB-CSIC-IDIBAPS), 08036 Barcelona, Spain
- Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, 08028 Barcelona, Spain
| | - Georgina Hotter
- Department of Experimental Pathology, Instituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Científicas Institut d’Investigacions Biomèdiques August Pi i Sunyer (IIBB-CSIC-IDIBAPS), 08036 Barcelona, Spain
- CIBER-BBN, Networking Center on Bioengineering, Biomaterials and Nanomedicine, 50018 Zaragoza, Spain
- Correspondence: (G.H.); (S.J.)
| | - Soraya Játiva
- M2rlab-XCELL, 28010 Madrid, Spain
- Department of Experimental Pathology, Instituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Científicas Institut d’Investigacions Biomèdiques August Pi i Sunyer (IIBB-CSIC-IDIBAPS), 08036 Barcelona, Spain
- Correspondence: (G.H.); (S.J.)
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13
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Sanz-Ros J, Mas-Bargues C, Romero-García N, Huete-Acevedo J, Dromant M, Borrás C. Therapeutic Potential of Extracellular Vesicles in Aging and Age-Related Diseases. Int J Mol Sci 2022; 23:ijms232314632. [PMID: 36498960 PMCID: PMC9735639 DOI: 10.3390/ijms232314632] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 11/21/2022] [Accepted: 11/22/2022] [Indexed: 11/25/2022] Open
Abstract
Aging is associated with an alteration of intercellular communication. These changes in the extracellular environment contribute to the aging phenotype and have been linked to different aging-related diseases. Extracellular vesicles (EVs) are factors that mediate the transmission of signaling molecules between cells. In the aging field, these EVs have been shown to regulate important aging processes, such as oxidative stress or senescence, both in vivo and in vitro. EVs from healthy cells, particularly those coming from stem cells (SCs), have been described as potential effectors of the regenerative potential of SCs. Many studies with different animal models have shown promising results in the field of regenerative medicine. EVs are now viewed as a potential cell-free therapy for tissue damage and several diseases. Here we propose EVs as regulators of the aging process, with an important role in tissue regeneration and a raising therapy for age-related diseases.
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Affiliation(s)
- Jorge Sanz-Ros
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), INCLIVA, 46010 Valencia, Spain
- Cardiology Department, Hospital Universitari i Politècnic La Fe, 46026 Valencia, Spain
| | - Cristina Mas-Bargues
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), INCLIVA, 46010 Valencia, Spain
| | - Nekane Romero-García
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), INCLIVA, 46010 Valencia, Spain
| | - Javier Huete-Acevedo
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), INCLIVA, 46010 Valencia, Spain
| | - Mar Dromant
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), INCLIVA, 46010 Valencia, Spain
| | - Consuelo Borrás
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), INCLIVA, 46010 Valencia, Spain
- Correspondence:
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14
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Huang W, Zhu XY, Lerman A, Lerman LO. Extracellular Vesicles as Theranostic Tools in Kidney Disease. Clin J Am Soc Nephrol 2022; 17:1418-1429. [PMID: 35260417 PMCID: PMC9625088 DOI: 10.2215/cjn.16751221] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Extracellular vesicles are important vectors for cell-cell communication and show potential value for diagnosis and treatment of kidney diseases. The pathologic diagnosis of kidney diseases relies on kidney biopsy, whereas collection of extracellular vesicles from urine or circulating blood may constitute a less invasive diagnostic tool. In particular, urinary extracellular vesicles released mainly from resident kidney cells might provide an alternative tool for detection of kidney injury. Because extracellular vesicles mirror many features of their parent cells, cargoes of several populations of urinary extracellular vesicles are promising biomarkers for disease processes, like diabetic kidney disease, kidney transplant, and lupus nephritis. Contrarily, extracellular vesicles derived from reparative cells, such as mesenchymal stem cells, tubular epithelial progenitor cells, and human umbilical cord blood represent promising regenerative tools for treatment of kidney diseases. Furthermore, induced pluripotent stem cells-derived and engineered extracellular vesicles are being developed for specific applications for the kidney. Nevertheless, some assumptions regarding the specificity and immunogenicity of extracellular vesicles remain to be established. This review focuses on the utility of extracellular vesicles as therapeutic and diagnostic (theranostic) tools in kidney diseases and future directions for studies.
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Affiliation(s)
- Weijun Huang
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
- Key Laboratory of Chinese Internal Medicine of the Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Xiang-Yang Zhu
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - Amir Lerman
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota
| | - Lilach O. Lerman
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
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15
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Ahrabi B, Abbaszadeh HA, Piryaei A, Shekari F, Ahmady Roozbahany N, Rouhollahi M, Azam Sayahpour F, Ahrabi M, Azimi H, Moghadasali R. Autophagy-induced mesenchymal stem cell-derived extracellular vesicles ameliorated renal fibrosis in an in vitro model. BIOIMPACTS : BI 2022; 13:359-372. [PMID: 37736337 PMCID: PMC10509741 DOI: 10.34172/bi.2022.24256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 06/20/2022] [Accepted: 06/28/2022] [Indexed: 09/23/2023]
Abstract
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.
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Affiliation(s)
- Behnaz Ahrabi
- Department of Biology and Anatomical Sciences, school of medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Laser Applications in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hojjat Allah Abbaszadeh
- Department of Biology and Anatomical Sciences, school of medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Laser Applications in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Hearing Disorders Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abbas Piryaei
- Department of Biology and Anatomical Sciences, school of medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Faezeh Shekari
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Advanced Therapy Medicinal Product Technology Development Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research, Tehran, Iran
| | | | - Mahya Rouhollahi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Forough Azam Sayahpour
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Mahnaz Ahrabi
- Department of Endodontics, Dental Faculty, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hadi Azimi
- Department of English Language Teaching, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reza Moghadasali
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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16
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Mesenchymal Stem Cells Alleviate Renal Fibrosis and Inhibit Autophagy via Exosome Transfer of miRNA-122a. Stem Cells Int 2022; 2022:1981798. [PMID: 35859725 PMCID: PMC9289760 DOI: 10.1155/2022/1981798] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 06/10/2022] [Indexed: 11/18/2022] Open
Abstract
Exosomes derived from mesenchymal stem cell (MSC) alleviate kidney damage through autophagy. This study determined whether MSCs relieve renal fibrosis and inhibit autophagy by exosome transfer of miRNA-122a. The gene expression involved in the mTOR signaling pathway and autophagy was assessed in TGF-β1-treated human renal tubular epithelial cells (HK-2) and unilateral ureteral obstruction (UUO) mice before and after MSC-derived exosomes and miRNA-122a mimic treatment. Small RNA (sRNA) next-generation sequencing was also performed on TGF-β1-treated HK-2 cells. MSC-derived exosomes relieve fibrosis caused by TGFβ in HK-2 via regulation of the mTOR signaling pathway and downstream autophagy. Furthermore, we found that MSC-derived exosomes mediate miRNA-122a to relieve renal fibrosis in HK-2 cells in response to TGF-β1 through the regulation of mTOR signaling and autophagy. In the UUO mouse model, miRNA-122a mimic-transfected MSC treatment and its combination with 3-MA both recapitulated the same results as the in vitro experiments, along with reduced expansion of renal tubule, interstitial expansion, and preservation of kidney architecture. The antifibrotic activity of MSC-derived exosomes after renal fibrosis occurs partially by autophagy suppression via excreted exosomes containing mainly miRNA-122a. These findings indicate that the export of miRNA-122a via MSC-derived exosomes represents a novel strategy to alleviate renal fibrosis.
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17
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Abstract
Extracellular vesicles are released by the majority of cell types and circulate in body fluids. They function as a long-distance cell-to-cell communication mechanism that modulates the gene expression profile and fate of target cells. Increasing evidence has established a central role of extracellular vesicles in kidney physiology and pathology. Urinary extracellular vesicles mediate crosstalk between glomerular and tubular cells and between different segments of the tubule, whereas circulating extracellular vesicles mediate organ crosstalk and are involved in the amplification of kidney damage and inflammation. The molecular profile of extracellular vesicles reflects the type and pathophysiological status of the originating cell so could potentially be exploited for diagnostic and prognostic purposes. In addition, robust preclinical data suggest that administration of exogenous extracellular vesicles could promote kidney regeneration and reduce inflammation and fibrosis in acute and chronic kidney diseases. Stem cells are thought to be the most promising source of extracellular vesicles with regenerative activity. Extracellular vesicles are also attractive candidates for drug delivery and various engineering strategies are being investigated to alter their cargo and increase their efficacy. However, rigorous standardization and scalable production strategies will be necessary to enable the clinical application of extracellular vesicles as potential therapeutics. In this Review, the authors discuss the roles of extracellular vesicles in kidney physiology and disease as well as the beneficial effects of stem cell-derived extracellular vesicles in preclinical models of acute kidney injury and chronic kidney disease. They also highlight current and future clinical applications of extracellular vesicles in kidney diseases.
Urinary extracellular vesicles have roles in intra-glomerular, glomerulo-tubular and intra-tubular crosstalk, whereas circulating extracellular vesicles might mediate organ crosstalk; these mechanisms could amplify kidney damage and contribute to disease progression. Urinary extracellular vesicles could potentially be analysed using multiplex diagnostic platforms to identify pathological processes and the originating cell types; technological advances including single extracellular vesicle analysis might increase the specificity of bulk analysis of extracellular vesicle preparations. Robust standardization and validation in large patient cohorts are required to enable clinical application of extracellular vesicle-based biomarkers. Stem cell-derived extracellular vesicles have been shown to improve renal recovery, limit progression of injury and reduce fibrosis in animal models of acute kidney injury and chronic kidney disease. Various engineering approaches can be used to load extracellular vesicles with therapeutic molecules and increase their delivery to the kidney. A small clinical trial that tested the efficacy of mesenchymal stem cell extracellular vesicle administration in patients with chronic kidney disease reported promising results; however, therapeutic application of extracellular vesicles is limited by a lack of scalable manufacturing protocols and clear criteria for standardization.
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18
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Ghorbani F, Movassaghpour AA, Talebi M, Yousefi M, Abbaszadeh H. Renoprotective effects of extracellular vesicles: A systematic review. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2021.101491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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19
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Extracellular Vesicles Derived from Human Liver Stem Cells Attenuate Chronic Kidney Disease Development in an In Vivo Experimental Model of Renal Ischemia and Reperfusion Injury. Int J Mol Sci 2022; 23:ijms23031485. [PMID: 35163409 PMCID: PMC8835844 DOI: 10.3390/ijms23031485] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 01/14/2022] [Accepted: 01/25/2022] [Indexed: 12/14/2022] Open
Abstract
The potential therapeutic effect of extracellular vesicles (EVs) that are derived from human liver stem cells (HLSCs) has been tested in an in vivo model of renal ischemia and reperfusion injury (IRI), that induce the development of chronic kidney disease (CKD). EVs were administered intravenously immediately after the IRI and three days later, then their effect was tested at different time points to evaluate how EV-treatment might interfere with fibrosis development. In IRI-mice that were sacrificed two months after the injury, EV- treatment decreased the development of interstitial fibrosis at the histological and molecular levels. Furthermore, the expression levels of pro-inflammatory genes and of epithelial-mesenchymal transition (EMT) genes were significantly reverted by EV-treatment. In IRI-mice that were sacrificed at early time points (two and three days after the injury), functional and histological analyses showed that EV-treatment induced an amelioration of the acute kidney injury (AKI) that was induced by IRI. Interestingly, at the molecular level, a reduction of pro-fibrotic and EMT-genes in sacrificed IRI-mice was observed at days two and three after the injury. These data indicate that in renal IRI, treatment with HLSC-derived EVs improves AKI and interferes with the development of subsequent CKD by modulating the genes that are involved in fibrosis and EMT.
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20
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Human Liver Stem Cell Derived Extracellular Vesicles Alleviate Kidney Fibrosis by Interfering with the β-Catenin Pathway through miR29b. Int J Mol Sci 2021; 22:ijms221910780. [PMID: 34639119 PMCID: PMC8509541 DOI: 10.3390/ijms221910780] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 09/29/2021] [Accepted: 10/02/2021] [Indexed: 02/07/2023] Open
Abstract
Human liver stem-cell-derived extracellular vesicles (HLSC-EVs) exhibit therapeutic properties in various pre-clinical models of kidney injury. We previously reported an overall improvement in kidney function following treatment with HLSC-EVs in a model of aristolochic acid nephropathy (AAN). Here, we provide evidence that HLSC-EVs exert anti-fibrotic effects by interfering with β-catenin signalling. A mouse model of AAN and an in vitro pro-fibrotic model were used. The β-catenin mRNA and protein expression, together with the pro-fibrotic markers α-SMA and collagen 1, were evaluated in vivo and in vitro following treatment with HLSC-EVs. Expression and functional analysis of miR29b was performed in vitro following HLSC-EV treatments through loss-of-function experiments. Results showed that expression of β-catenin was amplified both in vivo and in vitro, and β-catenin gene silencing in fibroblasts prevented AA-induced up-regulation of pro-fibrotic genes, revealing that β-catenin is an important factor in fibroblast activation. Treatment with HLSC-EVs caused increased expression of miR29b, which was significantly inhibited in the presence of α-amanitin. The suppression of the miR29b function with a selective inhibitor abolished the anti-fibrotic effects of HLSC-EVs, resulting in the up-regulation of β-catenin and pro-fibrotic α-Sma and collagen type 1 genes. Together, these data suggest a novel HLSC-EV-dependent regulatory mechanism in which β-catenin is down regulated by HLSC-EVs-induced miR29b expression.
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21
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Maanaoui M, Kerr-Conte J. Pushing the boundaries of organs before it's too late: pre-emptive regeneration. Transpl Int 2021; 34:1761-1769. [PMID: 34532871 DOI: 10.1111/tri.13969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 07/05/2021] [Accepted: 07/06/2021] [Indexed: 11/28/2022]
Abstract
Solid organ transplantation is marked by accelerated aging and inexorable fibrosis. It is crucial to promote strategies to attenuate, or to reverse, damage before organ failure. Hence, the objective of this article is to provide insight into strategies, which aim to regenerate or rejuvenate the transplanted organs. Cell therapy with mesenchymal stromal cells is currently under investigation because of their antifibrotic properties. Their ability to promote mitochondrial biogenesis, and to transfer mitochondria to wounded cells, is another approach to boost the organ regeneration. Other teams have investigated bioengineered organs, which consists of decellularization of the damaged organ followed by recellularization. Lastly, the development of CAR-T cell-based technologies may revolutionize the field of transplantation, as recent preclinical studies showed that CAR-T cells could efficiently clear senescent cells from an organ and reverse fibrosis. Ultimately, these cutting-edge strategies may bring the holy grail of a pre-emptive regenerated organ closer to reality.
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Affiliation(s)
- Mehdi Maanaoui
- Department of Nephrology, CHU Lille, Lille, France.,Inserm, CHU Lille, Institut Pasteur Lille, U1190 - EGID, Univ. Lille, Lille, France
| | - Julie Kerr-Conte
- Inserm, CHU Lille, Institut Pasteur Lille, U1190 - EGID, Univ. Lille, Lille, France
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22
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Moghadasi S, Elveny M, Rahman HS, Suksatan W, Jalil AT, Abdelbasset WK, Yumashev AV, Shariatzadeh S, Motavalli R, Behzad F, Marofi F, Hassanzadeh A, Pathak Y, Jarahian M. A paradigm shift in cell-free approach: the emerging role of MSCs-derived exosomes in regenerative medicine. J Transl Med 2021; 19:302. [PMID: 34253242 PMCID: PMC8273572 DOI: 10.1186/s12967-021-02980-6] [Citation(s) in RCA: 129] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 07/06/2021] [Indexed: 12/17/2022] Open
Abstract
Recently, mesenchymal stem/stromal cells (MSCs) due to their pro-angiogenic, anti-apoptotic, and immunoregulatory competencies along with fewer ethical issues are presented as a rational strategy for regenerative medicine. Current reports have signified that the pleiotropic effects of MSCs are not related to their differentiation potentials, but rather are exerted through the release of soluble paracrine molecules. Being nano-sized, non-toxic, biocompatible, barely immunogenic, and owning targeting capability and organotropism, exosomes are considered nanocarriers for their possible use in diagnosis and therapy. Exosomes convey functional molecules such as long non-coding RNAs (lncRNAs) and micro-RNAs (miRNAs), proteins (e.g., chemokine and cytokine), and lipids from MSCs to the target cells. They participate in intercellular interaction procedures and enable the repair of damaged or diseased tissues and organs. Findings have evidenced that exosomes alone are liable for the beneficial influences of MSCs in a myriad of experimental models, suggesting that MSC- exosomes can be utilized to establish a novel cell-free therapeutic strategy for the treatment of varied human disorders, encompassing myocardial infarction (MI), CNS-related disorders, musculoskeletal disorders (e.g. arthritis), kidney diseases, liver diseases, lung diseases, as well as cutaneous wounds. Importantly, compared with MSCs, MSC- exosomes serve more steady entities and reduced safety risks concerning the injection of live cells, such as microvasculature occlusion risk. In the current review, we will discuss the therapeutic potential of MSC- exosomes as an innovative approach in the context of regenerative medicine and highlight the recent knowledge on MSC- exosomes in translational medicine, focusing on in vivo researches.
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Affiliation(s)
- Soudeh Moghadasi
- Department of Biochemistry and Molecular Biology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Marischa Elveny
- DS & CI Research Group, Universitas Sumatera Utara, Medan, Indonesia
| | - Heshu Sulaiman Rahman
- College of Medicine, University of Sulaimani, Sulaymaniyah, Iraq
- Department of Medical Laboratory Sciences, Komar University of Science and Technology, Sulaymaniyah, Iraq
| | - Wanich Suksatan
- Faculty of Nursing, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok, 10210 Thailand
| | | | - Walid Kamal Abdelbasset
- Department of Health and Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, Al Kharj, Saudi Arabia
- Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | | | - Siavash Shariatzadeh
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Roza Motavalli
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farahnaz Behzad
- Research Institute of Bioscience and Biotechnology, University of Tabriz, Tabriz, Iran
| | - Faroogh Marofi
- Department of Hematology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Hassanzadeh
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Yashwant Pathak
- Taneja College of Pharmacy, University of South Florida, Tampa Florida, USA
| | - Mostafa Jarahian
- German Cancer Research Center, Toxicology and Chemotherapy Unit (G401), 69120 Heidelberg, Germany
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23
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Eirin A, Lerman LO. Mesenchymal Stem/Stromal Cell-Derived Extracellular Vesicles for Chronic Kidney Disease: Are We There Yet? Hypertension 2021; 78:261-269. [PMID: 34176287 DOI: 10.1161/hypertensionaha.121.14596] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Mesenchymal stem/stromal cells (MSCs) are the most utilized cell type for cellular therapy, partly due to their important proliferative potential and ability to differentiate into various cell types. MSCs produce large amounts of extracellular vesicles (EVs), which carry genetic and protein cargo to mediate MSC paracrine function. Recently, MSC-derived EVs have been successfully used in several preclinical models of chronic kidney disease. However, uncertainty remains regarding EV fate, safety, and long-term effects, which might impose important limitations on their path to clinical translation. This review discusses the therapeutic application of MSC-derived EV therapy for renal disease, with particular emphasis on potential mechanisms of kidney repair and major translational barriers. Emerging evidence indicates that the cargo of MSC-derived EVs is capable of modulating several pathways responsible for renal injury, including inflammation, oxidative stress, apoptosis, fibrosis, and microvascular remodeling. EV-induced modulation of these pathways has been associated with important renoprotective effects in experimental studies. However, scarce clinical data are available, and several challenges need to be addressed as we move toward clinical translation, including standardization of methods for EV isolation and characterization, EV fate, duration of EV effects, and effects of cardiovascular risk factors. MSC-derived EVs have the potential to preserve renal structure and function, but further experimental and clinical evidence is needed to confirm their protective effects in patients with chronic kidney disease.
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Affiliation(s)
- Alfonso Eirin
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN
| | - Lilach O Lerman
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN
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Mesenchymal Stem Cell-Derived Extracellular Vesicles to the Rescue of Renal Injury. Int J Mol Sci 2021; 22:ijms22126596. [PMID: 34202940 PMCID: PMC8235408 DOI: 10.3390/ijms22126596] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 06/09/2021] [Accepted: 06/16/2021] [Indexed: 12/14/2022] Open
Abstract
Acute kidney injury (AKI) and chronic kidney disease (CKD) are rising in global prevalence and cause significant morbidity for patients. Current treatments are limited to slowing instead of stabilising or reversing disease progression. In this review, we describe mesenchymal stem cells (MSCs) and their constituents, extracellular vesicles (EVs) as being a novel therapeutic for CKD. MSC-derived EVs (MSC-EVs) are membrane-enclosed particles, including exosomes, which carry genetic information that mimics the phenotype of their cell of origin. MSC-EVs deliver their cargo of mRNA, miRNA, cytokines, and growth factors to target cells as a form of paracrine communication. This genetically reprograms pathophysiological pathways, which are upregulated in renal failure. Since the method of exosome preparation significantly affects the quality and function of MSC-exosomes, this review compares the methodologies for isolating exosomes from MSCs and their role in tissue regeneration. More specifically, it summarises the therapeutic efficacy of MSC-EVs in 60 preclinical animal models of AKI and CKD and the cargo of biomolecules they deliver. MSC-EVs promote tubular proliferation and angiogenesis, and inhibit apoptosis, oxidative stress, inflammation, the epithelial-to-mesenchymal transition, and fibrosis, to alleviate AKI and CKD. By reprogramming these pathophysiological pathways, MSC-EVs can slow or even reverse the progression of AKI to CKD, and therefore offer potential to transform clinical practice.
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25
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Nowak N, Yamanouchi M, Satake E. The Nephroprotective Properties of Extracellular Vesicles in Experimental Models of Chronic Kidney Disease: a Systematic Review. Stem Cell Rev Rep 2021; 18:902-932. [PMID: 34110587 PMCID: PMC8942930 DOI: 10.1007/s12015-021-10189-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/17/2021] [Indexed: 01/14/2023]
Abstract
Extracellular vesicle (EV)-based therapy was hypothesized as a promising regenerative approach which has led to intensive research of EVs in various pathologies. In this study, we performed a comprehensive systematic review of the current experimental evidence regarding the protective properties of EVs in chronic kidney disease (CKD). We evaluated the EV-based experiments, EV characteristics, and effector molecules with their involvement in CKD pathways. Including all animal records with available creatinine or urea data, we performed a stratified univariable meta-analysis to assess the determinants of EV-based therapy effectiveness. We identified 35 interventional studies that assessed nephroprotective role of EVs and catalogued them according to their involvement in CKD mechanism. Systematic assessment of these studies suggested that EVs had consistently improved glomerulosclerosis, interstitial fibrosis, and cell damage, among different CKD models. Moreover, EV-based therapy reduced the progression of renal decline in CKD. The stratified analyses showed that the disease model, administered dose, and time of therapeutic intervention were potential predictors of therapeutic efficacy. Together, EV therapy is a promising approach for CKD progression in experimental studies. Further standardisation of EV-methods, continuous improvement of the study quality, and better understanding of the determinants of EV effectiveness will facilitate preclinical research, and may help development of clinical trials in people with CKD.
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Affiliation(s)
- Natalia Nowak
- Faculty of Medicine, Centre for Bioinformatics and Data Analysis, Medical University of Bialystok, Bialystok, Poland.
| | - Masayuki Yamanouchi
- Department of Nephrology and Laboratory Medicine Faculty of Medicine Institute of Medical, Pharmaceutical and Health Sciences Graduate School of Medical Sciences, Kanazawa University, Toranomon Hospital, Nephrology Center, Tokyo, Japan
| | - Eiichiro Satake
- Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, MA, Boston, USA
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26
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Corrêa RR, Juncosa EM, Masereeuw R, Lindoso RS. Extracellular Vesicles as a Therapeutic Tool for Kidney Disease: Current Advances and Perspectives. Int J Mol Sci 2021; 22:ijms22115787. [PMID: 34071399 PMCID: PMC8198688 DOI: 10.3390/ijms22115787] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 05/18/2021] [Accepted: 05/18/2021] [Indexed: 12/12/2022] Open
Abstract
Extracellular vesicles (EVs) have been described as important mediators of cell communication, regulating several physiological processes, including tissue recovery and regeneration. In the kidneys, EVs derived from stem cells have been shown to support tissue recovery in diverse disease models and have been considered an interesting alternative to cell therapy. For this purpose, however, several challenges remain to be overcome, such as the requirement of a high number of EVs for human therapy and the need for optimization of techniques for their isolation and characterization. Moreover, the kidney’s complexity and the pathological process to be treated require that EVs present a heterogeneous group of molecules to be delivered. In this review, we discuss the recent advances in the use of EVs as a therapeutic tool for kidney diseases. Moreover, we give an overview of the new technologies applied to improve EVs’ efficacy, such as novel methods of EV production and isolation by means of bioreactors and microfluidics, bioengineering the EV content and the use of alternative cell sources, including kidney organoids, to support their transfer to clinical applications.
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Affiliation(s)
- Raphael Rodrigues Corrêa
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil;
| | - Estela Mancheño Juncosa
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands;
| | - Rosalinde Masereeuw
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands;
- Correspondence: (R.M.); (R.S.L.); Tel.: +31-30-253-3529 (R.M.); Tel.: +55-21-3938-6520 (R.S.L.)
| | - Rafael Soares Lindoso
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil;
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands;
- National Institute of Science and Technology for Regenerative Medicine-REGENERA, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
- Correspondence: (R.M.); (R.S.L.); Tel.: +31-30-253-3529 (R.M.); Tel.: +55-21-3938-6520 (R.S.L.)
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Lee SA, Choi C, Yoo TH. Extracellular vesicles in kidneys and their clinical potential in renal diseases. Kidney Res Clin Pract 2021; 40:194-207. [PMID: 33866768 PMCID: PMC8237124 DOI: 10.23876/j.krcp.20.209] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 01/26/2021] [Indexed: 01/08/2023] Open
Abstract
Extracellular vesicles (EVs), such as exosomes and microvesicles, are cell-derived lipid bilayer membrane particles, which deliver information from host cells to recipient cells. EVs are involved in various biological processes including the modulation of the immune response, cell-to-cell communications, thrombosis, and tissue regeneration. Different types of kidney cells are known to release EVs under physiologic as well as pathologic conditions, and recent studies have found that EVs have a pathophysiologic role in different renal diseases. Given the recent advancement in EV isolation and analysis techniques, many studies have shown the diagnostic and therapeutic potential of EVs in various renal diseases, such as acute kidney injury, polycystic kidney disease, chronic kidney disease, kidney transplantation, and renal cell carcinoma. This review updates recent clinical and experimental findings on the role of EVs in renal diseases and highlights the potential clinical applicability of EVs as novel diagnostics and therapeutics.
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Affiliation(s)
- Sul A Lee
- Department of Internal Medicine and Institute of Kidney Disease Research, Yonsei University College of Medicine, Seoul, Republic of Korea.,Department of Internal Medicine, MetroWest Medical Center, Framingham, MA, USA
| | - Chulhee Choi
- ILIAS Biologics Inc., Daejeon, Republic of Korea.,Department of Bio and Brain Engineering, KAIST, Daejeon, Republic of Korea
| | - Tae-Hyun Yoo
- Department of Internal Medicine and Institute of Kidney Disease Research, Yonsei University College of Medicine, Seoul, Republic of Korea
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Kosanović M, Llorente A, Glamočlija S, Valdivielso JM, Bozic M. Extracellular Vesicles and Renal Fibrosis: An Odyssey toward a New Therapeutic Approach. Int J Mol Sci 2021; 22:ijms22083887. [PMID: 33918699 PMCID: PMC8069044 DOI: 10.3390/ijms22083887] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/06/2021] [Accepted: 04/07/2021] [Indexed: 12/11/2022] Open
Abstract
Renal fibrosis is a complex disorder characterized by the destruction of kidney parenchyma. There is currently no cure for this devastating condition. Extracellular vesicles (EVs) are membranous vesicles released from cells in both physiological and diseased states. Given their fundamental role in transferring biomolecules to recipient cells and their ability to cross biological barriers, EVs have been widely investigated as potential cell-free therapeutic agents. In this review, we provide an overview of EVs, focusing on their functional role in renal fibrosis and signaling messengers responsible for EV-mediated crosstalk between various renal compartments. We explore recent findings regarding the renoprotective effect of EVs and their use as therapeutic agents in renal fibrosis. We also highlight advantages and future perspectives of the therapeutic applications of EVs in renal diseases.
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Affiliation(s)
- Maja Kosanović
- Institute for the Application of Nuclear Energy, INEP, University of Belgrade, 11080 Belgrade, Serbia; (M.K.); (S.G.)
| | - Alicia Llorente
- Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway;
- Department for Mechanical, Electronics and Chemical Engineering, Oslo Metropolitan University, 0167 Oslo, Norway
| | - Sofija Glamočlija
- Institute for the Application of Nuclear Energy, INEP, University of Belgrade, 11080 Belgrade, Serbia; (M.K.); (S.G.)
| | - José M. Valdivielso
- Vascular and Renal Translational Research Group, Institute for Biomedical Research in Lleida (IRBLleida) and RedInRen RETIC, 25196 Lleida, Spain;
| | - Milica Bozic
- Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway;
- Vascular and Renal Translational Research Group, Institute for Biomedical Research in Lleida (IRBLleida) and RedInRen RETIC, 25196 Lleida, Spain;
- Correspondence:
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Huang J, Kong Y, Xie C, Zhou L. Stem/progenitor cell in kidney: characteristics, homing, coordination, and maintenance. Stem Cell Res Ther 2021; 12:197. [PMID: 33743826 PMCID: PMC7981824 DOI: 10.1186/s13287-021-02266-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 03/02/2021] [Indexed: 02/06/2023] Open
Abstract
Renal failure has a high prevalence and is becoming a public health problem worldwide. However, the renal replacement therapies such as dialysis are not yet satisfactory for its multiple complications. While stem/progenitor cell-mediated tissue repair and regenerative medicine show there is light at the end of tunnel. Hence, a better understanding of the characteristics of stem/progenitor cells in kidney and their homing capacity would greatly promote the development of stem cell research and therapy in the kidney field and open a new route to explore new strategies of kidney protection. In this review, we generally summarize the main stem/progenitor cells derived from kidney in situ or originating from the circulation, especially bone marrow. We also elaborate on the kidney-specific microenvironment that allows stem/progenitor cell growth and chemotaxis, and comment on their interaction. Finally, we highlight potential strategies for improving the therapeutic effects of stem/progenitor cell-based therapy. Our review provides important clues to better understand and control the growth of stem cells in kidneys and develop new therapeutic strategies.
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Affiliation(s)
- Jiewu Huang
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave, Guangzhou, 510515, China
| | - Yaozhong Kong
- Department of Nephrology, the First People's Hospital of Foshan, Foshan, Guangdong, China
| | - Chao Xie
- Department of Nephrology, the First People's Hospital of Foshan, Foshan, Guangdong, China
| | - Lili Zhou
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave, Guangzhou, 510515, China. .,Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China.
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Fuloria S, Subramaniyan V, Dahiya R, Dahiya S, Sudhakar K, Kumari U, Sathasivam K, Meenakshi DU, Wu YS, Sekar M, Malviya R, Singh A, Fuloria NK. Mesenchymal Stem Cell-Derived Extracellular Vesicles: Regenerative Potential and Challenges. BIOLOGY 2021; 10:172. [PMID: 33668707 PMCID: PMC7996168 DOI: 10.3390/biology10030172] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 02/09/2021] [Accepted: 02/19/2021] [Indexed: 02/07/2023]
Abstract
Evidence suggests that stem cells exert regenerative potential via the release of extracellular vesicles. Mesenchymal stem cell extracellular vesicles (MSCEVs) offer therapeutic benefits for various pathophysiological ailments by restoring tissues. Facts suggest that MSCEV action can be potentiated by modifying the mesenchymal stem cells culturing methodology and bioengineering EVs. Limited clinical trials of MSCEVs have questioned their superiority, culturing quality, production scale-up and isolation, and administration format. Translation of preclinically successful MSCEVs into a clinical platform requires paying attention to several critical matters, such as the production technique, quantification/characterization, pharmacokinetics/targeting/transfer to the target site, and the safety profile. Keeping these issues as a priority, the present review was designed to highlight the challenges in translating preclinical MSCEV research into clinical platforms and provide evidence for the regenerative potential of MSCEVs in various conditions of the liver, kidney, heart, nervous system, bone, muscle, cartilage, and other organs/tissues.
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Affiliation(s)
| | - Vetriselvan Subramaniyan
- Faculty of Medicine, Bioscience and Nursing, MAHSA University, Kuala Lumpur 42610, Malaysia; (V.S.); (Y.S.W.)
| | - Rajiv Dahiya
- School of Pharmacy, Faculty of Medical Sciences, The University of the West Indies, St. Augustine, Trinidad and Tobago;
| | - Sunita Dahiya
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Puerto Rico, Medical Sciences Campus, San Juan, PR 00936, USA;
| | - Kalvatala Sudhakar
- School of Pharmaceutical Sciences (LIT-Pharmacy), Lovely Professional University, Jalandhar 144411, India;
| | - Usha Kumari
- Faculty of Medicine, AIMST University, Kedah 08100, Malaysia;
| | | | | | - Yuan Seng Wu
- Faculty of Medicine, Bioscience and Nursing, MAHSA University, Kuala Lumpur 42610, Malaysia; (V.S.); (Y.S.W.)
| | - Mahendran Sekar
- Faculty of Pharmacy and Health Sciences, Universiti Kuala Lumpur Royal College of Medicine Perak, Ipoh 30450, Malaysia;
| | - Rishabha Malviya
- Department of Pharmacy, SMAS, Galgotias University, Greater Noida 203201, India; (R.M.); (A.S.)
| | - Amit Singh
- Department of Pharmacy, SMAS, Galgotias University, Greater Noida 203201, India; (R.M.); (A.S.)
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Sun B, Zhai S, Zhang L, Sun G. The role of extracellular vesicles in podocyte autophagy in kidney disease. J Cell Commun Signal 2021; 15:299-316. [PMID: 33619681 DOI: 10.1007/s12079-020-00594-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 11/02/2020] [Indexed: 02/06/2023] Open
Abstract
Podocytes are the key cells involved in protein filtration in the glomerulus. Once proteins appear in the urine when podocytes fail, patients will end with renal failure due to the progression of glomerular damage if no proper treatment is applied. The injury and loss of podocytes can be attributed to diverse factors, such as genetic, immunologic, toxic, or metabolic disorders. Recently, autophagy has emerged as a key mechanism to eliminate the unwanted cytoplasmic materials and to prolong the lifespan of podocytes by alleviating cell damage and stress. Typically, the fundamental function of extracellular vesicles (EVs) is to mediate the intercellular communication. Recent studies have suggested that, EVs, especially exosomes, play a certain role in information transfer by communicating proteins, mRNAs, and microRNAs with recipient cells. Under physiological and pathological conditions, EVs assist in the bioinformation interchange between kidneys and other organs. It is suggested that EVs are related to the pathogenesis of acute kidney injury and chronic kidney disease, including glomerular disease, diabetic nephropathy, renal fibrosis and end-stage renal disease. However, the role of EVs in podocyte autophagy remains unclear so far. Here, this study integrated the existing information about the relevancy, diagnostic value and therapeutic potential of EVs in a variety of podocytes-related diseases. The accumulating evidence highlighted that autophagy played a critical role in the homeostasis of podocytes in glomerular disease.
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Affiliation(s)
- Baichao Sun
- Department of Nephrology, The Second Hospital of Jilin University, 218 ZiQiang Street, Changchun, 130041, Jilin, People's Republic of China.,Department of Pediatric Nephrology, The First Hospital of Jilin University, Changchun, 130021, Jilin, People's Republic of China
| | - Shubo Zhai
- Department of Pediatric Nephrology, The First Hospital of Jilin University, Changchun, 130021, Jilin, People's Republic of China
| | - Li Zhang
- Department of Pediatric Nephrology, The First Hospital of Jilin University, Changchun, 130021, Jilin, People's Republic of China
| | - Guangdong Sun
- Department of Nephrology, The Second Hospital of Jilin University, 218 ZiQiang Street, Changchun, 130041, Jilin, People's Republic of China.
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Micro-vesicles from mesenchymal stem cells over-expressing miR-34a inhibit transforming growth factor-β1-induced epithelial-mesenchymal transition in renal tubular epithelial cells in vitro. Chin Med J (Engl) 2021; 133:800-807. [PMID: 32149762 PMCID: PMC7147664 DOI: 10.1097/cm9.0000000000000720] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND The use of microRNAs in the therapy of kidney disease is hampered by the difficulties in their effective delivery. Micro-vesicles (MVs) are known as natural carriers of small RNAs. Our prior research has demonstrated that MVs isolated from mesenchymal stem cells (MSCs) are capable of attenuating kidney injuries induced by unilateral ureteral obstruction and 5/6 sub-total nephrectomy in mice. The present study aimed to evaluate the effects of miR-34a-5p (miR-34a)-modified MSC-MVs on transforming growth factor (TGF)-β1-induced fibrosis and apoptosis in vitro. METHODS Bone marrow MSCs were modified by lentiviruses over-expressing miR-34a, from which MVs were collected for the treatment of human Kidney-2 (HK-2) renal tubular cells exposed to TGF-β1 (6 ng/mL). The survival of HK-2 cells was determined using 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) and Annexin V-Light 650/propidium iodide (PI) assays. The expression levels of epithelial markers (tight junction protein 1 [TJP1] and E-cadherin) and mesenchymal markers (smooth muscle actin alpha (α-SMA) and fibronectin) in HK-2 cells were measured using Western blot analysis and an immunofluorescence assay. In addition, changes in Notch-1/Jagged-1 signaling were analyzed using Western blotting. Data were analyzed using a Student's t test or one-way analysis of variance. RESULTS MiR-34a expression increased three-fold in MVs generated by miR-34a-modified MSCs compared with that expressed in control MVs (P < 0.01, t = 16.55). In HK-2 cells, TJP1 and E-cadherin levels decreased to 31% and 37% after treatment with TGF-β1, respectively, and were restored to 62% and 70% by miR-34a-enriched MSC-MVs, respectively. The expression of α-SMA and fibronectin increased by 3.9- and 5.0-fold following TGF-β1 treatment, and decreased to 2.0- and 1.7-fold after treatment of HK-2 cells with miR-34a-enriched MSC-MVs. The effects of miR-34a-enriched MSC-MVs on epithelial-mesenchymal transition (EMT) markers were stronger than control MSC-MVs. The effects of miR-34a-enriched MSC-MVs on these EMT markers were stronger than control MSC-MVs. Notch-1 receptor and Jagged-1 ligand, two major molecules of Notch signaling pathway, are predicted targets of miR-34a. It was further observed that elevation of Notch-1 and Jagged-1 induced by TGF-β1 was inhibited by miR-34a-enriched MSC-MVs. In addition, TGF-β1 exposure also induced apoptosis in HK-2 cells. Although miR-34a-mofidied MSC-MVs were able to inhibit TGF-β1-triggered apoptosis in HK-2 cells, the effects were less significant than control MSC-MVs (control:TGF-β1: miR-nc-MV:miR-34a-MV = 1.3:0.6:1.1:0.9 for MTT assay, 1.8%:23.3%:9.4%:17.4% for apoptosis assay). This phenomenon may be the result of the pro-apoptotic effects of miR-34a. CONCLUSIONS The present study demonstrated that miR-34a-over-expressing MSC-MVs inhibit EMT induced by pro-fibrotic TGF-β1 in renal tubular epithelial cells, possibly through inhibition of the Jagged-1/Notch-1 pathway. Genetic modification of MSC-MVs with an anti-fibrotic molecule may represent a novel strategy for the treatment of renal injuries.
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Yaker L, Kamel S, Ausseil J, Boullier A. Effects of Chronic Kidney Disease and Uremic Toxins on Extracellular Vesicle Biology. Toxins (Basel) 2020; 12:toxins12120811. [PMID: 33371311 PMCID: PMC7767379 DOI: 10.3390/toxins12120811] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 12/02/2020] [Accepted: 12/16/2020] [Indexed: 12/28/2022] Open
Abstract
Vascular calcification (VC) is a cardiovascular complication associated with a high mortality rate, especially in patients with diabetes, atherosclerosis or chronic kidney disease (CKD). In CKD patients, VC is associated with the accumulation of uremic toxins, such as indoxyl sulphate or inorganic phosphate, which can have a major impact in vascular remodeling. During VC, vascular smooth muscle cells (VSMCs) undergo an osteogenic switch and secrete extracellular vesicles (EVs) that are heterogeneous in terms of their origin and composition. Under physiological conditions, EVs are involved in cell-cell communication and the maintenance of cellular homeostasis. They contain high levels of calcification inhibitors, such as fetuin-A and matrix Gla protein. Under pathological conditions (and particularly in the presence of uremic toxins), the secreted EVs acquire a pro-calcifying profile and thereby act as nucleating foci for the crystallization of hydroxyapatite and the propagation of calcification. Here, we review the most recent findings on the EVs’ pathophysiological role in VC, the impact of uremic toxins on EV biogenesis and functions, the use of EVs as diagnostic biomarkers and the EVs’ therapeutic potential in CKD.
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Affiliation(s)
- Linda Yaker
- MP3CV-UR7517, CURS-Université de Picardie Jules Verne, Avenue de la Croix Jourdain, F-80054 Amiens, France; (L.Y.); (S.K.)
| | - Saïd Kamel
- MP3CV-UR7517, CURS-Université de Picardie Jules Verne, Avenue de la Croix Jourdain, F-80054 Amiens, France; (L.Y.); (S.K.)
- Laboratoire de Biochimie CHU Amiens-Picardie, Avenue de la Croix Jourdain, F-80054 Amiens, France
| | - Jérôme Ausseil
- INSERM UMR1043, CNRS UMR5282, University of Toulouse III, F-31024 Toulouse, France;
- CHU PURPAN—Institut Fédératif de Biologie, Laboratoire de Biochimie, Avenue de Grande Bretagne, F-31059 Toulouse, France
| | - Agnès Boullier
- MP3CV-UR7517, CURS-Université de Picardie Jules Verne, Avenue de la Croix Jourdain, F-80054 Amiens, France; (L.Y.); (S.K.)
- Laboratoire de Biochimie CHU Amiens-Picardie, Avenue de la Croix Jourdain, F-80054 Amiens, France
- Correspondence: ; Tel.: +33-322087019
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Metabolic Syndrome Alters the Cargo of Mitochondria-Related microRNAs in Swine Mesenchymal Stem Cell-Derived Extracellular Vesicles, Impairing Their Capacity to Repair the Stenotic Kidney. Stem Cells Int 2020; 2020:8845635. [PMID: 33281903 PMCID: PMC7685840 DOI: 10.1155/2020/8845635] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 10/27/2020] [Accepted: 10/29/2020] [Indexed: 02/06/2023] Open
Abstract
Background Coexisting metabolic syndrome (MetS) and renal artery stenosis (RAS) are linked to poor renal outcomes. Mesenchymal stem/stromal cell- (MSC-) derived extracellular vesicles (EVs) from lean animals show superior ability to repair the experimental MetS+RAS kidney compared to EVs from MetS pig MSCs. We hypothesized that MetS leads to selective packaging in porcine EVs of microRNAs capable of targeting mitochondrial genes, interfering with their capacity to repair the MetS+RAS kidney. Methods Five groups of pigs (n = 7 each) were studied after 16 weeks of diet-induced MetS and RAS (MetS+RAS) and MetS+RAS 4 weeks after a single intrarenal delivery of EVs harvested from allogeneic adipose tissue-derived MSCs isolated from Lean or MetS pigs, and Lean or MetS sham controls. Single-kidney blood flow (RBF) and glomerular filtration rate (GFR) were assessed in vivo with multidetector CT, whereas EV microRNA cargo, renal tubular mitochondrial structure and bioenergetics, and renal injury pathways were assessed ex vivo. Results microRNA sequencing revealed 19 dysregulated microRNAs capable of targeting several mitochondrial genes in MetS-EVs versus Lean-EVs. Lean- and MetS-EVs were detected in the stenotic kidney 4 weeks after administration. However, only MetS-EVs failed to improve renal mitochondrial density, structure, and function or attenuate oxidative stress, tubular injury, and fibrosis. Furthermore, Lean-EVs but not MetS-EVs restored RBF and GFR in MetS+RAS. Conclusion MetS alters the cargo of mitochondria-related microRNAs in swine MSC-derived EVs, which might impair their capacity to repair the poststenotic kidney in MetS+RAS. These observations may contribute to develop approaches to improve the efficacy of MSC-EVs for patients with MetS.
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Paeonol inhibits NLRP3 mediated inflammation in rat endothelial cells by elevating hyperlipidemic rats plasma exosomal miRNA-223. Eur J Pharmacol 2020; 885:173473. [PMID: 32800809 DOI: 10.1016/j.ejphar.2020.173473] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 08/07/2020] [Accepted: 08/07/2020] [Indexed: 12/17/2022]
Abstract
Atherosclerosis (AS) is a multifactorial chronic inflammatory disease, and hyperlipidemia is the important factors leading to AS, which can cause vascular endothelial dysfunction. Paeonol (Pae) is a potential therapeutic drug for AS, and we have previously shown that Pae regulated the expression of monocytes-derived exosomal microRNA-223 (miR-223). However, the mechanisms of the anti-AS effect of Pae are still not fully understood. In this study, we aim to investigate if Pae could inhibit NLRP3 inflammasome mediated inflammation via elevating hyperlipidemic rats plasma-derived exosomal miR-223. We used high-fat-diet induced hyperlipidemic rats as model for further investigation. Rats were treated with Pae (75, 150 or 300 mg/kg) orally, and then exosomes were isolated from hyperlipidemic rat plasma by ultracentrifugation. In vivo experiments confirmed that Pae markedly reduced serum TC, TG, IL-1β, and IL-6 levels. Both CCK-8 and trypan blue staining showed that the survival rate of rat aortic endothelial cells (RAECs) in the Pae-exo group was higher than that in the model group. Also, Pae-exo dose-dependently increased the survival rate of RAECs and reduced inflammatory cytokines level (IL-1β, and IL-6). Furthermore, Pae-exo successfully increased the expression of exosomal miR-223 and relieved inflammatory secretion. Finally, decreased expression of NLRP3, ASC, caspase-1 and ICAM-1 indicated that Pae-exo attenuated inflammatory reaction of RAECs by suppressing NLRP3 signaling pathway. Altogether, our results showed that Pae inhibited the downstream NLRP3 inflammasome pathway by increasing the level of miR-223 in plasma derived exosomes of hyperlipidemic rats, providing new insights in the treatment of AS with the use of Pae.
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Extracellular vesicles carrying miRNAs in kidney diseases: a systemic review. Clin Exp Nephrol 2020; 24:1103-1121. [DOI: 10.1007/s10157-020-01947-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 07/27/2020] [Indexed: 01/26/2023]
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Li X, Liao J, Su X, Li W, Bi Z, Wang J, Su Q, Huang H, Wei Y, Gao Y, Li J, Liu L, Wang C. Human urine-derived stem cells protect against renal ischemia/reperfusion injury in a rat model via exosomal miR-146a-5p which targets IRAK1. Theranostics 2020; 10:9561-9578. [PMID: 32863945 PMCID: PMC7449916 DOI: 10.7150/thno.42153] [Citation(s) in RCA: 120] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Accepted: 07/16/2020] [Indexed: 02/06/2023] Open
Abstract
Rationale: Ischemia/reperfusion injury (IRI) is a major cause of acute kidney injury (AKI) that is associated with high morbidity and mortality, and for which specific treatments are lacking. In this study, we investigated the protective effect of human urine-derived stem cells (USCs) and their exosomes against IRI-induced AKI to explore the potential of these cells as a new therapeutic strategy. Methods: USCs were derived from fresh human urine. Cell surface marker expression was analyzed by flow cytometry to determine the characteristics of the stem cells. Adult male Sprague-Dawley rats were used to generate a lethal renal IRI model. One dose of USCs (2×106 cells/ml) or exosomes (20 µg/1 ml) in the experimental groups or saline (1 ml) in the control group was administered intravenously immediately after blood reperfusion. Blood was drawn every other day for measurement of serum creatinine (sCr) and blood urea nitrogen (BUN) levels. The kidneys were harvested for RNA and protein extraction to examine the levels of apoptosis and tubule injury. In vitro, the hypoxia-reoxygenation (H/R) model in human kidney cortex/proximal tubule cells (HK2) was used to analyze the protective ability of USC-derived exosomes (USC-Exo). Quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR), western blotting, superoxide dismutase activity, and malonaldehyde content analyses were used to evaluate oxidative stress in HK2 cells treated with USC-Exo after H/R. Exosomal microRNA sequencing techniques and bioinformatics analysis were used to search for enriched miRNAs in the exosomes and interacting genes. The interaction between miRNAs and the 3' untranslated region of the target gene was detected using a dual luciferase reporting system. The miRNA mimic and inhibitor were used to regulate the miRNA level in HK2 cells. Results: Treatment with USCs led to reductions in the levels of sCr, BUN, and renal tubular cell apoptosis; inhibited the infiltration of inflammatory cells; and protected renal function in the rat IRI model. Additionally, USC-derived exosomes protected against IRI-induced renal damage. miR-146a-5p was the most abundant miRNA in exosomes obtained from the conditioned medium (CM) of USCs. miR-146a-5p targeted and degraded the 3'UTR of interleukin-1 receptor-associated kinase 1 (IRAK1) mRNA, subsequently inhibited the activation of nuclear factor (NF)-κB signaling, and protected HK2 cells from H/R injury. USC transplantation also upregulated miR-146a-5p expression, downregulated IRAK1 expression and inhibited nuclear translocation of NF-κB p65 in the kidney of the rat IRI model. Conclusions: According to our experimental results, USCs could protect against renal IRI via exosomal miR-146a-5p, which could target the 3'UTR of IRAK1 and subsequently inhibit the activation of NF-κB signaling and infiltration of inflammatory cells to protect renal function. As a novel cell source, USCs represent a promising non-invasive approach for the treatment of IRI.
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Abstract
Fibrosis is characterized by aberrant myofibroblast accumulation and excessive extracellular matrix deposition, which leads to organ failure and significantly contributes to mortality worldwide. Exosomes, which are extracellular nanovesicles with a diameter of 30-100 nm that are secreted into the extracellular space by various types of cells, facilitate intercellular communication by delivering different cargos such as proteins, mRNAs and microRNAs. Growing evidence indicates that exosomes play an important role in various fibrotic diseases. A deeper understanding of the effects of exosomes in fibrosis may help in exploring new diagnostic and therapeutic targets. In this review, we summarize recent findings on exosomes in fibrotic diseases, with a special focus on exosomal cargo dysregulation and their potential diagnostic and therapeutic value in fibrosis.
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Affiliation(s)
- Xi-Ji Qin
- Department of Critical Care Medicine, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China
| | - Jia-Xiang Zhang
- Department of Critical Care Medicine, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China
| | - Rui-Lan Wang
- Department of Critical Care Medicine, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China
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Wang Y, Guo YF, Fu GP, Guan C, Zhang X, Yang DG, Shi YC. Protective effect of miRNA-containing extracellular vesicles derived from mesenchymal stromal cells of old rats on renal function in chronic kidney disease. Stem Cell Res Ther 2020; 11:274. [PMID: 32641100 PMCID: PMC7346413 DOI: 10.1186/s13287-020-01792-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 06/03/2020] [Accepted: 06/26/2020] [Indexed: 12/20/2022] Open
Abstract
Introduction Mesenchymal stromal cells (MSCs) play an important role in the prevention of cell and tissue fibrosis. Senescence may decrease the function of MSCs during recovery from tissue and organ damage. Extracellular vesicles (EVs) released from MSCs contribute to the repair of kidney injury. We explored the influence of senescence on EVs derived from MSCs (MSC-EVs) and detected the protective effects of MSC-EVs expressing low levels of miR-294/miR-133 derived from old rats against chronic kidney disease (CKD). Methods The effects of MSC-EVs derived from 3-month-old and 18-month-old male Fisher 344 rats on renal fibrosis were explored in a unilateral ureteral obstruction (UUO) model. pLV-miR-294/pLV-miR-133 mimic/inhibitor were injected into young and old rats before UUO to detect the effects of miR-294/miR-133, which were decreased in MSC-EVs and sera from old rats, on renal function in CKD. Transforming growth factor-β1 (TGF-β1)-induced human renal proximal tubular epithelial (HK2) cells were used to imitate the pathological process of renal fibrosis in vitro. Western blotting was used to assess the expression of epithelial/mesenchymal markers and phosphorylation of proteins in HK2 cells. Results The inhibition of UUO-induced CKD by MSC-EVs was weaker in old rats than in young rats. Downregulation of miRNAs (miR-294 and miR-133) in both MSC-EVs and sera from old rats obviously attenuated UUO-induced renal injury in old rats. miR-294 and miR-133 overexpression mitigated TGF-β1-mediated epithelial-mesenchymal transition (EMT) in HK2 cells, and the obvious increase in the phosphorylation of both SMAD2/3 and ERK1/2 induced by TGF-β1 was prevented in miR-294- and miR-133-overexpressing HK2 cells. Conclusions The ability of MSC-EVs to inhibit renal fibrosis decreased with age. miR-294/miR-133 in MSC-EVs and sera had an important effect on renal fibrosis in old rats and on EMT in HK2 cells. Furthermore, miR-294/miR-133 overexpression prevented SMAD2/3 and ERK1/2 phosphorylation in HK2 cells during TGF-β1-mediated EMT. These findings show that miR-294/miR-133 may be therapeutic in renal fibrosis and related renal dysfunction in elderly individuals.
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Affiliation(s)
- Yan Wang
- Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, Hebei, China.
| | - Yi Fang Guo
- Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Guang Ping Fu
- Hebei Key Laboratory of Forensic Medicine, Department of Forensic Medical, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Chang Guan
- Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xin Zhang
- Northern College, Zhangjiakou, Hebei, China
| | | | - Yun Cong Shi
- Hebei Medical University, Shijiazhuang, Hebei, China
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Liu D, Cheng F, Pan S, Liu Z. Stem cells: a potential treatment option for kidney diseases. Stem Cell Res Ther 2020; 11:249. [PMID: 32586408 PMCID: PMC7318741 DOI: 10.1186/s13287-020-01751-2] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 05/26/2020] [Accepted: 05/29/2020] [Indexed: 02/06/2023] Open
Abstract
The prevalence of kidney diseases is emerging as a public health problem. Stem cells (SCs), currently considered as a promising tool for therapeutic application, have aroused considerable interest and expectations. With self-renewal capabilities and great potential for proliferation and differentiation, stem cell therapy opens new avenues for the development of renal function and structural repair in kidney diseases. Mounting evidence suggests that stem cells exert a therapeutic effect mainly by replacing damaged tissues and paracrine pathways. The benefits of various types of SCs in acute kidney disease and chronic kidney disease have been demonstrated in preclinical studies, and preliminary results of clinical trials present its safety and tolerability. This review will focus on the stem cell-based therapy approaches for the treatment of kidney diseases, including various cell sources used, possible mechanisms involved, and outcomes that are generated so far, along with prospects and challenges in clinical application.
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Affiliation(s)
- Dongwei Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, People's Republic of China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, People's Republic of China
- Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, 450052, People's Republic of China
| | - Fei Cheng
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, People's Republic of China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, People's Republic of China
- Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, 450052, People's Republic of China
| | - Shaokang Pan
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, People's Republic of China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, People's Republic of China
- Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, 450052, People's Republic of China
| | - Zhangsuo Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China.
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, People's Republic of China.
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, People's Republic of China.
- Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, 450052, People's Republic of China.
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Sveiven SN, Nordgren TM. Lung-resident mesenchymal stromal cells are tissue-specific regulators of lung homeostasis. Am J Physiol Lung Cell Mol Physiol 2020; 319:L197-L210. [PMID: 32401672 DOI: 10.1152/ajplung.00049.2020] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Until recently, data supporting the tissue-resident status of mesenchymal stromal cells (MSC) has been ambiguous since their discovery in the 1950-60s. These progenitor cells were first discovered as bone marrow-derived adult multipotent cells and believed to migrate to sites of injury, opposing the notion that they are residents of all tissue types. In recent years, however, it has been demonstrated that MSC can be found in all tissues and MSC from different tissues represent distinct populations with differential protein expression unique to each tissue type. Importantly, these cells are efficient mediators of tissue repair, regeneration, and prove to be targets for therapeutics, demonstrated by clinical trials (phase 1-4) for MSC-derived therapies for diseases like graft-versus-host-disease, multiple sclerosis, rheumatoid arthritis, and Crohn's disease. The tissue-resident status of MSC found in the lung is a key feature of their importance in the context of disease and injuries of the respiratory system, since these cells could be instrumental to providing more specific and targeted therapies. Currently, bone marrow-derived MSC have been established in the treatment of disease, including diseases of the lung. However, with lung-resident MSC representing a unique population with a different phenotypic and gene expression pattern than MSC derived from other tissues, their role in remediating lung inflammation and injury could provide enhanced efficacy over bone marrow-derived MSC methods. Through this review, lung-resident MSC will be characterized, using previously published data, by surface markers, gene expression patterns, and compared with bone-marrow MSC to highlight similarities and, importantly, differences in these cell types.
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Affiliation(s)
- Stefanie Noel Sveiven
- Division of Biomedical Sciences, School of Medicine, University of California-Riverside, Riverside, California
| | - Tara M Nordgren
- Division of Biomedical Sciences, School of Medicine, University of California-Riverside, Riverside, California
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Mesenchymal and Induced Pluripotent Stem Cells-Derived Extracellular Vesicles: The New Frontier for Regenerative Medicine? Cells 2020; 9:cells9051163. [PMID: 32397132 PMCID: PMC7290733 DOI: 10.3390/cells9051163] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 05/02/2020] [Accepted: 05/04/2020] [Indexed: 12/13/2022] Open
Abstract
Regenerative medicine aims to repair damaged, tissues or organs for the treatment of various diseases, which have been poorly managed with conventional drugs and medical procedures. To date, multimodal regenerative methods include transplant of healthy organs, tissues, or cells, body stimulation to activate a self-healing response in damaged tissues, as well as the combined use of cells and bio-degradable scaffold to obtain functional tissues. Certainly, stem cells are promising tools in regenerative medicine due to their ability to induce de novo tissue formation and/or promote organ repair and regeneration. Currently, several studies have shown that the beneficial stem cell effects, especially for mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs) in damaged tissue restore are not dependent on their engraftment and differentiation on the injury site, but rather to their paracrine activity. It is now well known that paracrine action of stem cells is due to their ability to release extracellular vesicles (EVs). EVs play a fundamental role in cell-to-cell communication and are directly involved in tissue regeneration. In the present review, we tried to summarize the molecular mechanisms through which MSCs and iPSCs-derived EVs carry out their therapeutic action and their possible application for the treatment of several diseases.
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Tsiapalis D, O’Driscoll L. Mesenchymal Stem Cell Derived Extracellular Vesicles for Tissue Engineering and Regenerative Medicine Applications. Cells 2020; 9:E991. [PMID: 32316248 PMCID: PMC7226943 DOI: 10.3390/cells9040991] [Citation(s) in RCA: 199] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 04/09/2020] [Accepted: 04/14/2020] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are being extensively investigated for their potential in tissue engineering and regenerative medicine. However, recent evidence suggests that the beneficial effects of MSCs may be manifest by their released extracellular vesicles (EVs); typically not requiring the administration of MSCs. This evidence, predominantly from pre-clinical in vitro and in vivo studies, suggests that MSC-EVs may exhibit substantial therapeutic properties in many pathophysiological conditions, potentially restoring an extensive range of damaged or diseased tissues and organs. These benefits of MSC EVs are apparently found, regardless of the anatomical or body fluid origin of the MSCs (and include e.g., bone marrow, adipose tissue, umbilical cord, urine, etc). Furthermore, early indications suggest that the favourable effects of MSC-EVs could be further enhanced by modifying the way in which the donor MSCs are cultured (for example, in hypoxic compared to normoxic conditions, in 3D compared to 2D culture formats) and/or if the EVs are subsequently bio-engineered (for example, loaded with specific cargo). So far, few human clinical trials of MSC-EVs have been conducted and questions remain unanswered on whether the heterogeneous population of EVs is beneficial or some specific sub-populations, how best we can culture and scale-up MSC-EV production and isolation for clinical utility, and in what format they should be administered. However, as reviewed here, there is now substantial evidence supporting the use of MSC-EVs in tissue engineering and regenerative medicine and further research to establish how best to exploit this approach for societal and economic benefit is warranted.
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Affiliation(s)
| | - Lorraine O’Driscoll
- School of Pharmacy and Pharmaceutical Sciences & Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland;
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Kholia S, Herrera Sanchez MB, Cedrino M, Papadimitriou E, Tapparo M, Deregibus MC, Bruno S, Antico F, Brizzi MF, Quesenberry PJ, Camussi G. Mesenchymal Stem Cell Derived Extracellular Vesicles Ameliorate Kidney Injury in Aristolochic Acid Nephropathy. Front Cell Dev Biol 2020; 8:188. [PMID: 32266268 PMCID: PMC7105599 DOI: 10.3389/fcell.2020.00188] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Accepted: 03/05/2020] [Indexed: 12/18/2022] Open
Abstract
Limitations in the current therapeutic strategies for the prevention of progression of chronic kidney disease (CKD) to end stage renal disease has been a drawback to improving patient recovery. It is therefore imperative that a solution is found to alleviate this problem and improve the health and well-being of patients overall. Aristolochic acid (AA) induced nephropathy, a type of nephrotoxic CKD is characterised by cortical tubular injury, inflammation, leading to interstitial fibrosis. Extracellular vesicles derived from human bone marrow mesenchymal stem cells (MSC-EVs) display therapeutic properties in various disease models including kidney injury. In the current study, we intended to investigate the ability of MSC-EVs on ameliorating tubular injury and interstitial fibrosis in a mouse model of aristolochic acid nephropathy (AAN). The chronic model of AAN is comprised of an intraperitoneal injection of AA in NSG mice, followed by a three-day incubation period and then inoculation of MSC-EVs intravenously. This routine was performed on a weekly basis for four consecutive weeks, accompanied by the monitoring of body weight of all mice. Blood and tissue samples were collected post sacrifice. All animals administered with AA developed kidney injury and renal fibrosis. A gradual loss of body weight was observed, together with a deterioration in kidney function. Although no significant recovery was observed in weight loss following treatment with MSC-EVs, a significant reduction in: blood creatinine and blood urea nitrogen (BUN), tubular necrosis, and interstitial fibrosis was observed. In addition, infiltration of CD45 positive immune cells, fibroblasts, and pericytes which were elevated in the interstitium post AA induced injury, were also significantly reduced by MSC-EVs. Kidneys were also subjected to molecular analyses to evaluate the regulation of pro-fibrotic genes. MSC-EVs significantly reduced AA induction of the pro-fibrotic genes α-Sma, Tgfb1 and Col1a1. A downregulation in pro-fibrotic genes was also observed in fibroblasts activated by AA injured mTECs in vitro. Furthermore, meta-analyses of miRNAs downregulated by MSC-EVs, such as miR21, revealed the regulation of multiple pathways involved in kidney injury including fibrosis, inflammation, and apoptosis. These results therefore suggest that MSC-EVs could play a regenerative and anti-fibrotic role in AAN through the transfer of biologically active cargo that regulates the disease both at a protein and genetic level.
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Affiliation(s)
- Sharad Kholia
- Department of Medical Sciences, University of Turin, Turin, Italy
- Molecular Biotechnology Center, University of Turin, Turin, Italy
| | - Maria Beatriz Herrera Sanchez
- Molecular Biotechnology Center, University of Turin, Turin, Italy
- 2i3T Società per la Gestione dell’Incubatore di Imprese e per il Trasferimento Tecnologico Scarl, University of Turin, Turin, Italy
| | - Massimo Cedrino
- Molecular Biotechnology Center, University of Turin, Turin, Italy
- 2i3T Società per la Gestione dell’Incubatore di Imprese e per il Trasferimento Tecnologico Scarl, University of Turin, Turin, Italy
| | | | - Marta Tapparo
- Department of Medical Sciences, University of Turin, Turin, Italy
- Molecular Biotechnology Center, University of Turin, Turin, Italy
| | - Maria Chiara Deregibus
- Molecular Biotechnology Center, University of Turin, Turin, Italy
- 2i3T Società per la Gestione dell’Incubatore di Imprese e per il Trasferimento Tecnologico Scarl, University of Turin, Turin, Italy
| | - Stefania Bruno
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Federica Antico
- FORB, Molecular Biotechnology Centre, University of Turin, Turin, Italy
| | | | - Peter J. Quesenberry
- Division of Hematology/Oncology, Rhode Island Hospital, Brown University, Providence, RI, United States
| | - Giovanni Camussi
- Department of Medical Sciences, University of Turin, Turin, Italy
- 2i3T Società per la Gestione dell’Incubatore di Imprese e per il Trasferimento Tecnologico Scarl, University of Turin, Turin, Italy
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Lindoso RS, Lopes JA, Binato R, Abdelhay E, Takiya CM, Miranda KRD, Lara LS, Viola A, Bussolati B, Vieyra A, Collino F. Adipose Mesenchymal Cells-Derived EVs Alleviate DOCA-Salt-Induced Hypertension by Promoting Cardio-Renal Protection. Mol Ther Methods Clin Dev 2020; 16:63-77. [PMID: 31871958 PMCID: PMC6909095 DOI: 10.1016/j.omtm.2019.11.002] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 11/02/2019] [Indexed: 12/20/2022]
Abstract
Hypertension is a long-term condition that can increase organ susceptibility to insults and lead to severe complications such as chronic kidney disease (CKD). Extracellular vesicles (EVs) are cell-derived membrane structures that participate in cell-cell communication by exporting encapsulated molecules to target cells, regulating physiological and pathological processes. We here demonstrate that multiple administration of EVs from adipose-derived mesenchymal stromal cells (ASC-EVs) in deoxycorticosterone acetate (DOCA)-salt hypertensive model can protect renal tissue by maintaining its filtration capacity. Indeed, ASC-EVs downregulated the pro-inflammatory molecules monocyte chemoattracting protein-1 (MCP-1) and plasminogen activating inhibitor-1 (PAI1) and reduced recruitment of macrophages in the kidney. Moreover, ASC-EVs prevented cardiac tissue fibrosis and maintained blood pressure within normal levels, thus demonstrating their multiple favorable effects in different organs. By applying microRNA (miRNA) microarray profile of the kidney of DOCA-salt rats, we identified a selective miRNA signature associated with epithelial-mesenchymal transition (EMT). One of the key pathways found was the axis miR-200-TGF-β, that was significantly altered by EV administration, thereby affecting the EMT signaling and preventing renal inflammatory response and fibrosis development. Our results indicate that EVs can be a potent therapeutic tool for the treatment of hypertension-induced CKD in cardio-renal syndrome.
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Affiliation(s)
- Rafael Soares Lindoso
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil
- National Center for Structural Biology and Bioimaging/CENABIO, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil
- National Institute of Science and Technology for Regenerative Medicine-REGENERA, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil
| | - Jarlene Alécia Lopes
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil
- National Center for Structural Biology and Bioimaging/CENABIO, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil
| | - Renata Binato
- Brazilian National Institute of Cancer, 20230-130 Rio de Janeiro, Brazil
| | - Eliana Abdelhay
- Brazilian National Institute of Cancer, 20230-130 Rio de Janeiro, Brazil
| | - Christina Maeda Takiya
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil
| | - Kildare Rocha de Miranda
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil
- National Center for Structural Biology and Bioimaging/CENABIO, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil
| | - Lucienne Silva Lara
- Institute of Biomedical Sciences, Federal University of Rio de Janeiro, 21941-590 Rio de Janeiro, Brazil
| | - Antonella Viola
- Department of Biomedical Sciences and Pediatric Research Institute “Citta della Speranza,” University of Padova, 35131 Padua, Italy
| | - Benedetta Bussolati
- Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Turin, Italy
| | - Adalberto Vieyra
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil
- National Center for Structural Biology and Bioimaging/CENABIO, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil
- National Institute of Science and Technology for Regenerative Medicine-REGENERA, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil
- Graduate Program of Translational Biomedicine/BIOTRANS, Grande Rio University, 25071-202 Duque de Caxias, Brazil
| | - Federica Collino
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil
- National Institute of Science and Technology for Regenerative Medicine-REGENERA, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil
- Department of Biomedical Sciences and Pediatric Research Institute “Citta della Speranza,” University of Padova, 35131 Padua, Italy
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Tsuji K, Kitamura S, Wada J. Immunomodulatory and Regenerative Effects of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Renal Diseases. Int J Mol Sci 2020; 21:ijms21030756. [PMID: 31979395 PMCID: PMC7037711 DOI: 10.3390/ijms21030756] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 01/21/2020] [Accepted: 01/21/2020] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have immunomodulatory and regenerative effects in many organs, including the kidney. Emerging evidence has shown that the trophic effects from MSCs are mainly mediated by the paracrine mechanism rather than the direct differentiation of MSCs into injured tissues. These secretomes from MSCs include cytokines, growth factors, chemokines and extracellular vesicles (EVs) containing microRNAs, mRNAs, and proteins. Many research studies have revealed that secretomes from MSCs have potential to ameliorate renal injury in renal disease models, including acute kidney injury and chronic kidney disease through a variety of mechanisms. These trophic mechanisms include immunomodulatory and regenerative effects. In addition, accumulating evidence has uncovered the specific factors and therapeutic mechanisms in MSC-derived EVs. In this article, we summarize the recent advances of immunomodulatory and regenerative effects of EVs from MSCs, especially focusing on the microRNAs.
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Affiliation(s)
| | - Shinji Kitamura
- Correspondence: ; Tel.: +81-86-235-7235; Fax: +81-86-222-5214
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Selective intrarenal delivery of mesenchymal stem cell-derived extracellular vesicles attenuates myocardial injury in experimental metabolic renovascular disease. Basic Res Cardiol 2020; 115:16. [PMID: 31938859 DOI: 10.1007/s00395-019-0772-8] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 12/27/2019] [Indexed: 02/07/2023]
Abstract
Extracellular vesicles (EVs) deliver genes and proteins to recipient cells, and mediate paracrine actions of their parent cells. Intrarenal delivery of mesenchymal stem cell (MSC)-derived EVs preserves stenotic-kidney function and reduces release of pro-inflammatory cytokines in a swine model of coexisting metabolic syndrome (MetS) and renal artery stenosis (RAS). We hypothesized that this approach is also capable of blunting cardiac injury and dysfunction. Five groups of pigs were studied after 16 weeks of diet-induced MetS and RAS (MetS + RAS), MetS and MetS + RAS treated 4 weeks earlier with a single intrarenal delivery of EVs-rich fraction harvested from autologous adipose tissue-derived MSCs, and lean and MetS Shams. Cardiac structure, function, and myocardial oxygenation were assessed in vivo using imaging, and cardiac inflammation, senescence, and fibrosis ex vivo. Inflammatory cytokine levels were measured in circulating and renal vein blood. Intrarenal EV delivery improved stenotic-kidney glomerular filtration rate and renal blood flow, and decreased renal release of monocyte-chemoattractant protein-1 and interleukin-6. Furthermore, despite unchanged systemic hemodynamics, intrarenal EV delivery in MetS + RAS normalized cardiac diastolic function, attenuated left ventricular remodeling, cellular senescence and inflammation, and improved myocardial oxygenation and capillary density in MetS + RAS. Intrarenal delivery of MSC-derived EVs blunts myocardial injury in experimental MetS + RAS, possibly related to improvement in renal function and systemic inflammatory profile. These observations underscore the central role of inflammation in the crosstalk between the kidney and heart, and the important contribution of renal function to cardiac structural and functional integrity in coexisting MetS and RAS.
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Ma Z, Wang Y, Li H. Applications of extracellular vesicles in tissue regeneration. BIOMICROFLUIDICS 2020; 14:011501. [PMID: 32002105 PMCID: PMC6984977 DOI: 10.1063/1.5127077] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 01/15/2020] [Indexed: 05/05/2023]
Abstract
Extracellular vesicles (EVs) can be classified into several types based on their different biosyntheses or release pathways, including exosomes, microvesicles, apoptotic bodies, and large oncosomes. As they contain DNAs, RNAs, proteins, and other bioactive signals, EVs have been utilized in the diagnosis field for a long time. Considering the fact that stem cells have been widely used for tissue regeneration and EVs possess similar biological properties to their source cells, tissue regeneration abilities of EVs have recently attracted much attention in the regenerative medicine field. In this paper, recent advances and challenges of EVs applied in the repair and regeneration of damaged tissues, such as skin, heart, liver, kidney, bone, and central nervous system, have been summarized. Specifically, critical bioactive molecules, which are encapsulated within EVs and play significant roles in the tissue regeneration, have been highlighted. Finally, the prospects and future development directions of the application of EVs in the field of tissue regeneration have been discussed.
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Affiliation(s)
| | | | - Haiyan Li
- Author to whom correspondence should be addressed:. Tel.: +86 18717902901
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Islam MN, Griffin TP, Sander E, Rocks S, Qazi J, Cabral J, McCaul J, McMorrow T, Griffin MD. Human mesenchymal stromal cells broadly modulate high glucose-induced inflammatory responses of renal proximal tubular cell monolayers. Stem Cell Res Ther 2019; 10:329. [PMID: 31744554 PMCID: PMC6862760 DOI: 10.1186/s13287-019-1424-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 09/08/2019] [Accepted: 09/24/2019] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Renal proximal tubular epithelial cells (RPTEC) are dysfunctional in diabetic kidney disease (DKD). Mesenchymal stromal cells (MSC) may modulate DKD pathogenesis through anti-inflammatory mediators. This study aimed to investigate the pro-inflammatory effect of extended exposure to high glucose (HG) concentration on stable RPTEC monolayers and the influence of MSC on this response. METHODS Morphologically stable human RPTEC/TERT1 cell monolayers were exposed to 5 mM and 30 mM (HG) D-glucose or to 5 mM D-glucose + 25 mM D-mannitol (MAN) for 5 days with sequential immunoassays of supernatants and end-point transcriptomic analysis by RNA sequencing. Under the same conditions, MSC-conditioned media (MSC-CM) or MSC-containing transwells were added for days 4-5. Effects of CM from HG- and MAN-exposed RPTEC/MSC co-cultures on cytokine secretion by monocyte-derived macrophages were determined. RESULTS After 72-80 h, HG resulted in increased RPTEC/TERT1 release of interleukin (IL)-6, IL-8, monocyte chemoattractant protein (MCP)-1 and neutrophil gelatinase-associated lipocalin (NGAL). The HG pro-inflammatory effect was attenuated by concentrated (10×) MSC-CM and, to a greater extent, by MSC transwell co-culture. Bioinformatics analysis of RNA sequencing data confirmed a predominant effect of HG on inflammation-related mediators and biological processes/KEGG pathways in RPTEC/TERT1 stable monolayers as well as the non-contact-dependent anti-inflammatory effect of MSC. Finally, CM from HG-exposed RPTEC/MSC transwell co-cultures was associated with attenuated secretion of inflammatory mediators by macrophages compared to CM from HG-stimulated RPTEC alone. CONCLUSIONS Stable RPTEC monolayers demonstrate delayed pro-inflammatory response to HG that is attenuated by close proximity to human MSC. In DKD, this MSC effect has potential to modulate hyperglycemia-associated RPTEC/macrophage cross-talk.
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Affiliation(s)
- Md Nahidul Islam
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, School of Medicine, National University of Ireland Galway, Galway, REMEDI, Biomedical Sciences, Corrib Village, Dangan, Galway, H91 TK33, Ireland
| | - Tomás P Griffin
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, School of Medicine, National University of Ireland Galway, Galway, REMEDI, Biomedical Sciences, Corrib Village, Dangan, Galway, H91 TK33, Ireland.,Centre for Endocrinology, Diabetes and Metabolism, Galway University Hospitals, Galway, Ireland
| | - Elizabeth Sander
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, School of Medicine, National University of Ireland Galway, Galway, REMEDI, Biomedical Sciences, Corrib Village, Dangan, Galway, H91 TK33, Ireland
| | - Stephanie Rocks
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, School of Medicine, National University of Ireland Galway, Galway, REMEDI, Biomedical Sciences, Corrib Village, Dangan, Galway, H91 TK33, Ireland
| | - Junaid Qazi
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, School of Medicine, National University of Ireland Galway, Galway, REMEDI, Biomedical Sciences, Corrib Village, Dangan, Galway, H91 TK33, Ireland
| | - Joana Cabral
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, School of Medicine, National University of Ireland Galway, Galway, REMEDI, Biomedical Sciences, Corrib Village, Dangan, Galway, H91 TK33, Ireland
| | - Jasmin McCaul
- School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin, Ireland
| | - Tara McMorrow
- School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin, Ireland
| | - Matthew D Griffin
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, School of Medicine, National University of Ireland Galway, Galway, REMEDI, Biomedical Sciences, Corrib Village, Dangan, Galway, H91 TK33, Ireland.
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Rockel JS, Rabani R, Viswanathan S. Anti-fibrotic mechanisms of exogenously-expanded mesenchymal stromal cells for fibrotic diseases. Semin Cell Dev Biol 2019; 101:87-103. [PMID: 31757583 DOI: 10.1016/j.semcdb.2019.10.014] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 10/11/2019] [Accepted: 10/30/2019] [Indexed: 12/17/2022]
Abstract
Most chronic diseases involving inflammation have a fibrotic component that involves remodeling and excess accumulation of extracellular matrix components. Left unchecked, fibrosis leads to organ failure and death. Mesenchymal stromal cells (MSCs) are emerging as a potent cell-based therapy for a wide spectrum of fibrotic conditions due to their immunomodulatory, anti-inflammatory and anti-fibrotic properties. This review provides an overview of known mechanisms by which MSCs mediate their anti-fibrotic actions and in relation to animal models of pulmonary, liver, renal and cardiac fibrosis. Recent MSC clinical trials results in liver, lung, skin, kidney and hearts are discussed and next steps for future MSC-based therapies including pre-activated or genetically-modified cells, or extracellular vesicles are also considered.
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Affiliation(s)
- Jason S Rockel
- Arthritis Program, University Health Network, Toronto, ON, Canada; Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON, Canada.
| | - Razieh Rabani
- Arthritis Program, University Health Network, Toronto, ON, Canada; Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON, Canada
| | - Sowmya Viswanathan
- Arthritis Program, University Health Network, Toronto, ON, Canada; Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada; Division of Hematology, Department of Medicine, University of Toronto, Toronto, Canada
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