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1
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Wang H, Liao J, Wang W, Zhang J. A crucial role of miR-155 in the pathomechanism of acute kidney injury. Front Pharmacol 2025; 16:1570000. [PMID: 40308762 PMCID: PMC12040948 DOI: 10.3389/fphar.2025.1570000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2025] [Accepted: 03/31/2025] [Indexed: 05/02/2025] Open
Abstract
Acute kidney injury (AKI) is one of the nonnegligible causes of mortality worldwide. It is important to understand the underlying molecular mechanism of AKI to effective therapeutic targets. miR-155 has been found to play a pivotal role in the development of AKI, while a comprehensive review on this topic is currently still lacking. Based on this review, we found that miR-155and is strongly correlated with the pathophysiological development of AKI by modulating cell apoptosis, inflammation, and proliferation. Mechanistically, miR-155 exerts a promoting function in multiple types of AKI by regulating multiple proteins or signaling pathways, such as SOCS-1, ERRFI1, SOCS-1, TRF1, CDK12, and TCF4/Wnt/β-catenin pathway. The inhibition of miR-155 has a renoprotective effect in drug- or substance-induced AKI. Therefore, drugs or biological compounds targeted by miR-155 and its pathways may recover the process of AKI by altering apoptosis, inflammation, and pyroptosis. A miRNA nanocarrier system that has already been developed could offer a novel approach to treat AKI, providing a direction for future research. Further large-scale studies are necessary to elucidate the clinical significance of miR-155 as a potential therapeutic target for multiple types of AKI.
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Affiliation(s)
- Hui Wang
- Department of Urology, The First People’s Hospital of Linhai, Linhai, Zhejiang, China
| | - Jian Liao
- Department of Nephrology, Jiaxing Hospital of Traditional Chinese Medicine, Jiaxing, China
| | - Wei Wang
- Department of Urology, Tiantai People’s Hospital of Zhejiang Province (Tiantai Branch of Zhejiang Provincial People’s Hospital), Hangzhou Medical College, Taizhou, Zhejiang, China
| | - Jianhua Zhang
- Department of Urology, Tiantai People’s Hospital of Zhejiang Province (Tiantai Branch of Zhejiang Provincial People’s Hospital), Hangzhou Medical College, Taizhou, Zhejiang, China
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Wang H, Wu X, Li Z, Rong K, Gao S, Tang W, Zhang J. Novel Glycyrrhetin Ureas Possessing 2-Hydroxy-3-enone A Ring: Modification, Anti-inflammatory Activity, and Targeted STING for the Remedy of Acute Kidney Injury. ACS OMEGA 2024; 9:48821-48834. [PMID: 39676967 PMCID: PMC11635493 DOI: 10.1021/acsomega.4c09003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 11/13/2024] [Accepted: 11/19/2024] [Indexed: 12/17/2024]
Abstract
Glycyrrhetin urea has emerged as a privileged scaffold with anti-inflammatory activity for the treatment and prevention of acute kidney injury (AKI). In this study, structural modifications of the A ring of glycyrrhetinic acid yielded a series of urea derivatives, among which compound 7o exhibited the most promising anti-inflammatory activity. 7o was confirmed to interact with STING through a cellular heat shift assay and to inhibit the STING/NF-κB pathway in RAW264.7 cells. It acted on the STING pathway, inhibited NF-κB phosphorylation, and subsequently reduced the level of release of inflammatory factors. Additionally, 7o significantly increased the survival rate of renal tubular epithelial cells, demonstrating a protective effect against cisplatin-induced cell death and mitigating inflammation activation. The in vivo AKI mouse model showed that 7o significantly downregulated serum creatinine (Scr), blood urea nitrogen (BUN), and levels of inflammatory factors (IL-1β, IL-6, and TNF-α), thereby improving renal function. Morphological analysis revealed that 7o attenuated the cisplatin-induced renal tubular injury. Therefore, 7o represents a promising lead for the prevention and treatment of AKI.
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Affiliation(s)
- Hongbo Wang
- Department
of Pharmacy, Shandong Medical College, Linyi 276000, People’s Republic of China
- School
of Pharmacy, Anhui Medical University, Hefei 230032, People’s Republic of China
| | - Xiaoming Wu
- School
of Pharmacy, Anhui Medical University, Hefei 230032, People’s Republic of China
| | - Ziyun Li
- School
of Pharmacy, Anhui Medical University, Hefei 230032, People’s Republic of China
| | - Kuanrong Rong
- School
of Pharmacy, Anhui Medical University, Hefei 230032, People’s Republic of China
| | - Shan Gao
- School
of Pharmacy, Anhui Medical University, Hefei 230032, People’s Republic of China
| | - Wenjian Tang
- School
of Pharmacy, Anhui Medical University, Hefei 230032, People’s Republic of China
| | - Jing Zhang
- Anhui
Province Key Laboratory of Occupational Health, Anhui No. 2 Provincial People’s Hospital, Hefei 230041, People’s Republic of China
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Habib R, Farhat R, Wahid M, Ainuddin J. Enhanced reno-protective effects of CHIR99021 modified mesenchymal stem cells against rat acute kidney injury model. BIOIMPACTS : BI 2024; 15:30600. [PMID: 40256225 PMCID: PMC12008493 DOI: 10.34172/bi.30600] [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: 07/01/2024] [Revised: 08/08/2024] [Accepted: 09/17/2024] [Indexed: 04/22/2025]
Abstract
Introduction Mesenchymal stem cells of human umbilical cord origin (hucMSCs) appear to be an attractive candidate for cell-based therapies. However, their efficacy requires improvement as poor survival and specific homing to the site of injury are the major barriers to their effective implementation in cell therapy. As Wnt signaling pathway is involved in the development and repair of organs, we adopted a preconditioning strategy of stem cells by using CHIR99021 compound (a Wnt pathway agonist) to potentiate hucMSCs beneficial effects and circumvent their therapeutic limitations. Methods We treated hucMSCs with 5 µM of CHIR99021 and evaluated the expression levels of genes involved in different biological processes through qRT-PCR. Subsequently, we examined the effectiveness of preconditioned cells (CHIR99021-hucMSCs) in a cisplatin-induced rat acute kidney injury model. Amelioration in tissue injury was evaluated by histopathology, immunohistochemistry and renal functional assessment. Results In treated groups, we observed preserved renal tissue architecture in terms of lesser epithelial cells necrosis (P ≤ 0.001) and cast formation ( ≤ 0.05). Accelerated proliferation of injured tubular cells (P ≤ 0.001) and low serum creatinine values (P ≤ 0.01) were observed in preconditioned hucMSCs group compared to untreated AKI rats. In addition, administration of preconditioned hucMSCs in kidney injury model offered better restoration of tubular cell membrane β-catenin molecules. Our findings showed that CHIR99021-modified hucMSCs may exhibit better capacity for cell migration and proliferation. Conclusion The results showed that preconditioning of stem cells with Wnt pathway activators could provide advanced benefits for organ repair, which may contribute to design a more effective therapeutic approach for renal regeneration.
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Affiliation(s)
- Rakhshinda Habib
- Dow Research Institute of Biotechnology and Biomedical Sciences, Dow University of Health Sciences (Ojha Campus), Karachi, Pakistan
| | - Rabia Farhat
- School of Postgraduate Studies, Dow University of Health Sciences (Ojha Campus), Karachi, Pakistan
| | - Mohsin Wahid
- Department of Pathology, Dow International Medical College, Dow University of Health Sciences (Ojha Campus), Karachi, Pakistan
| | - Jahanara Ainuddin
- Department of Gynecology and Obstetrics, Dow University Hospital, Karachi, Pakistan
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Gryguc A, Maciulaitis J, Mickevicius L, Laurinavicius A, Sutkeviciene N, Grigaleviciute R, Zigmantaite V, Maciulaitis R, Bumblyte IA. Prevention of Transition from Acute Kidney Injury to Chronic Kidney Disease Using Clinical-Grade Perinatal Stem Cells in Non-Clinical Study. Int J Mol Sci 2024; 25:9647. [PMID: 39273595 PMCID: PMC11394957 DOI: 10.3390/ijms25179647] [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: 06/24/2024] [Revised: 07/30/2024] [Accepted: 09/02/2024] [Indexed: 09/15/2024] Open
Abstract
Acute kidney injury (AKI) is widely recognized as a precursor to the onset or rapid progression of chronic kidney disease (CKD). However, there is currently no effective treatment available for AKI, underscoring the urgent need for the development of new strategies to improve kidney function. Human placental mesenchymal stromal cells (hpMSCs) were isolated from donor placentas, cultured, and characterized with regard to yield, viability, flow cytometry, and potency. To mimic AKI and its progression to CKD in a rat model, a dedicated sensitive non-clinical bilateral kidney ischemia-reperfusion injury (IRI) model was utilized. The experimental group received 3 × 105 hpMSCs into each kidney, while the control group received IRI and saline and the untreated group received IRI only. Urine, serum, and kidney tissue samples were collected over a period of 28 days. The hpMSCs exhibited consistent yields, viability, and expression of mesenchymal lineage markers, and were also shown to suppress T cell proliferation in a dose-dependent manner. To ensure optimal donor selection, manufacturing optimization, and rigorous quality control, the rigorous Good Manufacturing Practice (GMP) conditions were utilized. The results indicated that hpMSCs increased rat survival rates and improved kidney function by decreasing serum creatinine, urea, potassium, and fractionated potassium levels. Furthermore, the study demonstrated that hpMSCs can prevent the initial stages of kidney structural fibrosis and improve kidney function in the early stages by mitigating late interstitial fibrosis and tubular atrophy. Additionally, a robust manufacturing process with consistent technical parameters was established.
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Affiliation(s)
- Agne Gryguc
- Department of Nephrology, Medical Academy, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania
- Hospital of Lithuanian University of Health Science, 50161 Kaunas, Lithuania
| | - Justinas Maciulaitis
- Institute of Cardiology, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania
- Institute of Physiology and Pharmacology, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania
| | - Lukas Mickevicius
- Department of Urology, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania
| | - Arvydas Laurinavicius
- National Center of Pathology, Affiliate of Vilnius University Hospital Santaros Klinikos, 08661 Vilnius, Lithuania
| | - Neringa Sutkeviciene
- Large Animal Clinic, Veterinary Academy, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania
| | - Ramune Grigaleviciute
- Biological Research Center, Veterinary Academy, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania
| | - Vilma Zigmantaite
- Biological Research Center, Veterinary Academy, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania
| | - Romaldas Maciulaitis
- Department of Nephrology, Medical Academy, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania
- Institute of Physiology and Pharmacology, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania
- Faculty of Medicine, Medical Academy, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania
| | - Inga Arune Bumblyte
- Department of Nephrology, Medical Academy, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania
- Hospital of Lithuanian University of Health Science, 50161 Kaunas, Lithuania
- Faculty of Medicine, Medical Academy, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania
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Çam SB, Çiftci E, Gürbüz N, Altun B, Korkusuz P. Allogeneic bone marrow mesenchymal stem cell-derived exosomes alleviate human hypoxic AKI-on-a-Chip within a tight treatment window. Stem Cell Res Ther 2024; 15:105. [PMID: 38600585 PMCID: PMC11005291 DOI: 10.1186/s13287-024-03674-8] [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: 12/01/2023] [Accepted: 02/20/2024] [Indexed: 04/12/2024] Open
Abstract
BACKGROUND Acute hypoxic proximal tubule (PT) injury and subsequent maladaptive repair present high mortality and increased risk of acute kidney injury (AKI) - chronic kidney disease (CKD) transition. Human bone marrow mesenchymal stem cell-derived exosomes (hBMMSC-Exos) as potential cell therapeutics can be translated into clinics if drawbacks on safety and efficacy are clarified. Here, we determined the real-time effective dose and treatment window of allogeneic hBMMSC-Exos, evaluated their performance on the structural and functional integrity of 3D microfluidic acute hypoxic PT injury platform. METHODS hBMMSC-Exos were isolated and characterized. Real-time impedance-based cell proliferation analysis (RTCA) determined the effective dose and treatment window for acute hypoxic PT injury. A 2-lane 3D gravity-driven microfluidic platform was set to mimic PT in vitro. ZO-1, acetylated α-tubulin immunolabelling, and permeability index assessed structural; cell proliferation by WST-1 measured functional integrity of PT. RESULTS hBMMSC-Exos induced PT proliferation with ED50 of 172,582 µg/ml at the 26th hour. Hypoxia significantly decreased ZO-1, increased permeability index, and decreased cell proliferation rate on 24-48 h in the microfluidic platform. hBMMSC-Exos reinforced polarity by a 1.72-fold increase in ZO-1, restored permeability by 20/45-fold against 20/155 kDa dextran and increased epithelial proliferation 3-fold compared to control. CONCLUSIONS The real-time potency assay and 3D gravity-driven microfluidic acute hypoxic PT injury platform precisely demonstrated the therapeutic performance window of allogeneic hBMMSC-Exos on ischemic AKI based on structural and functional cellular data. The novel standardized, non-invasive two-step system validates the cell-based personalized theragnostic tool in a real-time physiological microenvironment prior to safe and efficient clinical usage in nephrology.
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Affiliation(s)
- Sefa Burak Çam
- Faculty of Medicine, Dept. of Histology and Embryology, Hacettepe University, Ankara, Ankara, 06230, Turkey
| | - Eda Çiftci
- Graduate School of Science and Engineering, Department of Bioengineering, Hacettepe University, Ankara, 06230, Turkey
| | - Nazlıhan Gürbüz
- Graduate School of Science and Engineering, Department of Bioengineering, Hacettepe University, Ankara, 06230, Turkey
| | - Bülent Altun
- Faculty of Medicine, Dept. of Nephrology, Hacettepe University, Ankara, 06230, Turkey
| | - Petek Korkusuz
- Faculty of Medicine, Dept. of Histology and Embryology, Hacettepe University, Ankara, Ankara, 06230, Turkey.
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Starr MC, Barreto E, Charlton J, Vega M, Brophy PD, Ray Bignall ON, Sutherland SM, Menon S, Devarajan P, Akcan Arikan A, Basu R, Goldstein S, Soranno DE. Advances in pediatric acute kidney injury pathobiology: a report from the 26th Acute Disease Quality Initiative (ADQI) conference. Pediatr Nephrol 2024; 39:941-953. [PMID: 37792076 PMCID: PMC10817846 DOI: 10.1007/s00467-023-06154-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 08/08/2023] [Accepted: 08/29/2023] [Indexed: 10/05/2023]
Abstract
BACKGROUND In the past decade, there have been substantial advances in our understanding of the pathobiology of pediatric acute kidney injury (AKI). In particular, animal models and studies focused on the relationship between kidney development, nephron number, and kidney health have identified a number of heterogeneous pathophysiologies underlying AKI. Despite this progress, gaps remain in our understanding of the pathobiology of pediatric AKI. METHODS During the 26th Acute Disease Quality Initiative (ADQI) Consensus conference, a multidisciplinary group of experts discussed the evidence and used a modified Delphi process to achieve consensus on recommendations for opportunities to advance translational research in pediatric AKI. The current state of research understanding as well as gaps and opportunities for advancement in research was discussed, and recommendations were summarized. RESULTS Consensus was reached that to improve translational pediatric AKI advancements, diverse teams spanning pre-clinical to epidemiological scientists must work in concert together and that results must be shared with the community we serve with patient involvement. Public and private research support and meaningful partnerships with adult research efforts are required. Particular focus is warranted to investigate the pediatric nuances of AKI, including the effect of development as a biological variable on AKI incidence, severity, and outcomes. CONCLUSIONS Although AKI is common and associated with significant morbidity, the biologic basis of the disease spectrum throughout varying nephron developmental stages remains poorly understood. An incomplete understanding of factors contributing to kidney health, the diverse pathobiologies underlying AKI in children, and the historically siloed approach to research limit advances in the field. The recommendations outlined herein identify gaps and outline a strategic approach to advance the field of pediatric AKI via multidisciplinary translational research.
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Affiliation(s)
- Michelle C Starr
- Department of Pediatrics, Division of Nephrology, Indiana University School of Medicine, Riley Hospital for Children, 1044 W. Walnut Street, Indianapolis, IN, 46202, USA
- Pediatric and Adolescent Comparative Effectiveness Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Erin Barreto
- Department of Pharmacy, Mayo Clinic, Rochester, MN, USA
| | - Jennifer Charlton
- Department of Pediatrics, Division of Nephrology, University of Virginia, Charlottesville, VA, USA
| | - Molly Vega
- Renal and Apheresis Services, Texas Children's Hospital, Houston, TX, USA
| | - Patrick D Brophy
- Department of Pediatrics, Golisano Children's Hospital, University of Rochester, Rochester, NY, USA
| | - O N Ray Bignall
- Department of Pediatrics, Division of Nephrology and Hypertension, Nationwide Children's Hospital and The Ohio State University College of Medicine, Columbus, OH, USA
| | - Scott M Sutherland
- Department of Pediatrics, Division of Nephrology, Stanford University School of Medicine, Stanford, CA, USA
| | - Shina Menon
- Division of Pediatric Nephrology, Seattle Children's Hospital and University of Washington, Seattle, WA, USA
| | - Prasad Devarajan
- Department of Pediatrics, Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA
| | - Ayse Akcan Arikan
- Department of Pediatrics, Divisions of Critical Care and Nephrology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA
| | - Rajit Basu
- Department of Pediatrics, Division of Critical Care, Northwestern University, Chicago, IL, USA
| | - Stuart Goldstein
- Department of Pediatrics, Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA
| | - Danielle E Soranno
- Department of Pediatrics, Division of Nephrology, Indiana University School of Medicine, Riley Hospital for Children, 1044 W. Walnut Street, Indianapolis, IN, 46202, USA.
- Department of Bioengineering, Purdue University, West Lafayette, IN, USA.
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7
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Liu Y, Han J, Fang J, Li R. The Beneficial Effects of Mesenchymal Stem Cells in Acute Kidney Injury: A Narrative Review. Curr Stem Cell Res Ther 2024; 19:200-209. [PMID: 36748221 PMCID: PMC10680085 DOI: 10.2174/1574888x18666230206115046] [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: 08/17/2022] [Revised: 12/29/2022] [Accepted: 01/10/2023] [Indexed: 02/08/2023]
Abstract
BACKGROUND Acute kidney injury (AKI) is a multifaced disease characterized by a rapid decline in renal function. However, with growing insight into the pathophysiologic mechanisms of AKI, currently available interventions for AKI are merely supportive. Thus, novel therapies are urgently needed to improve the outcomes of patients with AKI. This narrative review aims to explore enhancing the beneficial effects of Mesenchymal Stem Cells(MSCs) in AKI. METHODS The authors examined all studies regarding the role of MSCs in AKI. And the authors undertook a structured search of bibliographic databases for peer-reviewed research literature using a focused review question. The most relevant and up-to-date research was included. RESULTS AND DISCUSSION Based on encouraging preclinical results, stem cell therapy has been widely explored over the last decade. Among the various stem cell types investigated, mesenchymal stem cells are being intensely investigated by virtue of their numerous strengths, such as easy derivation, undemanding cell culture conditions, anti-apoptosis, immunomodulation, and anti-inflammation effects. Mounting evidence suggests that MSCs hold great potential in accelerating kidney repair following AKI in various preclinical models. Unfortunately, low engrafting efficiency and poor survival rate of injected MSCs in the injured renal tissue are major obstacles MSCs clinical application faces. CONCLUSION Various strategies, including genetic manipulation, mimicking the cellular microenvironment with different culture conditions, optimizing MSCs preparation and administration schedule, and screening patients who may more like benefit from MSCs therapy, have been developed to enhance the therapeutic potential of MSCs in AKI.
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Affiliation(s)
- Yuxiang Liu
- Department of Nephrology, Fifth Hospital of Shanxi Medical University (Shanxi Provincial People’s Hospital), Taiyuan, 030012, Shanxi, China
- Department of the Fifth Clinical Medical College, Shanxi Medical University, Taiyuan, 030001, Shanxi, China
- Department of Nephrology, First Hospital of Shanxi Medical University, Taiyuan, Taiyuan, 030012, Shanxi, China
| | - Jibin Han
- Department of Critical Care Medicine, First Hospital of Shanxi Medical University, Taiyuan, 030012, Shanxi, China
| | - Jingai Fang
- Department of Nephrology, First Hospital of Shanxi Medical University, Taiyuan, Taiyuan, 030012, Shanxi, China
| | - Rongshan Li
- Department of Nephrology, Fifth Hospital of Shanxi Medical University (Shanxi Provincial People’s Hospital), Taiyuan, 030012, Shanxi, China
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Lindoso RS, Collino F, Kasai-Brunswick TH, Costa MR, Verdoorn KS, Einicker-Lamas M, Vieira-Beiral HJ, Wessely O, Vieyra A. Resident Stem Cells in Kidney Tissue. RESIDENT STEM CELLS AND REGENERATIVE THERAPY 2024:159-203. [DOI: 10.1016/b978-0-443-15289-4.00009-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Gooch AM, Chowdhury SS, Zhang PM, Hu ZM, Westenfelder C. Significant expansion of the donor pool achieved by utilizing islets of variable quality in the production of allogeneic "Neo-Islets", 3-D organoids of Mesenchymal Stromal and islet cells, a novel immune-isolating biotherapy for Type I Diabetes. PLoS One 2023; 18:e0290460. [PMID: 37616230 PMCID: PMC10449143 DOI: 10.1371/journal.pone.0290460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 08/09/2023] [Indexed: 08/26/2023] Open
Abstract
Novel biotherapies for Type 1 Diabetes that provide a significantly expanded donor pool and that deliver all islet hormones without requiring anti-rejection drugs are urgently needed. Scoring systems have improved islet allotransplantation outcomes, but their use may potentially result in the waste of valuable cells for novel therapies. To address these issues, we created "Neo-Islets" (NIs), islet-sized organoids, by co-culturing in ultralow adhesion flasks culture-expanded islet (ICs) and Mesenchymal Stromal Cells (MSCs) (x 24 hrs, 1:1 ratio). The MSCs exert powerful immune- and cyto-protective, anti-inflammatory, proangiogenic, and other beneficial actions in NIs. The robust in vitro expansion of all islet hormone-producing cells is coupled to their expected progressive de-differentiation mediated by serum-induced cell cycle entry and Epithelial-Mesenchymal Transition (EMT). Re-differentiation in vivo of the ICs and resumption of their physiological functions occurs by reversal of EMT and serum withdrawal-induced exit from the cell cycle. Accordingly, we reported that allogeneic, i.p.-administered NIs engraft in the omentum, increase Treg numbers and reestablish permanent normoglycemia in autoimmune diabetic NOD mice without immunosuppression. Our FDA-guided pilot study (INAD 012-0776) in insulin-dependent pet dogs showed similar responses, and both human- and canine-NIs established normoglycemia in STZ-diabetic NOD/SCID mice even though the utilized islets would be scored as unsuitable for transplantation. The present study further demonstrates that islet gene expression profiles (α, β, γ, δ) in human "non-clinical grade" islets obtained from diverse, non-diabetic human and canine donors (n = 6 each) closely correlate with population doublings, and the in vivo re-differentiation of endocrine islet cells clearly corresponds with the reestablishment of euglycemia in diabetic mice. Conclusion: human-NIs created from diverse, "non-clinical grade" donors have the potential to greatly expand patient access to this curative therapy of T1DM, facilitated by the efficient in vitro expansion of ICs that can produce ~ 270 therapeutic NI doses per donor for 70 kg recipients.
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Affiliation(s)
- Anna M. Gooch
- SymbioCellTech, LLC, Salt Lake City, Utah, United States of Ameirca
| | | | - Ping M. Zhang
- SymbioCellTech, LLC, Salt Lake City, Utah, United States of Ameirca
| | - Zhuma M. Hu
- SymbioCellTech, LLC, Salt Lake City, Utah, United States of Ameirca
| | - Christof Westenfelder
- SymbioCellTech, LLC, Salt Lake City, Utah, United States of Ameirca
- University of Utah, Health Sciences Center, Salt Lake City, Utah, United States of America
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10
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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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11
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Oka M, Kameishi S, Cho YK, Song SU, Grainger DW, Okano T. Clinically Relevant Mesenchymal Stem/Stromal Cell Sheet Transplantation Method for Kidney Disease. Tissue Eng Part C Methods 2023; 29:54-62. [PMID: 36719774 DOI: 10.1089/ten.tec.2022.0200] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Chronic kidney disease (CKD) is the irreversible loss of nephron function, leading to a build-up of toxins, prolonged inflammation, and ultimately fibrosis. Currently, no effective therapies exist to treat CKD due to its complex pathophysiology. Mesenchymal stem/stromal cell (MSC) transplantation is a promising strategy to treat kidney diseases, and multiple clinical trials are currently ongoing. We previously demonstrated that rat bone marrow-derived MSC (BMSC) sheets transplanted onto surgically decapsulated kidney exert therapeutic effects that suppressed renal fibrosis progression based on enhanced vascularization. However, there are clinical concerns about kidney decapsulation such as impaired glomerular filtration rate and Na+ ion and H2O excretion, leading to kidney dysfunction. Therefore, for transitioning from basic research to translational research using cell sheet therapy for kidney disease, it is essential to develop a new cell sheet transplantation strategy without kidney decapsulation. Significantly, we employed cell sheets engineered from clinical-grade human clonal BMSC (cBMSC) and transplanted these onto intact renal capsule to evaluate their therapeutic ability in the rat ischemia-reperfusion injury (IRI) model. Histological analysis 1-day postsurgery showed that cBMSC sheets engrafted well onto intact renal capsule. Interestingly, some grafted cBMSCs migrated into the renal parenchyma. At 1-3 days postsurgery (acute stage), grafted cBMSC sheets prevented tubular epithelial cell injury. At 28 days postsurgery (chronic phase), we observed that grafted cBMSC sheets suppressed renal fibrosis in the rat IRI model. Taken together, engineered cBMSC sheet transplantation onto intact renal capsule suppresses tubular epithelial cell injury and renal fibrosis, supporting further development as a possible clinically relevant strategy. Impact statement Chronic kidney disease (CKD) produces irreversible loss of nephron function, leading to toxemia, prolonged inflammation, and ultimately kidney fibrosis. Currently, no therapies exist to effectively treat CKD due to its complex pathophysiology. Mesenchymal stem/stromal cells (MSCs) are widely known to secret therapeutic paracrine factors, which is expected to provide a new effective therapy for unmet medical needs. However, unsatisfied MSC quality and administration methods to patients limit their therapeutic effects. In this study, we engineered clonal bone marrow-derived MSC sheets and established clinically relevant cell sheet transplantation strategy to treat renal fibrosis, which would improve MSC treatment for kidney disease.
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Affiliation(s)
- Masatoshi Oka
- Cell Sheet Tissue Engineering Center (CSTEC), University of Utah, Salt Lake City, Utah, USA.,Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, Utah, USA.,Department of Nephrology, Tokyo Women's Medical University, Tokyo, Japan
| | - Sumako Kameishi
- Cell Sheet Tissue Engineering Center (CSTEC), University of Utah, Salt Lake City, Utah, USA.,Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, Utah, USA
| | - Yun-Kyoung Cho
- Department of Nephrology, Tokyo Women's Medical University, Tokyo, Japan
| | - Sun U Song
- Department of Nephrology, Tokyo Women's Medical University, Tokyo, Japan
| | - David W Grainger
- Cell Sheet Tissue Engineering Center (CSTEC), University of Utah, Salt Lake City, Utah, USA.,SCM Lifescience Co., Ltd., Republic of Korea
| | - Teruo Okano
- Cell Sheet Tissue Engineering Center (CSTEC), University of Utah, Salt Lake City, Utah, USA.,Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, Utah, USA.,Department of Biomedical Engineering, University of Utah, Salt Lake City, Utah, USA
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12
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Kim W, Gwon Y, Park S, Kim H, Kim J. Therapeutic strategies of three-dimensional stem cell spheroids and organoids for tissue repair and regeneration. Bioact Mater 2023; 19:50-74. [PMID: 35441116 PMCID: PMC8987319 DOI: 10.1016/j.bioactmat.2022.03.039] [Citation(s) in RCA: 86] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 03/16/2022] [Accepted: 03/25/2022] [Indexed: 02/07/2023] Open
Abstract
Three-dimensional (3D) stem cell culture systems have attracted considerable attention as a way to better mimic the complex interactions between individual cells and the extracellular matrix (ECM) that occur in vivo. Moreover, 3D cell culture systems have unique properties that help guide specific functions, growth, and processes of stem cells (e.g., embryogenesis, morphogenesis, and organogenesis). Thus, 3D stem cell culture systems that mimic in vivo environments enable basic research about various tissues and organs. In this review, we focus on the advanced therapeutic applications of stem cell-based 3D culture systems generated using different engineering techniques. Specifically, we summarize the historical advancements of 3D cell culture systems and discuss the therapeutic applications of stem cell-based spheroids and organoids, including engineering techniques for tissue repair and regeneration.
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Affiliation(s)
- Woochan Kim
- Department of Convergence Biosystems Engineering, Chonnam National University, Gwangju, 61186, Republic of Korea
- Department of Rural and Biosystems Engineering, Chonnam National University, Gwangju, 61186, Republic of Korea
- Interdisciplinary Program in IT-Bio Convergence System, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Yonghyun Gwon
- Department of Convergence Biosystems Engineering, Chonnam National University, Gwangju, 61186, Republic of Korea
- Department of Rural and Biosystems Engineering, Chonnam National University, Gwangju, 61186, Republic of Korea
- Interdisciplinary Program in IT-Bio Convergence System, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Sunho Park
- Department of Convergence Biosystems Engineering, Chonnam National University, Gwangju, 61186, Republic of Korea
- Department of Rural and Biosystems Engineering, Chonnam National University, Gwangju, 61186, Republic of Korea
- Interdisciplinary Program in IT-Bio Convergence System, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Hyoseong Kim
- Department of Convergence Biosystems Engineering, Chonnam National University, Gwangju, 61186, Republic of Korea
- Department of Rural and Biosystems Engineering, Chonnam National University, Gwangju, 61186, Republic of Korea
- Interdisciplinary Program in IT-Bio Convergence System, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Jangho Kim
- Department of Convergence Biosystems Engineering, Chonnam National University, Gwangju, 61186, Republic of Korea
- Department of Rural and Biosystems Engineering, Chonnam National University, Gwangju, 61186, Republic of Korea
- Interdisciplinary Program in IT-Bio Convergence System, Chonnam National University, Gwangju, 61186, Republic of Korea
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13
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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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Rafiee Z, Orazizadeh M, Nejad Dehbashi F, Neisi N, Babaahmadi-Rezaei H, Mansouri E. Mesenchymal stem cells derived from the kidney can ameliorate diabetic nephropathy through the TGF-β/Smad signaling pathway. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:53212-53224. [PMID: 35278177 DOI: 10.1007/s11356-021-17954-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 12/01/2021] [Indexed: 06/14/2023]
Abstract
Diabetic nephropathy (DN) has been introduced as one of the main microvascular complications in diabetic patients, the most common cause of end-stage renal disease (ESRD). Based on the therapeutic potential of mesenchymal stem cells in tissue repair, we aimed to test the hypothesis that kidney stem cells (KSCs) might be effective in the kidney regeneration process. Stem cells from rat kidney were separated, and the surface stem cell markers were determined by flow cytometry analysis. Thirty-two Sprague Dawley rats were divided into four groups (control, control that received kidney stem cells, diabetic, diabetic treated with stem cells). To establish diabetic, model STZ (streptozotocin) (60 mg/kg) was used. The KSCs were injected into experimental groups via tail vein (2 × 106 cells/rat). In order to determine the impact of stem cells on the function and structure of the kidney, biochemical and histological parameters were measured. Further, the expression of miRNA-29a, miR-192, IL-1β, and TGF-β was determined through the real-time PCR technique. Phosphorylation of Smad2/3 was evaluated by using the standard western blotting. The KSCs significantly reduced blood nitrogen (BUN), serum creatinine (Scr), and 24-h urinary proteins in DN (P < 0.05). IL-1β and TGF-β significantly increased in the kidney of diabetic rats. In addition, the expression of miR-29a is significantly increased, whereas miR-192 decreased after treatment with KSCs (P < 0.05). Diabetic rats showed an increased level of phosphorylation of both Smad2 and Smad3 (P < 0.05). Periodic acid-Schiff (PAS) staining showed improved histopathological changes in the presence of KSCs. Stem cells derived from adult rat kidney may be an option for treating the early DN to improve the functions and structure of kidneys in rats with DN.
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Affiliation(s)
- Zeinab Rafiee
- Medical Basic Sciences Research Institute, Cellular and Molecular Research Center, Department of Anatomical Sciences, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, 61335, Ahvaz, Iran
| | - Mahmoud Orazizadeh
- Medical Basic Sciences Research Institute, Cellular and Molecular Research Center, Department of Anatomical Sciences, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, 61335, Ahvaz, Iran
| | - Fereshteh Nejad Dehbashi
- Medical Basic Sciences Research Institute, Cellular and Molecular Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Niloofar Neisi
- Alimentary Tract Research Center, Imam Khomeini Hospital Clinical Research Development Unit, Infectious and Tropical Diseases Research Center, Department of Virology, the School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hossein Babaahmadi-Rezaei
- Hyperlipidemia Research Center, Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Esrafil Mansouri
- Medical Basic Sciences Research Institute, Cellular and Molecular Research Center, Department of Anatomical Sciences, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, 61335, Ahvaz, Iran.
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15
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Wang S, Lei B, Zhang E, Gong P, Gu J, He L, Han L, Yuan Z. Targeted Therapy for Inflammatory Diseases with Mesenchymal Stem Cells and Their Derived Exosomes: From Basic to Clinics. Int J Nanomedicine 2022; 17:1757-1781. [PMID: 35469174 PMCID: PMC9034888 DOI: 10.2147/ijn.s355366] [Citation(s) in RCA: 84] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 04/09/2022] [Indexed: 12/13/2022] Open
Abstract
Inflammation is a beneficial and physiological process, but there are a number of inflammatory diseases which have detrimental effects on the body. In addition, the drugs used to treat inflammation have toxic side effects when used over a long period of time. Mesenchymal stem cells (MSCs) are pluripotent stem cells that can be isolated from a variety of tissues and can be differentiate into diverse cell types under appropriate conditions. They also exhibit noteworthy anti-inflammatory properties, providing new options for the treatment of inflammatory diseases. The therapeutic potential of MSCs is currently being investigated for various inflammatory diseases, such as kidney injury, lung injury, osteoarthritis (OA), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD). MSCs can perform multiple functions, including immunomodulation, homing, and differentiation, to enable damaged tissues to form a balanced inflammatory and regenerative microenvironment under severe inflammatory conditions. In addition, accumulated evidence indicates that exosomes from extracellular vesicles of MSCs (MSC-Exos) play an extraordinary role, mainly by transferring their components to recipient cells. In this review, we summarize the mechanism and clinical trials of MSCs and MSC-Exos in various inflammatory diseases in detail, with a view to contributing to the treatment of MSCs and MSC-Exos in inflammatory diseases.
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Affiliation(s)
- Shuo Wang
- College of Pharmacy, Southwest Minzu University, Chengdu, 610041, Sichuan, People’s Republic of China
| | - Biyu Lei
- College of Pharmacy, Southwest Minzu University, Chengdu, 610041, Sichuan, People’s Republic of China
| | - E Zhang
- Department of Basic Sciences, Officers College of People’s Armed Police, Chengdu, Sichuan, 610213, People’s Republic of China
| | - Puyang Gong
- College of Pharmacy, Southwest Minzu University, Chengdu, 610041, Sichuan, People’s Republic of China
| | - Jian Gu
- College of Pharmacy, Southwest Minzu University, Chengdu, 610041, Sichuan, People’s Republic of China
| | - Lili He
- College of Pharmacy, Southwest Minzu University, Chengdu, 610041, Sichuan, People’s Republic of China
| | - Lu Han
- College of Pharmacy, Southwest Minzu University, Chengdu, 610041, Sichuan, People’s Republic of China
| | - Zhixiang Yuan
- College of Pharmacy, Southwest Minzu University, Chengdu, 610041, Sichuan, People’s Republic of China
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16
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Yang Y, Gao J, Wang S, Wang W, Zhu FL, Wang X, Liang S, Feng Z, Lin S, Zhang L, Chen X, Cai G. Efficacy of umbilical cord mesenchymal stem cell transfusion for the treatment of severe AKI: a protocol for a randomised controlled trial. BMJ Open 2022; 12:e047622. [PMID: 35190406 PMCID: PMC8862499 DOI: 10.1136/bmjopen-2020-047622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
INTRODUCTION Acute kidney injury (AKI) is a common and severe clinical problem that is associated with high mortality, a long hospital stays and high healthcare resource consumption. Approximately a quarter of AKI survivors will develop chronic kidney disease. Mesenchymal stem cells (MSCs) are multipotent stem cells with antiapoptotic, immunomodulatory, antioxidative and proangiogenic properties. Therefore, MSCs have been considered as a potential new therapy for the treatment of AKI. Several clinical trials have been performed, but the results have been inconsistent. This trial investigated whether MSCs can improve renal recovery and mortality in patients with severe AKI. METHODS AND ANALYSIS One hundred subjects suffering from severe AKI will participate in this patient-blinded, randomised, placebo-controlled, parallel design clinical trial. Participants will be randomly assigned to receive two doses of MSCs or placebo (saline) on days 0 and 7. Urinary biomarkers of renal injury and repair will be measured using commercially available ELISA kits. The main outcome measures are changes in renal function levels within the first 28 days following MSC infusion. ETHICS AND DISSEMINATION The study was approved by the Ethics Committee of the Chinese PLA General Hospital. The findings of the study will be disseminated through public and scientific channels. TRIAL REGISTRATION NUMBER NCT04194671.
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Affiliation(s)
- Yuanjun Yang
- Department of Nephrology, Chinese PLA General Hospital, Beijing, China
| | - Jianjun Gao
- Department of Nephrology, Chinese PLA General Hospital, Beijing, China
| | - Siyang Wang
- Department of Nephrology, Chinese PLA General Hospital, Beijing, China
| | - Wenjuan Wang
- Department of Nephrology, Chinese PLA General Hospital, Beijing, China
| | - Fang-Lei Zhu
- Department of Nephrology, Chinese PLA General Hospital, Beijing, China
| | - Xiaolong Wang
- Department of Nephrology, Chinese PLA General Hospital, Beijing, China
| | - Shuang Liang
- Department of Nephrology, Chinese PLA General Hospital, Beijing, China
| | - Zhe Feng
- Department of Nephrology, Chinese PLA General Hospital, Beijing, China
| | - Shupeng Lin
- Department of Nephrology, Chinese PLA General Hospital, Beijing, China
| | - Li Zhang
- Department of Nephrology, Chinese PLA General Hospital, Beijing, China
| | - Xiangmei Chen
- Department of Nephrology, Chinese PLA General Hospital, Beijing, China
| | - Guangyan Cai
- Department of Nephrology, Chinese PLA General Hospital, Beijing, China
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17
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Molecular Mechanisms of Kidney Injury and Repair. Int J Mol Sci 2022; 23:ijms23031542. [PMID: 35163470 PMCID: PMC8835923 DOI: 10.3390/ijms23031542] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 01/24/2022] [Accepted: 01/26/2022] [Indexed: 12/17/2022] Open
Abstract
Chronic kidney disease (CKD) will become the fifth global cause of death by 2040, thus emphasizing the need to better understand the molecular mechanisms of damage and regeneration in the kidney. CKD predisposes to acute kidney injury (AKI) which, in turn, promotes CKD progression. This implies that CKD or the AKI-to-CKD transition are associated with dysfunctional kidney repair mechanisms. Current therapeutic options slow CKD progression but fail to treat or accelerate recovery from AKI and are unable to promote kidney regeneration. Unraveling the cellular and molecular mechanisms involved in kidney injury and repair, including the failure of this process, may provide novel biomarkers and therapeutic tools. We now review the contribution of different molecular and cellular events to the AKI-to-CKD transition, focusing on the role of macrophages in kidney injury, the different forms of regulated cell death and necroinflammation, cellular senescence and the senescence-associated secretory phenotype (SAPS), polyploidization, and podocyte injury and activation of parietal epithelial cells. Next, we discuss key contributors to repair of kidney injury and opportunities for their therapeutic manipulation, with a focus on resident renal progenitor cells, stem cells and their reparative secretome, certain macrophage subphenotypes within the M2 phenotype and senescent cell clearance.
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Karathanasis D, Karathanasis CR, Karaolia A. Cardiac surgery-associated acute kidney injury: The core of etiology, treatment, and prognosis. JOURNAL OF CLINICAL AND PREVENTIVE CARDIOLOGY 2022. [DOI: 10.4103/jcpc.jcpc_5_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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19
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Westenfelder C, Hu Z, Zhang P, Gooch A. Intraperitoneal administration of human "Neo-Islets", 3-D organoids of mesenchymal stromal and pancreatic islet cells, normalizes blood glucose levels in streptozotocin-diabetic NOD/SCID mice: Significance for clinical trials. PLoS One 2021; 16:e0259043. [PMID: 34710142 PMCID: PMC8553138 DOI: 10.1371/journal.pone.0259043] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 10/11/2021] [Indexed: 11/21/2022] Open
Abstract
Globally, individuals with autoimmune Type 1 diabetes mellitus (T1DM) continue to depend for survival on insulin injections. While pancreas and intrahepatic pancreatic islet transplants can produce insulin-independence and ameliorate serious complications, both therapies depend on potentially toxic anti-rejection drugs. Furthermore, the scarcity of pancreas donors and islet transplant failures limit the general availability of such interventions. Recently, fetal and induced Pluripotent Stem Cells have been successfully differentiated to generate insulin producing β-like cells that generate euglycemia in diabetic mice. However, their clinical use still depends on anti-rejection drugs or immune-isolating encapsulation systems. We reported recently that allogeneic “Neo-Islets” (NI), 3-D organoids of Mesenchymal Stromal and Islet Cells are immune protected and permanently correct autoimmune diabetes in NOD mice by omental engraftment and endocrine cell redifferentiation. This new “endocrine pancreas” delivers islet hormones physiologically into the hepatic portal vein. Furthermore, treatment of insulin-dependent dogs with allogeneic canine NIs (ongoing FDA-approved Pilot Study) consistently improved glycemic control without the need for antirejection drugs. As there remains a critical need for curative therapies of T1DM, we engineered human NIs and tested their ability, after i.p. administration, to reestablish euglycemia in streptozotocin (STZ)-diabetic NOD/SCID mice. This diabetes model reproduces, in part, the clinical situation in which recipients of allogeneic biotherapies must take potent anti-rejection drugs that similarly create a life-long immune-compromised status. The present study demonstrates that human NI therapy (2x10e5/kg bw NIs/mouse) of STZ-diabetic NOD/SCID mice (n = 6), compared to controls (n = 6) significantly improved glycemic control, and most importantly, that a second dose given to the initial group normalized blood glucose levels long-term. Conclusion: Despite the limitations of the utilized diabetic NOD/SCID mouse model, the obtained data show that human NIs are curative, an observation that has high translational relevance and significantly supports the planned conduct of clinical trials with human NIs.
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Affiliation(s)
- Christof Westenfelder
- Department of Medicine, Division of Nephrology, University of Utah, Salt Lake City, UT, United States of America
- SymbioCellTech, Salt Lake City, UT, United States of America
- * E-mail:
| | - Zhuma Hu
- SymbioCellTech, Salt Lake City, UT, United States of America
| | - Ping Zhang
- SymbioCellTech, Salt Lake City, UT, United States of America
| | - Anna Gooch
- SymbioCellTech, Salt Lake City, UT, United States of America
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20
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Lee PW, Wu BS, Yang CY, Lee OKS. Molecular Mechanisms of Mesenchymal Stem Cell-Based Therapy in Acute Kidney Injury. Int J Mol Sci 2021; 22:11406. [PMID: 34768837 PMCID: PMC8583897 DOI: 10.3390/ijms222111406] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/18/2021] [Accepted: 10/20/2021] [Indexed: 12/12/2022] Open
Abstract
Acute kidney injury (AKI) causes a lot of harm to human health but is treated by only supportive therapy in most cases. Recent evidence shows that mesenchymal stem cells (MSCs) benefit kidney regeneration through releasing paracrine factors and extracellular vesicles (EVs) to the recipient kidney cells and are considered to be promising cellular therapy for AKI. To develop more efficient, precise therapies for AKI, we review the therapeutic mechanism of MSCs and MSC-derived EVs in AKI and look for a better understanding of molecular signaling and cellular communication between donor MSCs and recipient kidney cells. We also review recent clinical trials of MSC-EVs in AKI. This review summarizes the molecular mechanisms of MSCs' therapeutic effects on kidney regeneration, expecting to comprehensively facilitate future clinical application for treating AKI.
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Grants
- Yin Yen-Liang Foundation Development and Construction Plan (107F-M01-0504) National Yang-Ming University
- MOST 108-2923-B-010-002-MY3, MOST 109-2314-B-010-053-MY3, MOST 109-2811-B-010-532, MOST 109-2926-I-010-502, MOST 109-2823-8-010-003-CV, MOST 109-2622-B-010-006, MOST 109-2321-B-010-006, MOST 110-2923-B-A49A-501-MY3, and MOST 110-2321-B-A49-003 Ministry of Science and Technology, Taiwan
- V106D25-003-MY3, VGHUST107-G5-3-3, VGHUST109-V5-1-2, and V110C-194 Taipei Veterans General Hospital
- Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B) Ministry of Education
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Affiliation(s)
- Pei-Wen Lee
- Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan; (P.-W.L.); (B.-S.W.)
- Hong Deh Clinic, Taipei 11251, Taiwan
| | - Bo-Sheng Wu
- Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan; (P.-W.L.); (B.-S.W.)
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Chih-Yu Yang
- Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan; (P.-W.L.); (B.-S.W.)
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
- Department of Medicine, Division of Nephrology, Taipei Veterans General Hospital, Taipei 11217, Taiwan
- Center for Intelligent Drug Systems and Smart Bio-Devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu 30010, Taiwan
- Stem Cell Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Oscar Kuang-Sheng Lee
- Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan; (P.-W.L.); (B.-S.W.)
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
- Stem Cell Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
- Department of Orthopedics, China Medical University Hospital, Taichung 40447, Taiwan
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21
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Shang Z, Jiang Y, Guan X, Wang A, Ma B. Therapeutic Effects of Stem Cells From Different Source on Renal Ischemia- Reperfusion Injury: A Systematic Review and Network Meta-analysis of Animal Studies. Front Pharmacol 2021; 12:713059. [PMID: 34539400 PMCID: PMC8444551 DOI: 10.3389/fphar.2021.713059] [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] [Received: 05/24/2021] [Accepted: 08/17/2021] [Indexed: 12/20/2022] Open
Abstract
Objective: Although stem cell therapy for renal ischemia-reperfusion injury (RIRI) has made immense progress in animal studies, conflicting results have been reported by the investigators. Therefore, we aimed to systematically evaluate the effects of different stem cells on renal function of animals with ischemia-reperfusion injury and to compare the efficacies of stem cells from various sources. Methods: PubMed, Web of Science, Embase, Cochrane, CNKI, VIP, CBM, and WanFang Data were searched for records until April 2021. Two researchers independently conducted literature screening, data extraction, and literature quality evaluation. Results and conclusion: Seventy-two animal studies were included for data analysis. Different stem cells significantly reduced serum creatinine and blood urea nitrogen levels in the early and middle stages (1 and 7 days) compared to the negative control group, however there was no significant difference in the late stage among all groups (14 days); In the early stage (1 day), the renal histopathological score in the stem cell group was significantly lower than that in the negative control group, and there was no significant difference among these stem cells. In addition, there was no significant difference between stem cell and negative control in proliferation of resident cells, however, significantly less apoptosis of resident cells than negative control. In conclusion, the results showed that stem cells from diverse sources could improve the renal function of RIRI animals. ADMSCs and MDMSCs were the most-researched stem cells, and they possibly hold the highest therapeutic potential. However, the quality of evidence included in this study is low, and there are many risks of bias. The exact efficacy of the stem cells and the requirement for further clinical studies remain unclear.
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Affiliation(s)
- Zhizhong Shang
- Evidence Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China.,The Second Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Yanbiao Jiang
- Evidence Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China.,The Second Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Xin Guan
- The Second Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Anan Wang
- The Second Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Bin Ma
- Evidence Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China
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22
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Calcat-i-Cervera S, Sanz-Nogués C, O'Brien T. When Origin Matters: Properties of Mesenchymal Stromal Cells From Different Sources for Clinical Translation in Kidney Disease. Front Med (Lausanne) 2021; 8:728496. [PMID: 34616756 PMCID: PMC8488400 DOI: 10.3389/fmed.2021.728496] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 08/19/2021] [Indexed: 12/14/2022] Open
Abstract
Advanced therapy medicinal products (ATMPs) offer new prospects to improve the treatment of conditions with unmet medical needs. Kidney diseases are a current major health concern with an increasing global prevalence. Chronic renal failure appears after many years of impairment, which opens a temporary window to apply novel therapeutic approaches to delay or halt disease progression. The immunomodulatory, anti-inflammatory, and pro-regenerative properties of mesenchymal stromal cells (MSCs) have sparked interest for their use in cell-based regenerative therapies. Currently, several early-phase clinical trials have been completed and many are ongoing to explore MSC safety and efficacy in a wide range of nephropathies. However, one of the current roadblocks to the clinical translation of MSC therapies relates to the lack of standardization and harmonization of MSC manufacturing protocols, which currently hinders inter-study comparability. Studies have shown that cell culture processing variables can have significant effects on MSC phenotype and functionality, and these are highly variable across laboratories. In addition, heterogeneity within MSC populations is another obstacle. Furthermore, MSCs may be isolated from several sources which adds another variable to the comparative assessment of outcomes. There is now a growing body of literature highlighting unique and distinctive properties of MSCs according to the tissue origin, and that characteristics such as donor, age, sex and underlying medical conditions may alter the therapeutic effect of MSCs. These variables must be taken into consideration when developing a cell therapy product. Having an optimal scale-up strategy for MSC manufacturing is critical for ensuring product quality while minimizing costs and time of production, as well as avoiding potential risks. Ideally, optimal scale-up strategies must be carefully considered and identified during the early stages of development, as making changes later in the bioprocess workflow will require re-optimization and validation, which may have a significant long-term impact on the cost of the therapy. This article provides a summary of important cell culture processing variables to consider in the scale-up of MSC manufacturing as well as giving a comprehensive review of tissue of origin-specific biological characteristics of MSCs and their use in current clinical trials in a range of renal pathologies.
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Affiliation(s)
| | | | - Timothy O'Brien
- Regenerative Medicine Institute (REMEDI), CÚRAM, Biomedical Science Building, National University of Ireland, Galway, Ireland
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23
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Geng J, Zhang W, Chen C, Zhang H, Zhou A, Huang Y. Tracking the Differentiation Status of Human Neural Stem Cells through Label-Free Raman Spectroscopy and Machine Learning-Based Analysis. Anal Chem 2021; 93:10453-10461. [PMID: 34282890 DOI: 10.1021/acs.analchem.0c04941] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The ability to noninvasively monitor stem cells' differentiation is important to stem cell studies. Raman spectroscopy is a non-harmful imaging approach that acquires the cellular biochemical signatures. Herein, we report the first use of label-free Raman spectroscopy to characterize the gradual change during the differentiation process of live human neural stem cells (NSCs) in the in vitro cultures. Raman spectra of 600-1800 cm-1 were measured with human NSC cultures from the undifferentiated stage (NSC-predominant) to the highly differentiated one (neuron-predominant) and subsequently analyzed using various mathematical methods. Hierarchical cluster analysis distinguished two cell types (NSCs and neurons) through the spectra. The subsequently derived differentiation rate matched that measured by immunocytochemistry. The key spectral biomarkers were identified by time-dependent trend analysis and principal component analysis. Furthermore, through machine learning-based analysis, a set of eight spectral data points were found to be highly accurate in classifying cell types and predicting the differentiation rate. The predictive accuracy was the highest using the artificial neural network (ANN) and slightly lowered using the logistic regression model and linear discriminant analysis. In conclusion, label-free Raman spectroscopy with the aid of machine learning analysis can provide the noninvasive classification of cell types at the single-cell level and thus accurately track the human NSC differentiation. A set of eight spectral data points combined with the ANN method were found to be the most efficient and accurate. Establishing this non-harmful and efficient strategy will shed light on the in vivo and clinical studies of NSCs.
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Affiliation(s)
- Junnan Geng
- Department of Biological Engineering, Utah State University, 4105 Old Main Hill, ENGR 402, Logan, Utah 84322, United States
| | - Wei Zhang
- Department of Biological Engineering, Utah State University, 4105 Old Main Hill, ENGR 402, Logan, Utah 84322, United States
| | - Cheng Chen
- Department of Biological Engineering, Utah State University, 4105 Old Main Hill, ENGR 402, Logan, Utah 84322, United States
| | - Han Zhang
- Department of Biological Engineering, Utah State University, 4105 Old Main Hill, ENGR 402, Logan, Utah 84322, United States
| | - Anhong Zhou
- Department of Biological Engineering, Utah State University, 4105 Old Main Hill, ENGR 402, Logan, Utah 84322, United States
| | - Yu Huang
- Department of Biological Engineering, Utah State University, 4105 Old Main Hill, ENGR 402, Logan, Utah 84322, United States
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24
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Wong CY. Current advances of stem cell-based therapy for kidney diseases. World J Stem Cells 2021; 13:914-933. [PMID: 34367484 PMCID: PMC8316868 DOI: 10.4252/wjsc.v13.i7.914] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 04/10/2021] [Accepted: 07/12/2021] [Indexed: 02/06/2023] Open
Abstract
Kidney diseases are a prevalent health problem around the world. Multidrug therapy used in the current routine treatment for kidney diseases can only delay disease progression. None of these drugs or treatments can reverse the progression to an end-stage of the disease. Therefore, it is crucial to explore novel therapeutics to improve patients’ quality of life and possibly cure, reverse, or alleviate the kidney disease. Stem cells have promising potentials as a form of regenerative medicine for kidney diseases due to their unlimited replication and their ability to differentiate into kidney cells in vitro. Mounting evidences from the administration of stem cells in an experimental kidney disease model suggested that stem cell-based therapy has therapeutic or renoprotective effects to attenuate kidney damage while improving the function and structure of both glomerular and tubular compartments. This review summarises the current stem cell-based therapeutic approaches to treat kidney diseases, including the various cell sources, animal models or in vitro studies. The challenges of progressing from proof-of-principle in the laboratory to widespread clinical application and the human clinical trial outcomes reported to date are also highlighted. The success of cell-based therapy could widen the scope of regenerative medicine in the future.
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Affiliation(s)
- Chee-Yin Wong
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Kajang 43000, Selangor, Malaysia
- Research Department, Cytopeutics, Cyberjaya 63000, Selangor, Malaysia
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25
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Textor SC, Abumoawad A, Saad A, Ferguson C, Dietz A. Stem Cell Therapy for Microvascular Injury Associated with Ischemic Nephropathy. Cells 2021; 10:cells10040765. [PMID: 33807289 PMCID: PMC8066553 DOI: 10.3390/cells10040765] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 03/22/2021] [Accepted: 03/26/2021] [Indexed: 12/15/2022] Open
Abstract
Ischemic nephropathy reflects progressive loss of kidney function due to large vessel atherosclerotic occlusive disease. Recent studies indicate that this process is characterized by microvascular rarefaction, increased tissue hypoxia and activation of inflammatory processes of tissue injury. This review summarizes the rationale and application of functional MR imaging to evaluate tissue oxygenation in human subjects that defines the limits of renal adaptation to reduction in blood flow, development of increasingly severe tissue hypoxia and recruitment of inflammatory injury pathways in ischemic nephropathy. Human mesenchymal stromal/stem cells (MSC) are capable of modifying angiogenic pathways and immune responses, but the potency of these effects vary between individuals and various clinical characteristics including age and chronic kidney disease and levels of hypoxia. We summarize recently completed first-in-human studies applying intrarenal infusion of autologous adipose-derived MSC in human subjects with ischemic nephropathy that demonstrate a rise in blood flow and reduction in tissue hypoxia consistent with partial repair of microvascular injury, even without restoring main renal arterial blood flow. Inflammatory biomarkers in the renal vein of post-stenotic kidneys fell after MSC infusion. These changes were associated with modest but significant dose-related increments in kidney function. These data provide support a role for autologous MSC in repair of microvascular injury associated with tissue hypoxia.
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Affiliation(s)
- Stephen C. Textor
- Mayo Clinic, Division of Nephrology and Hypertension, Rochester, MN 55905, USA;
- Correspondence:
| | - Abdu Abumoawad
- Department of Medicine University of Missouri, Kansas, MO 64108, USA;
| | - Ahmed Saad
- Department of Medicine Creighton University School of Medicine, Omaha, NE 68124, USA;
| | | | - Allan Dietz
- Mayo Clinic, Human Cell Therapy Laboratory, Rochester, MN 55905, USA;
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26
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Li JK, Yang C, Su Y, Luo JC, Luo MH, Huang DL, Tu GW, Luo Z. Mesenchymal Stem Cell-Derived Extracellular Vesicles: A Potential Therapeutic Strategy for Acute Kidney Injury. Front Immunol 2021; 12:684496. [PMID: 34149726 PMCID: PMC8209464 DOI: 10.3389/fimmu.2021.684496] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 05/18/2021] [Indexed: 02/05/2023] Open
Abstract
Acute kidney injury (AKI) is a common and potential life-threatening disease in patients admitted to hospital, affecting 10%-15% of all hospitalizations and around 50% of patients in the intensive care unit. Severe, recurrent, and uncontrolled AKI may progress to chronic kidney disease or end-stage renal disease. AKI thus requires more efficient, specific therapies, rather than just supportive therapy. Mesenchymal stem cells (MSCs) are considered to be promising cells for cellular therapy because of their ease of harvesting, low immunogenicity, and ability to expand in vitro. Recent research indicated that the main therapeutic effects of MSCs were mediated by MSC-derived extracellular vesicles (MSC-EVs). Furthermore, compared with MSCs, MSC-EVs have lower immunogenicity, easier storage, no tumorigenesis, and the potential to be artificially modified. We reviewed the therapeutic mechanism of MSCs and MSC-EVs in AKI, and considered recent research on how to improve the efficacy of MSC-EVs in AKI. We also summarized and analyzed the potential and limitations of EVs for the treatment of AKI to provide ideas for future clinical trials and the clinical application of MSC-EVs in AKI.
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Affiliation(s)
- Jia-Kun Li
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Cheng Yang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ying Su
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jing-Chao Luo
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ming-Hao Luo
- Shanghai Medical College, Fudan University, Shanghai, China
| | - Dan-Lei Huang
- Shanghai Medical College, Fudan University, Shanghai, China
- *Correspondence: Zhe Luo, ; Guo-Wei Tu,
| | - Guo-Wei Tu
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
- *Correspondence: Zhe Luo, ; Guo-Wei Tu,
| | - Zhe Luo
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Critical Care Medicine, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China
- *Correspondence: Zhe Luo, ; Guo-Wei Tu,
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27
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Zhao L, Hu C, Han F, Chen D, Ma Y, Wang J, Chen J. Cellular senescence, a novel therapeutic target for mesenchymal stem cells in acute kidney injury. J Cell Mol Med 2021. [PMCID: PMC7812305 DOI: 10.1111/jcmm.16163] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Cellular senescence is a widespread cellular programme that is characterized by permanent cell cycle arrest. Senescent cells adopt a changed secretory phenotype that can alter cellular function. For years, cellular senescence has been thought to be a protective factor against cancer; however, it is now recognized that it has a dual effect on individuals. Co‐ordinated activation of cellular senescence provides advantages during embryogenesis, wound healing, tissue repair and inhibition of tumorigenesis. On the other hand, the aberrant generation and accumulation of abnormal senescent cells lead to the development of age‐related conditions and tissue deterioration. During acute kidney injury (AKI), the kidney faces multiple types of stressors and challenges, which can easily drive cellular senescence. How to appropriately progress through the cell cycle and minimize long‐term damage is of great importance to the acquisition of adaptive repair considering that no available therapeutic interventions can reliably limit injury, speedy recovery or improve the prognosis of this syndrome. Whether the manipulation of cellular senescence can become a novel therapeutic target in AKI and reignite clinical and research interest remains to be determined. Here, we share our current understanding of the role of cellular senescence in AKI, along with examples of the application of mesenchymal stem cells (MSCs) for targeting this disorder during its treatment.
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Affiliation(s)
- Lingfei Zhao
- Kidney Disease Center The First Affiliated Hospital College of Medicine Zhejiang University Hangzhou China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province Institute of Nephrology Zhejiang University Hangzhou China
| | - Chenxia Hu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases The First Affiliated Hospital College of Medicine Zhejiang University Hangzhou Zhejiang China
| | - Fei Han
- Kidney Disease Center The First Affiliated Hospital College of Medicine Zhejiang University Hangzhou China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province Institute of Nephrology Zhejiang University Hangzhou China
| | - Dajin Chen
- Kidney Disease Center The First Affiliated Hospital College of Medicine Zhejiang University Hangzhou China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province Institute of Nephrology Zhejiang University Hangzhou China
| | - Yanhong Ma
- Kidney Disease Center The First Affiliated Hospital College of Medicine Zhejiang University Hangzhou China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province Institute of Nephrology Zhejiang University Hangzhou China
| | - Junni Wang
- Kidney Disease Center The First Affiliated Hospital College of Medicine Zhejiang University Hangzhou China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province Institute of Nephrology Zhejiang University Hangzhou China
| | - Jianghua Chen
- Kidney Disease Center The First Affiliated Hospital College of Medicine Zhejiang University Hangzhou China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province Institute of Nephrology Zhejiang University Hangzhou China
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28
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Zuo J, Wang SM, Jiang X, Cao M, Zhang Z, Shi T, Qin HL, Tang W. Design, synthesis and biological evaluation of novel arylpropionic esters for the treatment of acute kidney injury. Bioorg Chem 2020; 105:104455. [PMID: 33197847 DOI: 10.1016/j.bioorg.2020.104455] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 10/29/2020] [Accepted: 10/31/2020] [Indexed: 12/27/2022]
Abstract
Acute kidney injury (AKI) is associated with a strong inflammatory response, and inhibiting the response effectively prevents or ameliorates AKI. A series of novel arylpropionic esters were designed, synthesized and evaluated their biological activity in LPS-stimulated RAW264.7 cells. Novel arylpropionic esters bearing multi-functional groups showed significant anti-inflammatory activity, in which, compound 13b exhibited the most potent activity through dose-dependent inhibiting the production of nitric oxide (NO, IC50 = 3.52 μM), TNF-α and IL-6 (84.1% and 33.6%, respectively), as well as suppressing the expression of iNOS, COX-2 and TLR4 proteins. In C57BL/6 mice with cisplatin-induced AKI, compound 13b improved kidney function, inhibited inflammatory development, and reduced pathological damage of kidney tissues. In brief, this arylpropionic ester scaffold may be developed as anti-inflammatory agents.
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Affiliation(s)
- Jiawei Zuo
- School of Pharmacy, Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei 230032, China; First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China
| | - Shi-Meng Wang
- School of Life Science, Wuchang University of Technology, Wuhan 430223, China; School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan 430070, China
| | - Xia Jiang
- School of Pharmacy, Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei 230032, China
| | - Mengxin Cao
- School of Pharmacy, Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei 230032, China
| | - Ziwen Zhang
- School of Pharmacy, Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei 230032, China
| | - Tianlu Shi
- First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China
| | - Hua-Li Qin
- School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan 430070, China.
| | - Wenjian Tang
- School of Pharmacy, Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei 230032, China.
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29
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Lu J, Zhang J, Chen M, Chen C, Li Z, Liao P. Regulatory T Cells as a Novel Candidate for Cell-Based Therapy in Kidney Disease. Front Physiol 2020; 11:621. [PMID: 32581852 PMCID: PMC7296170 DOI: 10.3389/fphys.2020.00621] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 05/18/2020] [Indexed: 01/04/2023] Open
Abstract
Kidney disease is a significant health concern worldwide. Ineffective treatment can lead to disastrous consequences, such as organ failure and death. Research has turned to cell-based therapy, but has yet to produce an effective and reliable treatment for kidney disease. To address this problem, we examined four datasets of gene expression profiles from diseased and healthy kidney tissue in humans, mice, and rats. Differentially expressed genes (DEGs) were screened and subjected to enrichment analyses. Up-regulated genes in diseased kidney tissue were significantly enriched in pathways associated with regulatory T cells (Tregs). Analysis with the xCell tool showed that Tregs were generally increased in diseased kidney tissue in all species. To validate these results in vivo, kidneys were removed from mice with Adriamycin-induced nephropathy, and histology confirmed increase of Tregs. Furthermore, Tregs were adoptively transferred from healthy mice into mice with kidney injury, restoring normal structure to the damaged kidneys. Treg cells that were co-cultured with M2c macrophages exhibited up-regulation of chemokine receptors CCR2, CCR5, CCR7, CD62L, and CX3CR1. This may be the mechanism by which M2c cells enhance the migration of Tregs to the site of inflammation. We propose that Tregs may be an effective, novel candidate for cell-based therapy in pre-clinical kidney injury models.
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Affiliation(s)
- Junyu Lu
- The First Clinical Medical College of Jinan University, Guangzhou, China.,Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jianfeng Zhang
- Department of Emergency Medicine, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Menghua Chen
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Chun Chen
- Department of Cardiology and Endocrinology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Zhengzhao Li
- Department of Emergency Medicine, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Pinhu Liao
- The First Clinical Medical College of Jinan University, Guangzhou, China.,Department of Emergency Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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30
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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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31
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Ng NN, Thakor AS. Locoregional delivery of stem cell-based therapies. Sci Transl Med 2020; 12:eaba4564. [PMID: 32522806 DOI: 10.1126/scitranslmed.aba4564] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 02/24/2020] [Accepted: 05/20/2020] [Indexed: 12/13/2022]
Abstract
Interventional regenerative medicine (IRM) uses image-guided, minimally invasive procedures for the targeted delivery of stem cell-based therapies to regenerate, replace, or repair damaged organs. Although many cellular therapies have shown promise in the preclinical setting, clinical results have been suboptimal. Most intravenously delivered cells become trapped in the lungs and reticuloendothelial system, resulting in little therapy reaching target tissues. IRM aims to increase the efficacy of cell-based therapies by locoregional stem cell delivery via endovascular, endoluminal, or direct injection into tissues. This review highlights routes of delivery, disease states, and mechanisms of action involved in the targeted delivery of stem cells.
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Affiliation(s)
- Nathan Norton Ng
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University School of Medicine, Stanford, CA 94304, USA
| | - Avnesh Sinh Thakor
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University School of Medicine, Stanford, CA 94304, USA.
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32
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Liu Y, Cui J, Wang H, Hezam K, Zhao X, Huang H, Chen S, Han Z, Han ZC, Guo Z, Li Z. Enhanced therapeutic effects of MSC-derived extracellular vesicles with an injectable collagen matrix for experimental acute kidney injury treatment. Stem Cell Res Ther 2020; 11:161. [PMID: 32321594 PMCID: PMC7178991 DOI: 10.1186/s13287-020-01668-w] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 03/13/2020] [Accepted: 04/01/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) have been shown to have therapeutic potential for ischemic diseases and are considered an alternative to cell therapy. However, the low retention and poor stability of EVs post-transplantation in vivo remain obstacle prior to the clinical application of EVs. METHODS This study was designed to investigate whether collagen matrix could increase the retention and stability of EVs and further improve the therapeutic effects in murine acute kidney injury (AKI) model. EVs were isolated from human placental MSCs (hP-MSC-EVs) and encapsulated in a collagen matrix. Then, we investigated whether collagen matrix can prolong the retention of EVs in vivo, further enhancing the therapeutic efficiency of EVs in AKI. RESULTS Our results indicated that collagen matrix could effectively encapsulate EVs, significantly increase the stability of EVs, and promote the sustained release of EVs. Collagen matrix has improved the retention of EVs in the AKI model, which was proved by Gaussia luciferase (Gluc) imaging. The application of collagen matrix remarkably facilitated the proliferation of renal tubular epithelial cells in AKI compared with EVs alone. Moreover, collagen matrix could further augment the therapeutic effects of hP-MSC-EVs as revealed by angiogenesis, fibrosis and apoptosis, and functional analysis. Finally, we found that EVs play a therapeutic role by inhibiting endoplasmic reticulum (ER) stress. CONCLUSIONS Collagen matrix markedly enhanced the retention of EVs and further augmented the therapeutic effects of EVs for AKI. This strategy for improving the efficacy of EVs therapy provides a new direction for cell-free therapy.
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Affiliation(s)
- Yue Liu
- School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China.,The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, the College of Life Science, Tianjin, 300071, China
| | - Jian Cui
- Department of Intensive Care Unit (ICU), People's Hospital of Rizhao, Rizhao, 276826, Shandong, China
| | - Hongfen Wang
- State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing, 102218, China
| | - Kamal Hezam
- School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China
| | - Xiaotong Zhao
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, 453003, Henan, China
| | - Haoyan Huang
- School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China
| | - Shang Chen
- School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China
| | - Zhibo Han
- Jiangxi Engineering Research Center for Stem Cell, Shangrao, 334001, Jiangxi, China.,Tianjin Key Laboratory of Engineering Technologies for Cell Pharmaceutical, National Engineering Research Center of Cell Products, AmCellGene Co., Ltd., Tianjin, China
| | - Zhong-Chao Han
- Jiangxi Engineering Research Center for Stem Cell, Shangrao, 334001, Jiangxi, China.,Tianjin Key Laboratory of Engineering Technologies for Cell Pharmaceutical, National Engineering Research Center of Cell Products, AmCellGene Co., Ltd., Tianjin, China
| | - Zhikun Guo
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, 453003, Henan, China.
| | - Zongjin Li
- School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China. .,The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, the College of Life Science, Tianjin, 300071, China. .,State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing, 102218, China. .,Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, 453003, Henan, China.
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Abstract
Human bone marrow (BM) derived mesenchymal stem cells (MSC) have high capacity to propagate ex vivo with superior reparative, immunosuppressive, and anti-inflammatory properties. Here we describe standardized protocols and culture conditions that enable the isolation, expansion and maintenance of a highly purified and homogenous population of human MSC. These third party-derived off-the-shelf MSC from healthy human bone marrow donors can potently inhibit mitogenically or allogeneically activated human T cells in proliferation assays. The standard operating procedures described in this chapter can be applied to researchers aiming to enhance MSC immunosuppressive properties and defining MSC mechanisms of action. Importantly, these assays can be incorporated into clinical protocols where the safety and efficacy of human BM MSC can be verified in diseases that are modulated by T cell responses.
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Affiliation(s)
- Kisha N Sivanathan
- Faculty of Health and Medical Sciences, School of Medicine, University of Adelaide, Adelaide, SA, Australia.
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.
| | - Patrick T Coates
- Faculty of Health and Medical Sciences, School of Medicine, University of Adelaide, Adelaide, SA, Australia
- Central Northern Adelaide Renal Transplantation Service, Royal Adelaide Hospital, Adelaide, SA, Australia
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Tetta C, Deregibus MC, Camussi G. Stem cells and stem cell-derived extracellular vesicles in acute and chronic kidney diseases: mechanisms of repair. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:570. [PMID: 32775371 PMCID: PMC7347774 DOI: 10.21037/atm.2020.03.19] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Acute and chronic renal failure have long been described and now renamed as acute kidney injury (AKI) and chronic kidney disease (CKD). New concepts are emerging in the pathophysiology of kidney diseases. AKI is often caused by triggering factors (e.g., toxic, ischemic, immunologic) either individually or combined such as in sepsis (inflammation and hypoxia), and it is initiated at a defined time. Several experimental models of AKI have provided deep insight and have convincingly shown important proof-of-concepts of therapeutic relevance over the years. CKD is now considered a slowly developing disease with often an insidious course, lasting many years whereby co-morbidities (e.g., diabetes, hypertension, dysmetabolic syndrome) may act as worsening factors. It has become increasingly evident that even a single event of AKI may lead to a higher predisposition to develop a progressive CKD. In the present review, we will report studies on the renal protection by adult stem cells in different experimental models and clinical trials. The emerging role of extracellular vesicles (EVs) in cell-to-cell communication and their predominant effect in the paracrine mechanisms of stem cell-dependent actions have prompted several studies on their ability to attenuate both AKI and fibrosis occurring in CKD. We discuss several critical issues that need to be addressed before EVs may have a therapeutic application in humans.
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Affiliation(s)
- Ciro Tetta
- Unicyte Srl, University of Turin, Turin, Italy
| | - Maria Chiara Deregibus
- Department of Medical Sciences, University of Turin, Turin, Italy.,2i3T Incubator and Technology Transfer, University of Turin, Turin, Italy
| | - Giovanni Camussi
- Department of Medical Sciences, University of Turin, Turin, Italy
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35
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Sun DZ, Abelson B, Babbar P, Damaser MS. Harnessing the mesenchymal stem cell secretome for regenerative urology. Nat Rev Urol 2020; 16:363-375. [PMID: 30923338 DOI: 10.1038/s41585-019-0169-3] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The extensive arsenal of bioactive molecules secreted by mesenchymal stem cells (MSCs), known as the secretome, has demonstrated considerable therapeutic benefit in regenerative medicine. Investigation into the therapeutic potential of the secretome has enabled researchers to replicate the anti-inflammatory, pro-angiogenic and trophic effects of stem cells without the need for the cells themselves. Furthermore, treatment with the MSC secretome could circumvent hurdles associated with cellular therapy, including oncogenic transformation, immunoreactivity and cost. Thus, a clear rationale exists for investigating the therapeutic potential of the MSC secretome in regenerative urology. Indeed, preclinical studies have demonstrated the therapeutic benefits of the MSC secretome in models of stress urinary incontinence, renal disease, bladder dysfunction and erectile dysfunction. However, the specific mechanisms underpinning therapeutic activity are unclear and require further research before clinical translation. Improvements in current proteomic methods used to characterize the secretome will be necessary to provide further insight into stem cells and their secretome in regenerative urology.
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Affiliation(s)
- Daniel Z Sun
- Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA. .,Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, OH, USA. .,Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
| | - Benjamin Abelson
- Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA.,Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, OH, USA.,Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Paurush Babbar
- Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA.,Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, OH, USA.,Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Margot S Damaser
- Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA.,Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, OH, USA.,Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.,Advanced Platform Technology Center, Louis Stokes Cleveland VA Medical Center, Cleveland, OH, USA
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Sávio-Silva C, Soinski-Sousa PE, Balby-Rocha MTA, Lira ÁDO, Rangel ÉB. Mesenchymal stem cell therapy in acute kidney injury (AKI): review and perspectives. REVISTA DA ASSOCIAÇÃO MÉDICA BRASILEIRA 2020; 66:s45-s54. [DOI: 10.1590/1806-9282.66.s1.45] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Zhao L, Han F, Wang J, Chen J. Current understanding of the administration of mesenchymal stem cells in acute kidney injury to chronic kidney disease transition: a review with a focus on preclinical models. Stem Cell Res Ther 2019; 10:385. [PMID: 31843011 PMCID: PMC6916462 DOI: 10.1186/s13287-019-1507-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Revised: 11/03/2019] [Accepted: 11/22/2019] [Indexed: 12/11/2022] Open
Abstract
Incomplete recovery from acute kidney injury (AKI) can result in long-term functional deficits and has been recognized as a major contributor to chronic kidney disease (CKD), which is termed the AKI-CKD transition. Currently, an effective intervention for this disorder is still lacking. Principally, therapeutic strategies targeting the AKI-CKD transition can be divided into those reducing the severity of AKI or promoting the regenerative process towards beneficially adaptive repair pathways. Considering the fact that mesenchymal stem cells (MSCs) have the potential to address both aspects, therapeutic regimens based on MSCs have a promising future. In light of this information, we focus on the currently available evidence associated with MSC therapy involved in the treatment of the AKI-CKD transition and the underlying mechanisms. All of these discussions will contribute to the establishment of a reliable therapeutic strategy for patients with this problem, who can be easily ignored by physicians, and will lead to a better clinical outcome for them.
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Affiliation(s)
- Lingfei Zhao
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China
| | - Fei Han
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China
| | - Junni Wang
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China
| | - Jianghua Chen
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China. .,Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China.
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Zhao L, Hu C, Zhang P, Jiang H, Chen J. Melatonin preconditioning is an effective strategy for mesenchymal stem cell-based therapy for kidney disease. J Cell Mol Med 2019; 24:25-33. [PMID: 31747719 PMCID: PMC6933322 DOI: 10.1111/jcmm.14769] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 09/13/2019] [Accepted: 10/02/2019] [Indexed: 12/14/2022] Open
Abstract
Based on multiple studies in animal models, mesenchymal stem cell (MSC)‐based therapy appears to be an innovative intervention approach with tremendous potential for the management of kidney disease. However, the clinical therapeutic effects of MSCs in either acute kidney injury (AKI) or chronic kidney disease (CKD) are still under debate. Hurdles originate from the harsh microenvironment in vivo that decreases the cell survival rate, paracrine activity and migratory capacity of MSCs after transplantation, which are believed to be the main reasons for their limited effects in clinical applications. Melatonin is traditionally regarded as a circadian rhythm‐regulated neurohormone but in recent years has been found to exhibit antioxidant and anti‐inflammatory properties. Because inflammation, oxidative stress, thermal injury, and hypoxia are abnormally activated in kidney disease, application of melatonin preconditioning to optimize the MSC response to the hostile in vivo microenvironment before transplantation is of great importance. In this review, we discuss current knowledge concerning the beneficial effects of melatonin preconditioning in MSC‐based therapy for kidney disease. By summarizing the available information and discussing the underlying mechanisms, we aim to improve the therapeutic effects of MSC‐based therapy for kidney disease and accelerate translation to clinical application.
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Affiliation(s)
- Lingfei Zhao
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China.,Institute of Nephrology, Zhejiang University, Hangzhou, China
| | - Chenxia Hu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Ping Zhang
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China.,Institute of Nephrology, Zhejiang University, Hangzhou, China
| | - Hua Jiang
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China.,Institute of Nephrology, Zhejiang University, Hangzhou, China
| | - Jianghua Chen
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China.,Institute of Nephrology, Zhejiang University, Hangzhou, China
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Bushkalova R, Farno M, Tenailleau C, Duployer B, Cussac D, Parini A, Sallerin B, Girod Fullana S. Alginate-chitosan PEC scaffolds: A useful tool for soft tissues cell therapy. Int J Pharm 2019; 571:118692. [DOI: 10.1016/j.ijpharm.2019.118692] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 08/13/2019] [Accepted: 09/09/2019] [Indexed: 12/28/2022]
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The Anti-Inflammatory, Anti-Oxidative, and Anti-Apoptotic Benefits of Stem Cells in Acute Ischemic Kidney Injury. Int J Mol Sci 2019; 20:ijms20143529. [PMID: 31330934 PMCID: PMC6678402 DOI: 10.3390/ijms20143529] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 07/17/2019] [Accepted: 07/18/2019] [Indexed: 12/11/2022] Open
Abstract
Ischemia-reperfusion injury (IRI) plays a significant role in the pathogenesis of acute kidney injury (AKI). The complicated interaction between injured tubular cells, activated endothelial cells, and the immune system leads to oxidative stress and systemic inflammation, thereby exacerbating the apoptosis of renal tubular cells and impeding the process of tissue repair. Stem cell therapy is an innovative approach to ameliorate IRI due to its antioxidative, immunomodulatory, and anti-apoptotic properties. Therefore, it is crucial to understand the biological effects and mechanisms of action of stem cell therapy in the context of acute ischemic AKI to improve its therapeutic benefits. The recent finding that treatment with conditioned medium (CM) derived from stem cells is likely an effective alternative to conventional stem cell transplantation increases the potential for future therapeutic uses of stem cell therapy. In this review, we discuss the recent findings regarding stem cell-mediated cytoprotection, with a focus on the anti-inflammatory effects via suppression of oxidative stress and uncompromised immune responses following AKI. Stem cell-derived CM represents a favorable approach to stem cell-based therapy and may serve as a potential therapeutic strategy against acute ischemic AKI.
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Rota C, Morigi M, Imberti B. Stem Cell Therapies in Kidney Diseases: Progress and Challenges. Int J Mol Sci 2019; 20:ijms20112790. [PMID: 31181604 PMCID: PMC6600599 DOI: 10.3390/ijms20112790] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 05/31/2019] [Accepted: 06/05/2019] [Indexed: 12/15/2022] Open
Abstract
The prevalence of renal diseases is emerging as a public health problem. Despite major progress in supportive therapy, mortality rates among patients remain high. In an attempt to find innovative treatments to stimulate kidney regeneration, stem cell-based technology has been proposed as a potentially promising strategy. Here, we summarise the renoprotective potential of pluripotent and adult stem cell therapy in experimental models of acute and chronic kidney injury and we explore the different mechanisms at the basis of stem cell-induced kidney regeneration. Specifically, cell engraftment, incorporation into renal structures, or paracrine activities of embryonic or induced pluripotent stem cells as well as mesenchymal stem cells and renal precursors are analysed. We also discuss the relevance of stem cell secretome-derived bioproducts, including soluble factors and extracellular vesicles, and the option of using them as cell-free therapy to induce reparative processes. The translation of the experimental results into clinical trials is also addressed, highlighting the safety and feasibility of stem cell treatments in patients with kidney injury.
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Affiliation(s)
- Cinzia Rota
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano 87, 24126 Bergamo, Italy.
| | - Marina Morigi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano 87, 24126 Bergamo, Italy.
| | - Barbara Imberti
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano 87, 24126 Bergamo, Italy.
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42
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Potential and Therapeutic Efficacy of Cell-based Therapy Using Mesenchymal Stem Cells for Acute/chronic Kidney Disease. Int J Mol Sci 2019; 20:ijms20071619. [PMID: 30939749 PMCID: PMC6479813 DOI: 10.3390/ijms20071619] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Revised: 03/21/2019] [Accepted: 03/28/2019] [Indexed: 12/15/2022] Open
Abstract
Kidney disease can be either acute kidney injury (AKI) or chronic kidney disease (CKD) and it can lead to the development of functional organ failure. Mesenchymal stem cells (MSCs) are derived from a diverse range of human tissues. They are multipotent and have immunomodulatory effects to assist in the recovery from tissue injury and the inhibition of inflammation. Numerous studies have investigated the feasibility, safety, and efficacy of MSC-based therapies for kidney disease. Although the exact mechanism of MSC-based therapy remains uncertain, their therapeutic value in the treatment of a diverse range of kidney diseases has been studied in clinical trials. The use of MSCs is a promising therapeutic strategy for both acute and chronic kidney disease. The mechanism underlying the effects of MSCs on survival rate after transplantation and functional repair of damaged tissue is still ambiguous. The paracrine effects of MSCs on renal recovery, optimization of the microenvironment for cell survival, and control of inflammatory responses are thought to be related to their interaction with the damaged kidney environment. This review discusses recent experimental and clinical findings related to kidney disease, with a focus on the role of MSCs in kidney disease recovery, differentiation, and microenvironment. The therapeutic efficacy and current applications of MSC-based kidney disease therapies are also discussed.
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Li JS, Li B. Renal Injury Repair: How About the Role of Stem Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1165:661-670. [PMID: 31399989 DOI: 10.1007/978-981-13-8871-2_32] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Renal failure is one of the most important causes of mortality and morbidity all over the world. Acute kidney injury (AKI) is a major clinical problem that affects up to 5% of all hospitalized patients. Although the kidney has a remarkable capacity for regeneration after acute injury, the mortality among patients with severe AKI remains dismally high, and in clinical practice, most patients cannot be cured completely and suffer from chronic kidney disease (CKD). Recently, the incidence and prevalence of CKD have increased, largely as a result of the enhanced prevalence of diabetes and obesity. The progressive nature of CKD and the ensuing end-stage renal disease (ESRD) place a substantial burden on global healthcare resources. Currently, dialysis and transplantation remain the only treatment options. Finding new therapeutic methods to fight AKI and CKD remains an ongoing quest. Although the human renal histological structure is complex, stem cell therapies have been applied to repair injured kidneys. The curative effects of mesenchymal stem cells (MSCs), hematopoietic stem cells (HSCs), induced pluripotent stem cells (iPSCs), and nephron progenitor cells (NPCs) on renal repair have also been reported by researchers. This review focuses on stem cell therapy and mechanisms for renal injury repair.
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Affiliation(s)
- Jian-Si Li
- Department of Nephrology, 2nd Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Bing Li
- Department of Nephrology, 2nd Affiliated Hospital, Harbin Medical University, Harbin, China.
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Danjuma L, Mok PL, Higuchi A, Hamat RA, Teh SW, Koh AEH, Munusamy MA, Arulselvan P, Rajan M, Nambi A, Swamy K, Vijayaraman K, Murugan K, Natarajaseenivasan K, Subbiah SK. Modulatory and regenerative potential of transplanted bone marrow-derived mesenchymal stem cells on rifampicin-induced kidney toxicity. Regen Ther 2018; 9:100-110. [PMID: 30525080 PMCID: PMC6223029 DOI: 10.1016/j.reth.2018.09.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 09/03/2018] [Indexed: 12/26/2022] Open
Abstract
INTRODUCTION Anti-tuberculosis agent rifampicin is extensively used for its effectiveness. Possible complications of tuberculosis and prolonged rifampicin treatment include kidney damage; these conditions can lead to reduced efficiency of the affected kidney and consequently to other diseases. Bone marrow-derived mesenchymal stem cells (BMMSCs) can be used in conjunction with rifampicin to avert kidney damage; because of its regenerative and differentiating potentials into kidney cells. This research was designed to assess the modulatory and regenerative potentials of MSCs in averting kidney damage due to rifampicin-induced kidney toxicity in Wistar rats and their progenies. BMMSCs used in this research were characterized according to the guidelines of International Society for Cellular Therapy. METHODS The rats (male and female) were divided into three experimental groups, as follows: Group 1: control rats (4 males & 4 females); Group 2: rats treated with rifampicin only (4 males & 4 females); and Group 3: rats treated with rifampicin plus MSCs (4 males & 4 females). Therapeutic doses of rifampicin (9 mg/kg/day for 3-months) and MSCs infusions (twice/month for 3-months) were administered orally and intravenously respectively. At the end of the three months, the animals were bred together to determine if the effects would carry over to the next generation. Following breeding, the rats were sacrificed to harvest serum for biochemical analysis and the kidneys were also harvested for histological analysis and quantification of the glomeruli size, for the adult rats and their progenies. RESULTS The results showed some level of alterations in the biochemical indicators and histopathological damage in the rats that received rifampicin treatment alone, while the control and stem cells treated group showed apparently normal to nearly normal levels of both bio-indicators and normal histological architecture. CONCLUSIONS Intravenous administration of MSCs yielded sensible development, as seen from biochemical indicators, histology and the quantitative cell analysis, hence implying the modulatory and regenerative properties of MSCs.
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Affiliation(s)
- Lawal Danjuma
- Department of Medical Microbiology and Parasitology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
- Department of Microbiology and Biotechnology, Faculty of Science, Federal University Duste, P.M.B 7156, Duste, Jigawa, Nigeria
| | - Pooi Ling Mok
- Department of Biomedical Science, Faculty of Medicine and Health Science Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
- Genetics and Regenerative Medicine Research Centre, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, P.O. Box 2014, Sakaka, Aljouf Province, Saudi Arabia
| | - Akon Higuchi
- Department of Chemical and Materials Engineering, National Central University, Jhong-li, Taoyuan, 32001, Taiwan
- Department of Reproduction, National Research Institute for Child Health and Development, Tokyo, 157-8535, Japan
- Department of Botany and Microbiology, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Rukman Awang Hamat
- Department of Medical Microbiology and Parasitology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
| | - Seoh Wei Teh
- Department of Biomedical Science, Faculty of Medicine and Health Science Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
| | - Avin Ee-Hwan Koh
- Department of Biomedical Science, Faculty of Medicine and Health Science Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
| | - Murugan A. Munusamy
- Department of Botany and Microbiology, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Palanisamy Arulselvan
- Laboratory of Vaccines and Immunotherapeutics, Institute of Bioscience, Universiti Putra Malaysia, Serdang, 43400, Selangor, Malaysia
| | - Mariappan Rajan
- Biomaterials in Medicinal Chemistry Laboratory, Department of Natural Products Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai, 625 021, Tamil Nadu, India
| | - Arivudai Nambi
- Faculty of Medicine, Lincoln University College, Malaysia
| | - K.B. Swamy
- Faculty of Medicine, Lincoln University College, Malaysia
| | - Kiruthiga Vijayaraman
- Department of Medical Biotechnology, Division of Applied Biomedical Sciences and Biotechnology, School of Health Sciences, International Medical University, Malaysia
| | - Kadarkarai Murugan
- Division of Entomology, Department of Zoology, School of Life Sciences, Bharathiar University, Coimbatore, Tamil Nadu, 641 046, India
| | - Kalimuthusamy Natarajaseenivasan
- Medical Microbiology Laboratory, Department of Microbiology, Centre of Excellence in Life Sciences, Bharathidasan University, Tiruchirappalli, India
| | - Suresh Kumar Subbiah
- Department of Medical Microbiology and Parasitology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
- Genetics and Regenerative Medicine Research Centre, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
- Muthayammal Centre for Advanced Research, Muthayammal College of Arts and Science, Rasipuram, Namakkal, Tamil Nadu, 637408, India
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Zhao L, Hu C, Zhang P, Jiang H, Chen J. Novel preconditioning strategies for enhancing the migratory ability of mesenchymal stem cells in acute kidney injury. Stem Cell Res Ther 2018; 9:225. [PMID: 30139368 PMCID: PMC6108125 DOI: 10.1186/s13287-018-0973-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Acute kidney injury (AKI) remains a worldwide public health issue due to its increasing incidence, significant mortality, and lack of specific target-orientated therapy. Developments in mesenchymal stem cell (MSC) research make MSCs a promising candidate for AKI management but relevant clinical trials show confusing results (NCT00733876, NCT01602328). One primary cause of the limited therapeutic effect may result from poor engraftment of transplanted cells. To solve this problem, investigators have developed a series of preconditioning strategies to improve MSC engraftment in animal AKI models. In this review, we summarize these previous studies, providing an integrated and updated view of different preconditioning strategies aimed at promoting the therapeutic effect of MSCs in AKI patients.
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Affiliation(s)
- Lingfei Zhao
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, Zhejiang Province, People's Republic of China.,Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Chenxia Hu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Ping Zhang
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, Zhejiang Province, People's Republic of China.,Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Hua Jiang
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, Zhejiang Province, People's Republic of China.,Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Jianghua Chen
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China. .,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, Zhejiang Province, People's Republic of China. .,Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
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Miller BLK, Garg P, Bronstein B, LaPointe E, Lin H, Charytan DM, Tilles AW, Parekkadan B. Extracorporeal Stromal Cell Therapy for Subjects With Dialysis-Dependent Acute Kidney Injury. Kidney Int Rep 2018; 3:1119-1127. [PMID: 30197978 PMCID: PMC6127415 DOI: 10.1016/j.ekir.2018.05.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 05/14/2018] [Accepted: 05/21/2018] [Indexed: 12/29/2022] Open
Abstract
Introduction The pathophysiology of acute kidney injury (AKI) involves damage to renal epithelial cells, podocytes, and vascular beds that manifests into a deranged, self-perpetuating immune response and peripheral organ dysfunction. Such an injury pattern requires a multifaceted therapeutic to alter the wound healing response systemically. Mesenchymal stromal cells (MSCs) are a unique source of secreted factors that can modulate an inflammatory response to acute organ injury and enhance the repair of injured tissue at the parenchymal and endothelial levels. This phase Ib/IIa clinical trial evaluates SBI-101, a combination product that administers MSCs extracorporeally to overcome pharmacokinetic barriers of MSC transplantation. SBI-101 contains allogeneic human MSCs inoculated into a hollow-fiber hemofilter for the treatment of patients with severe AKI who are receiving continuous renal replacement therapy (CRRT). SBI-101 therapy is designed to reprogram the molecular and cellular components of blood in patients with severe organ injury. Methods This study is a prospective, multicenter, randomized, double-blind, sham-controlled, study of subjects with a clinical diagnosis of AKI who are receiving CRRT. Up to 32 subjects may be enrolled to provide 24 evaluable subjects (as a per protocol population). Subjects will receive CRRT in tandem with a sham control (0 MSCs), or the low- (250 × 106 MSCs) or high-dose (750 × 106 MSCs) SBI-101 therapeutic. Results The study will measure dose-dependent safety, renal efficacy, and exploratory biomarkers to characterize the pharmacokinetics and pharmacodynamics of SBI-101 in treated subjects. Conclusion This first-in-human clinical trial will evaluate the safety and tolerability of SBI-101 in patients with AKI who require CRRT.
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Affiliation(s)
| | - Payal Garg
- Sentien Biotechnologies, Inc., Lexington, Massachusetts, USA
| | - Ben Bronstein
- Cold Spring Venture Advisors, LLC, Watertown, Massachusetts, USA
| | | | - Herb Lin
- Department of Nephrology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - David M Charytan
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Arno W Tilles
- Sentien Biotechnologies, Inc., Lexington, Massachusetts, USA
| | - Biju Parekkadan
- Sentien Biotechnologies, Inc., Lexington, Massachusetts, USA.,Department of Surgery, Center for Surgery, Innovation, and Bioengineering, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospitals for Children, Boston, Massachusetts, USA.,Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.,Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey, USA
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Benoit SW, Devarajan P. Acute kidney injury: emerging pharmacotherapies in current clinical trials. Pediatr Nephrol 2018; 33:779-787. [PMID: 28601936 PMCID: PMC5723563 DOI: 10.1007/s00467-017-3695-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2017] [Revised: 05/02/2017] [Accepted: 05/03/2017] [Indexed: 12/11/2022]
Abstract
Acute kidney injury (AKI) is a significant source of morbidity and mortality in pediatric patients, affecting more than one quarter of critically ill children. Despite significant need, there are no targeted therapies to reliably prevent or treat AKI. Recent advances in our understanding of renal injury and repair signaling pathways have enabled the development of several targeted pharmaceuticals. Here we review emerging pharmacotherapies for AKI that are currently in clinical trials. Categorized by their general mechanism of action, the therapies discussed include anti-inflammatory agents (recAP, AB103, ABT-719), antioxidants (iron chelators, heme arginate), vasodilators (levosimendan), apoptosis inhibitors (QPI-1002), and repair agents (THR-184, BB-3, mesenchymal stem cells).
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Affiliation(s)
| | - Prasad Devarajan
- Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 7022, Cincinnati, OH, 45229-3039, USA.
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Tan H, Yi H, Zhao W, Ma JX, Zhang Y, Zhou X. Intraglomerular crosstalk elaborately regulates podocyte injury and repair in diabetic patients: insights from a 3D multiscale modeling study. Oncotarget 2018; 7:73130-73146. [PMID: 27683034 PMCID: PMC5341968 DOI: 10.18632/oncotarget.12233] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2016] [Accepted: 09/12/2016] [Indexed: 11/30/2022] Open
Abstract
Podocytes are mainly involved in the regulation of glomerular filtration rate (GFR) under physiological condition. Podocyte depletion is a crucial pathological alteration in diabetic nephropathy (DN) and results in a broad spectrum of clinical syndromes such as protein urine and renal insufficiency. Recent studies indicate that depleted podocytes can be regenerated via differentiation of the parietal epithelial cells (PECs), which serve as the local progenitors of podocytes. However, the podocyte regeneration process is regulated by a complicated mechanism of cell-cell interactions and cytokine stimulations, which has been studied in a piecemeal manner rather than systematically. To address this gap, we developed a high-resolution multi-scale multi-agent mathematical model in 3D, mimicking the in situ glomerulus anatomical structure and micro-environment, to simulate the podocyte regeneration process under various cytokine perturbations in healthy and diabetic conditions. Our model showed that, treatment with pigment epithelium derived factor (PEDF) or insulin-like growth factor-1 (IGF-1) alone merely ameliorated the glomerulus injury, while co-treatment with both cytokines replenished the damaged podocyte population gradually. In addition, our model suggested that continuous administration of PEDF instead of a bolus injection sustained the regeneration process of podocytes. Part of the results has been validated by our in vivo experiments. These results indicated that amelioration of the glomerular stress by PEDF and promotion of PEC differentiation by IGF-1 are equivalently critical for podocyte regeneration. Our 3D multi-scale model represents a powerful tool for understanding the signaling regulation and guiding the design of cytokine therapies in promoting podocyte regeneration.
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Affiliation(s)
- Hua Tan
- Center for Bioinformatics and Systems Biology, Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Hualin Yi
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China.,Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Weiling Zhao
- Center for Bioinformatics and Systems Biology, Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Jian-Xing Ma
- Department of Physiology, University of Oklahoma College of Medicine, Oklahoma, OK 73104, USA
| | - Yuanyuan Zhang
- Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Xiaobo Zhou
- Center for Bioinformatics and Systems Biology, Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.,College of Computer Science and Software Engineering, Shenzhen University, Shenzhen, China
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Uchida N, Kumagai N, Kondo Y. Application of Muse Cell Therapy for Kidney Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1103:199-218. [PMID: 30484231 DOI: 10.1007/978-4-431-56847-6_11] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The kidney plays an essential role in the maintenance of homeostasis in healthy individuals, e.g., by regulating the amount of water and concentration of electrolyte in the body. Owing to the structural complexity, renal dysfunction is caused by a myriad of diseases and conditions, and in severe cases, it progresses to end-stage renal disease in which patients require renal replacement therapy, i.e., maintenance dialysis or kidney transplantation. The currently available therapeutic modalities, with the exception of renal transplantation, cannot recover severely deteriorated renal function. Thus, regenerative medicine holds considerable promise as a potential means for developing next-generation renal therapeutics. Mesenchymal stem cell (MSC) transplantation has been investigated in acute kidney injury and chronic kidney disease models, and clinical studies have already been started for some kinds of kidney diseases. However, most of these studies concluded that the main underlying mechanism of therapeutic effect of MSC transplantation was paracrine. Recently, we reported that Muse cell therapy in a murine model of chronic kidney disease resulted in differentiation of intravenously injected Muse cells into glomerular cells after preferential homing to damaged glomerulus and improvement in renal function. The result suggested the potentiality of Muse cell therapy for glomerular regeneration. Muse cells are a promising cell source for regenerative therapy for kidney diseases.
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Affiliation(s)
- Nao Uchida
- Departments of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan.
| | - Naonori Kumagai
- Departments of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoshiaki Kondo
- Department of Healthcare Services Management, Nihon University School of Medicine, Tokyo, Japan
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Zou YF, Zhang W. Role of microRNA in the detection, progression, and intervention of acute kidney injury. Exp Biol Med (Maywood) 2017; 243:129-136. [PMID: 29264947 DOI: 10.1177/1535370217749472] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Acute kidney injury, characterized by sharply decreased renal function, is a common and important complication in hospitalized patients. The pathological mechanism of acute kidney injury is mainly related to immune activation and inflammation. Given the high morbidity and mortality rates of hospitalized patients with acute kidney injury, the identification of biomarkers useful for assessing risk, making an early diagnosis, evaluating the prognosis, and classifying the injury severity is urgently needed. Furthermore, investigation into the development of acute kidney injury and potential therapeutic targets is required. While microRNA was first discovered in Caenorhabditis elegans, Gary Ruvkun's laboratory identified the first microRNA target gene. Together, these two important findings confirmed the existence of a novel post-transcriptional gene regulatory mechanism. Considering that serum creatinine tests often fail in the early detection of AKI, testing for microRNAs as early diagnostic biomarkers has shown great potential. Numerous studies have identified microRNAs that can serve as biomarkers for the detection of acute kidney injury. In addition, as microRNAs can control the expression of multiple proteins through hundreds or thousands of targets influencing multiple signaling pathways, the number of studies on the functions of microRNAs in AKI progression is increasing. Here, we mainly focus on research into microRNAs as biomarkers and explorations of their functions in acute kidney injury. Impact statement Firstly, we have discussed the potential advantages and limitations of miRNA as biomarkers. Secondly, we have summarized the role of miRNA in the progress of AKI. Finally, we have made a vision of miRNA's potential and advantages as therapeutic target intervention AKI.
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Affiliation(s)
- Yan-Fang Zou
- Department of Nephrology, 66281 School of Medicine, Ruijin Hospital, Shanghai Jiao Tong University , Shanghai 200025, PR China
| | - Wen Zhang
- Department of Nephrology, 66281 School of Medicine, Ruijin Hospital, Shanghai Jiao Tong University , Shanghai 200025, PR China
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