|
1
|
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.
Collapse
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
| |
Collapse
|
|
2
|
Peng J, Yang T, Chen S, Deng N, Luo X, Liao R, Su B. Utilization of Hydrogels in Mesenchymal Stem Cell-Based Therapy for Kidney Diseases. TISSUE ENGINEERING. PART B, REVIEWS 2024; 30:315-326. [PMID: 37819717 DOI: 10.1089/ten.teb.2023.0196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/13/2023]
Abstract
Kidney diseases are major global health problems, with high prevalence and mortality. However, current treatment strategies for kidney diseases fail to achieve satisfactory efficacy. Mesenchymal stem cell (MSC)-based therapy has been a promising strategy for treating kidney diseases. Preclinical studies have proven their safety and effectiveness in treating acute kidney injury (AKI) and chronic kidney disease (CKD), but the outcomes of clinical trials have shown very limited clinical efficacy. A variety of innovative approaches have been proposed to enhance the therapeutic potential of MSCs, and hydrogels are attractive candidates. Hydrogels are three-dimensional (3D) networks formed by hydrophilic polymers of natural or synthetic origin with diverse physical and chemical properties. They have been widely applied in the field of drug delivery and regenerative medicine, including MSC-based therapy. Many studies have proven that hydrogels can improve the therapeutic efficacy of MSCs for kidney diseases, but there are still challenges limiting the widespread application of this method. In this review, we introduce the application of MSCs in kidney diseases and the factors that influence therapeutic efficiency and focus on the beneficial effects of hydrogels in MSC-based therapy for AKI and CKD.
Collapse
Affiliation(s)
- Jing Peng
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, China
| | - Tinghang Yang
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, China
| | - Shanshan Chen
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, China
| | - Ningyue Deng
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, China
| | - Xinyao Luo
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, China
| | - Ruoxi Liao
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, China
| | - Baihai Su
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
|
3
|
Paul Owens E, Grania Healy H, Andrew Vesey D, Elizabeth Hoy W, Carolyn Gobe G. Targeted biomarkers of progression in chronic kidney disease. Clin Chim Acta 2022; 536:18-28. [PMID: 36041551 DOI: 10.1016/j.cca.2022.08.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 08/22/2022] [Accepted: 08/24/2022] [Indexed: 11/03/2022]
Abstract
BACKGROUND Chronic kidney disease (CKD) is an increasingly significant health issue worldwide. Early stages of CKD can be asymptomatic and disease trajectory difficult to predict. Not everyone with CKD progresses to kidney failure, where kidney replacement therapy is the only life-sustaining therapy. Predicting which patients will progress to kidney failure would allow better use of targeted treatments and more effective allocation of health resources. Current diagnostic tests to identify patients with progressive disease perform poorly but there is a suite of new and emerging predictive biomarkers with great clinical promise. METHODS This narrative review describes new and emerging biomarkers of pathophysiologic processes of CKD development and progression, accessible in blood or urine liquid biopsies. Biomarkers were selected based on their reported pathobiological functions in kidney injury, inflammation, oxidative stress, repair and fibrosis. Biomarker function and evidence of involvement in CKD development and progression are reported. CONCLUSION Many biomarkers reviewed here have received little attention to date, perhaps because of conflicting conclusions of their utility in CKD. The functional roles of the selected biomarkers in the underlying pathobiology of progression of CKD are a powerful rationale for advancing and validating these molecules as prognosticators and predictors of CKD trajectory.
Collapse
Affiliation(s)
- Evan Paul Owens
- NHMRC CKD CRE (CKD.QLD), The University of Queensland, Brisbane 4072, Australia; Faculty of Medicine, The University of Queensland, Brisbane 4072, Australia; Kidney Disease Research Collaborative, Translational Research Institute, Brisbane 4102, Australia
| | - Helen Grania Healy
- NHMRC CKD CRE (CKD.QLD), The University of Queensland, Brisbane 4072, Australia; Faculty of Medicine, The University of Queensland, Brisbane 4072, Australia; Kidney Health Service, Royal Brisbane and Women's Hospital, Brisbane 4029, Australia
| | - David Andrew Vesey
- NHMRC CKD CRE (CKD.QLD), The University of Queensland, Brisbane 4072, Australia; Faculty of Medicine, The University of Queensland, Brisbane 4072, Australia
| | - Wendy Elizabeth Hoy
- NHMRC CKD CRE (CKD.QLD), The University of Queensland, Brisbane 4072, Australia; Faculty of Medicine, The University of Queensland, Brisbane 4072, Australia; Centre for Chronic Disease, The University of Queensland, Brisbane 4072, Australia
| | - Glenda Carolyn Gobe
- NHMRC CKD CRE (CKD.QLD), The University of Queensland, Brisbane 4072, Australia; Faculty of Medicine, The University of Queensland, Brisbane 4072, Australia; Kidney Disease Research Collaborative, Translational Research Institute, Brisbane 4102, Australia.
| |
Collapse
|
|
4
|
The therapeutic potential of Camel Wharton jelly mesenchymal stem cells (CWJ-MSCs) in canine chronic kidney disease model. Stem Cell Res Ther 2022; 13:387. [PMID: 35908006 PMCID: PMC9338563 DOI: 10.1186/s13287-022-03076-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 04/14/2022] [Indexed: 11/10/2022] Open
Abstract
Background Chronic kidney disease (CKD) is a worldwide health problem that its incidence increases nowadays with the increase in the risk of environmental pollution. CKD can progress to end-stage renal disease (ESRD) which usually ends fatally. This study aimed to examine the therapeutic potential of Camel Wharton jelly-mesenchymal stem cells (CWJ-MSCs) in chronic kidney disease model induced in dogs. Methods CWJ-MSCs were injected directed to the kidney with ultrasonographic guidance in dogs with 5/6 nephrectomy to evaluate its therapeutic potency in such cases. Analysis of variance was applied in normally distributed quantitative variables while a non-parametric Mann–Whitney test was used for non-normally distributed quantitative variables. Results The serum urea and creatinine in the treated group were significantly decreased transferring dogs in the treated group from stage 3 to stage 2 CKD according to the IRIS staging system. Histopathology of renal tissue revealed improving CKD lesions by increasing regeneration of degenerated tubules, maintaining the integrity of glomeruli. New vascularization with blood vessels remodeling were common findings. Periodic acid Schiff stain of renal tissue showed the integrity of renal tubules and thickness of the glomerular basement membrane. Fibrosis of cortex and medulla was lower in the treated group than in the CKD model as monitored by Mallory’s trichrome stain (MTC). NGAL and KIM-1 genes expression were decreased while VEGF and EGF genes expression were increased indicating renal tissue repair. Conclusions CWJ-MSCs have a therapeutic potential in the CKD model induced in dogs.
Collapse
|
|
5
|
Sharun K, Jambagi K, Kumar R, Gugjoo MB, Pawde AM, Tuli HS, Dhama K, Amarpal. Clinical applications of adipose-derived stromal vascular fraction in veterinary practice. Vet Q 2022; 42:151-166. [PMID: 35841195 PMCID: PMC9364732 DOI: 10.1080/01652176.2022.2102688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Adipose tissue-derived stromal vascular fraction (AdSVF) comprises a heterogeneous cell population, including the multipotent mesenchymal stem cells, hematopoietic stem cells, immune cells, endothelial cells, fibroblasts, and pericytes. As such, multipotent adipose tissue-derived mesenchymal stem cells (AdMSCs), are one of the important components of AdSVF. Commonly used techniques to harvest AdSVF involve enzymatic or non-enzymatic methods. The enzymatic method is considered to be the gold standard technique due to its higher yield. The cellular components of AdSVF can be resuspended in normal saline, platelet-rich plasma, or phosphate-buffered saline to produce a ready-to-use solution. Freshly isolated AdSVF has exhibited promising osteogenic and vasculogenic capacity. AdSVF has already been proven to possess therapeutic potential for osteoarthritis management. It is also an attractive therapeutic option for enhancing wound healing. In addition, the combined use of AdSVF and platelet-rich plasma has an additive stimulatory effect in accelerating wound healing and can be considered an alternative to AdMSC treatment. It is also widely used for managing various orthopaedic conditions in clinical settings and has the potential for regenerating bone, cartilage, and tendons. Autologous AdSVF cells are used along with bone substitutes and other biological factors as an alternative to conventional bone grafting techniques owing to their promising osteogenic and vasculogenic capacity. It can also be used for treating osteonecrosis, meniscus tear, chondromalacia, and tendon injuries in veterinary practice. It has several advantages over in vitro expanded AdMSC, including precluding the need for culturing, reduced risk of cell contamination, and cost-effectiveness, making it ideal for clinical use.
Collapse
Affiliation(s)
- Khan Sharun
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh-243122, India
| | - Kaveri Jambagi
- Division of Medicine, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh-243122, India
| | - Rohit Kumar
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh-243122, India
| | - Mudasir Bashir Gugjoo
- Division of Veterinary Clinical Complex, Faculty of Veterinary Sciences & Animal Husbandry, SKUAST-Kashmir, Shuhama, Srinagar, Jammu and Kashmir-190006, India
| | - Abhijit M Pawde
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh-243122, India
| | - Hardeep Singh Tuli
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala 133207, Haryana, India
| | - Kuldeep Dhama
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh-243122, India
| | - Amarpal
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh-243122, India
| |
Collapse
|
|
6
|
Hoseinynejad K, Radan M, Dianat M, Nejaddehbashi F. Adipose-derived mesenchymal stem cells protects renal function in a rat model of emphysema. Tissue Cell 2021; 73:101613. [PMID: 34364156 DOI: 10.1016/j.tice.2021.101613] [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: 06/10/2021] [Revised: 07/15/2021] [Accepted: 07/29/2021] [Indexed: 11/24/2022]
Abstract
BACKGROUND AND OBJECTIVE The link between lung disease and kidney disorders has already been confirmed. Previous studies have documented that obstructive pulmonary disease is an independent predictor of decreased renal function, which reduces glomerular filtration rate. Recently, mesenchymal stem cells are the most important cell used in cell therapy. Accordingly, the present experiment was designed to evaluate the efficacy of adipose-derived mesenchymal stem cells (AMSCs) on improvement of renal function in elastase induced-pulmonary emphysema rats. MATERIALS AND METHODS Thirty male Sprague-Dawley rats divided into the 3 groups. Following intra-tracheal administration of elastase, the in vivo emphysema model established and confirmed according to the specific markers. Subsequently, systemic AMSCs injection was developed. the kidney injuries markers such as Blood urea nitrogen (BUN), creatinine, sodium and potassium as well as the kidney histopathologic parameters were assessed in all groups. Moreover, the oxidative stress markers levels including Malondialdehyde (MDA), Total antioxidant capacity (TAC), Catalase (CAT) and Glutathione peroxidase (GPx) were measured in kidney tissue and also inflammatory cytokines including IL-10, IL-6, and IFN-Ƴ were assessed in serum samples. RESULTS The marked rise in kidney injuries markers were observed which showed by enhancement of BUN and Creatinine levels in emphysema rats compared to the control. Furthermore, the results demonstrated increases in MDA levels and decreases in antioxidant activity which was in line with increases in inflammation cytokines in renal tissue. Conversely, AMSCs treatment improved renal function as shown by the decreases BUN, Creatinine and proteinuria. Furthermore, renal histological assay demonstrate improvement in glomerular and tubular damage and inflammatory cells accumulation. CONCLUSIONS Our results documented the promising kidney-protective properties of Adipose-Derived Mesenchymal Stem Cells in the kidney injuries induced by emphysema.
Collapse
Affiliation(s)
- Khojasteh Hoseinynejad
- Department of Physiology, Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| | - Maryam Radan
- Department of Physiology, Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mahin Dianat
- Department of Physiology, Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Fereshteh Nejaddehbashi
- Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| |
Collapse
|
|
7
|
Akan E, Cetinkaya B, Kipmen-Korgun D, Ozmen A, Koksoy S, Mendilcioğlu İ, Sakinci M, Suleymanlar G, Korgun ET. Effects of amnion derived mesenchymal stem cells on fibrosis in a 5/6 nephrectomy model in rats. Biotech Histochem 2021; 96:594-607. [PMID: 33522283 DOI: 10.1080/10520295.2021.1875502] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Chronic kidney disease (CKD) is characterized by disruption of the glomerulus, tubule and vascular structures by renal fibrosis. Mesenchymal stem cells (MSC) ameliorate CKD. We investigated the effects of human amnion derived MSC (hAMSC) on fibrosis using expression of transforming growth factor beta (TGF-β), collagen type I (COL-1) and bone morphogenetic protein (BMP-7). We also investigated levels of urinary creatinine and nitrogen in CKD. We used a 5/6 nephrectomy (5/6 Nx) induced CKD model. We used 36 rats in six groups of six animals: sham group, 5/6 Nx group, 15 days after 5/6 Nx (5/6 Nx + 15) group, 30 days after 5/6 Nx (5/6 Nx + 30) group, transfer of hAMSC 15 days after 5/6 Nx (5/6 Nx + hAMSC + 15) group and transfer of hAMSC 30 days after 5/6 Nx (5/6 Nx + hAMSC + 30) group. We isolated 106 hAMSC from the amnion and transplanted them via the rat tail vein into the 5/6 Nx + hAMSC + 15 and 5/6 Nx + hAMSC + 30 groups. We measured the expression of BMP-7, COL-1 and TGF-β using western blot and immunohistochemistry, and their gene expressions were analyzed by quantitative real time PCR. TGF-β and COL-1 protein, and gene expressions were increased in the 5/6 Nx +30 group compared to the 5/6 Nx + hAMSC + 30 group. Conversely, both protein and gene expression of BMP-7 was increased in 5/6 Nx + hAMSC + 30 group compared to the 5/6 Nx groups. Increased TGF-β together with decreased BMP-7 expression may cause fibrosis by epithelial-mesenchymal transition due to chronic renal injury. Increased COL-1 levels cause accumulation of extracellular matrix in CKD. Levels of urea, creatinine and nitrogen were increased significantly in 5/6 Nx + 15 and 5/6 Nx + 30 groups compared to the hAMSC groups. We found that hAMSC ameliorate CKD.
Collapse
Affiliation(s)
- Ezgi Akan
- Department of Medical Biochemistry, Akdeniz University Medical School, Antalya, Turkey
| | - Busra Cetinkaya
- Department of Histology and Embryology, Akdeniz University, Medical School, Antalya, Turkey.,Department of Histology and Embryology, Medical Faculty, Bulent Ecevit University, Zonguldak, Turkey
| | - Dijle Kipmen-Korgun
- Department of Medical Biochemistry, Akdeniz University Medical School, Antalya, Turkey
| | - Aslı Ozmen
- Department of Histology and Embryology, Akdeniz University, Medical School, Antalya, Turkey
| | - Sadi Koksoy
- Department of Medical Microbiology and Immunology, Akdeniz University Medical School, Antalya, Turkey
| | - İnanc Mendilcioğlu
- Department of Obstetrics and Gynecology, Akdeniz University Medical School, Antalya, Turkey
| | - Mehmet Sakinci
- Department of Obstetrics and Gynecology, Akdeniz University Medical School, Antalya, Turkey
| | - Gultekin Suleymanlar
- Division of Nephrology, Department of Internal Medicine, Medical Faculty, Akdeniz University, Antalya, Turkey
| | - Emin Turkay Korgun
- Department of Histology and Embryology, Akdeniz University, Medical School, Antalya, Turkey
| |
Collapse
|
|
8
|
Sávio-Silva C, Beyerstedt S, Soinski-Sousa PE, Casaro EB, Balby-Rocha MTA, Simplício-Filho A, Alves-Silva J, Rangel ÉB. Mesenchymal Stem Cell Therapy for Diabetic Kidney Disease: A Review of the Studies Using Syngeneic, Autologous, Allogeneic, and Xenogeneic Cells. Stem Cells Int 2020; 2020:8833725. [PMID: 33505469 PMCID: PMC7812547 DOI: 10.1155/2020/8833725] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 10/31/2020] [Accepted: 11/03/2020] [Indexed: 12/18/2022] Open
Abstract
Diabetic kidney disease (DKD) is a microvascular complication of diabetes mellitus (DM) and comprises multifactorial pathophysiologic mechanisms. Despite current treatment, around 30-40% of individuals with type 1 and type 2 DM (DM1 and DM2) have progressive DKD, which is the most common cause of end-stage chronic kidney disease worldwide. Mesenchymal stem cell- (MSC-) based therapy has important biological and therapeutic implications for curtailing DKD progression. As a chronic disease, DM may impair MSC microenvironment, but there is compelling evidence that MSC derived from DM1 individuals maintain their cardinal properties, such as potency, secretion of trophic factors, and modulation of immune cells, so that both autologous and allogeneic MSCs are safe and effective. Conversely, MSCs derived from DM2 individuals are usually dysfunctional, exhibiting higher rates of senescence and apoptosis and a decrease in clonogenicity, proliferation, and angiogenesis potential. Therefore, more studies in humans are needed to reach a conclusion if autologous MSCs from DM2 individuals are effective for treatment of DM-related complications. Importantly, the bench to bedside pathway has been constructed in the last decade for assessing the therapeutic potential of MSCs in the DM setting. Laboratory research set the basis for establishing further translation research including preclinical development and proof of concept in model systems. Phase I clinical trials have evaluated the safety profile of MSC-based therapy in humans, and phase II clinical trials (proof of concept in trial participants) still need to answer important questions for treating DKD, yet metabolic control has already been documented. Therefore, randomized and controlled trials considering the source, optimal cell number, and route of delivery in DM patients are further required to advance MSC-based therapy. Future directions include strategies to reduce MSC heterogeneity, standardized protocols for isolation and expansion of those cells, and the development of well-designed large-scale trials to show significant efficacy during a long follow-up, mainly in individuals with DKD.
Collapse
Affiliation(s)
- Christian Sávio-Silva
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - Stephany Beyerstedt
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - Poliana E. Soinski-Sousa
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - Expedito B. Casaro
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | | | - Antônio Simplício-Filho
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - Jamille Alves-Silva
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - Érika B. Rangel
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
- Nephrology Division, Federal University of São Paulo, São Paulo, SP, Brazil
| |
Collapse
|
|
9
|
Wiafe B, Kadam R, Metcalfe PD. Intraperitoneal administration of mesenchymal stem cells is effective at mitigating detrusor deterioration after pBOO. Am J Physiol Renal Physiol 2020; 318:F549-F556. [PMID: 31904287 DOI: 10.1152/ajprenal.00486.2019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Partial bladder outlet obstruction (pBOO) results in bladder fibrosis that is initiated by an inflammatory cascade and the decompensation after smooth muscle hypertrophy. We have been using an animal model to develop the hypothesis that mesenchymal stem cells (MSCs) are able to mitigate this cytokine cascade and prevent bladder deterioration. We hypothesized that intraperitoneal administration of MSCs can produce the same effects as intravenously administered cells but may require higher dosing. Intraperitoneal treatment will provide insights into the mechanisms of action and may offer advantages over intravenous administration, as it will permit allow higher doses and potentially reduce systemic exposure. Rats underwent a surgical induction of pBOO and instillation of either 1 × 106 or 5 × 106 commercially acquired MSCs into the peritoneum. RT-PCR, immunohistochemistry, and urodynamics were used to compare treatment groups with controls. pBOO resulted in a marked, statistically significant, upregulation of inflammatory markers in the bladder, including transforming growth factor-β, hypoxia-inducible factor-1α, hypoxia-inducible factor-3α, mammalian target of rapamycin, and collagen types I and III. Moderate but inconsistent levels of downregulation were seen with 1 × 106 MSCs, but excellent and reliable downregulation was seen with 5 × 106 MSCs (P < 0.05). Immunohistochemistry confirmed that protein levels were affected in accordance with mRNA upregulation. Urodynamics demonstrated MSC treatment resulted in whole organ physiological benefits, as they prevented elevations in detrusor pressure. In conclusion, intraperitoneal administration of MSCs resulted in a similar effect as intravenous administration; however, this required a higher dose. This has significant implications for determining the mechanism of action and potential clinical application for human therapy.
Collapse
Affiliation(s)
- Bridget Wiafe
- Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Rutuja Kadam
- Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Peter D Metcalfe
- Division of Urology and Pediatric Surgery, University of Alberta, Edmonton, Alberta, Canada
| |
Collapse
|
|
10
|
Rangel ÉB, Gomes SA, Kanashiro-Takeuchi R, Hare JM. Progenitor/Stem Cell Delivery by Suprarenal Aorta Route in Acute Kidney Injury. Cell Transplant 2019; 28:1390-1403. [PMID: 31409111 PMCID: PMC6802150 DOI: 10.1177/0963689719860826] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Revised: 05/14/2019] [Accepted: 06/03/2019] [Indexed: 02/06/2023] Open
Abstract
Progenitor/stem cell-based kidney regenerative strategies are a key step towards the development of novel therapeutic regimens for kidney disease treatment. However, the route of cell delivery, e.g., intravenous, intra-arterial, or intra-parenchymal, may affect the efficiency for kidney repair in different models of acute and chronic injury. Here, we describe a protocol of intra-aorta progenitor/stem cell injection in rats following either acute ischemia-reperfusion injury or acute proteinuria induced by puromycin aminonucleoside (PAN) - the experimental prototype of human minimal change disease and early stages of focal and segmental glomerulosclerosis. Vascular clips were applied across both renal pedicles for 35 min, or a single dose of PAN was injected via intra-peritoneal route, respectively. Subsequently, 2 x 106 stem cells [green fluorescent protein (GFP)-labeled c-Kit+ progenitor/stem cells or GFP-mesenchymal stem cells] or saline were injected into the suprarenal aorta, above the renal arteries, after application of a vascular clip to the abdominal aorta below the renal arteries. This approach contributed to engraftment rates of ∼10% at day 8 post ischemia-reperfusion injury, when c-Kit+ progenitor/stem cells were injected, which accelerated kidney recovery. Similar rates of engraftment were found after PAN-induced podocyte damage at day 21. With practice and gentle surgical technique, 100% of the rats could be injected successfully, and, in the week following injection, ∼ 85% of the injected rats will recover completely. Given the similarities in mammals, much of the data obtained from intra-arterial delivery of progenitor/stem cells in rodents can be tested in translational research and clinical trials with endovascular catheters in humans.
Collapse
Affiliation(s)
- Érika B. Rangel
- Interdisciplinary Stem Cell Institute, Leonard M Miller School of
Medicine, University of Miami, USA
- Hospital Israelita Albert Einstein, São Paulo, Brazil
- Federal University of São Paulo, Brazil
| | - Samirah A. Gomes
- Interdisciplinary Stem Cell Institute, Leonard M Miller School of
Medicine, University of Miami, USA
- Laboratory of Cellular, Genetic, and Molecular Nephrology, Renal
Division, University of São Paulo, Brazil
| | - Rosemeire Kanashiro-Takeuchi
- Interdisciplinary Stem Cell Institute, Leonard M Miller School of
Medicine, University of Miami, USA
- Department of Molecular and Cellular Pharmacology, Leonard M Miller
School of Medicine, University of Miami, USA
| | - Joshua M. Hare
- Interdisciplinary Stem Cell Institute, Leonard M Miller School of
Medicine, University of Miami, USA
- Department of Molecular and Cellular Pharmacology, Leonard M Miller
School of Medicine, University of Miami, USA
- Division of Cardiology, Leonard M Miller School of Medicine,
University of Miami, USA
| |
Collapse
|
|
11
|
Hamed GM, Morsy WE, Hamid MSAE, Hassan AAEM, Zahra FAA. Effect of Bone Marrow-Derived Mesenchymal Stem Cells on Ischaemic-Reperfused Hearts in Adult Rats with Established Chronic Kidney Disease. Int J Stem Cells 2019; 12:304-314. [PMID: 31022998 PMCID: PMC6657945 DOI: 10.15283/ijsc18114] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 03/07/2019] [Accepted: 03/08/2019] [Indexed: 12/29/2022] Open
Abstract
Background and Objectives Bone marrow-derived mesenchymal stem cells (BM-MSCs) are adult multipotent non-haematopoietic stem cells that have regeneration potential. The current study aimed to detect the ability of BM-MSCs to improve kidney and cardiac functions in adult rats with established chronic kidney disease. Methods Rats were divided into sham-operated control, untreated sub totally nephrectomised and treated sub totally nephrectomised groups. Body weight, kidney and cardiac tissue weights, plasma creatinine and urea levels and arterial blood pressure were measured. ECG was recorded, and an in vitro isolated heart study was performed. Results Stem cell treatment decreased the elevated plasma creatinine and urea levels and decreased systolic, diastolic and mean arterial blood pressure values. These changes were accompanied by a decrease in glomerular hypertrophy with apparent normal renal parenchyma. Additionally, BM-MSCs shortened Q-To and Q-Tc intervals, all time to peak tension values, the half relaxation value at 30 min of reperfusion and the contraction time at 15 and 30 min of reperfusion. Moreover, stem cell treatment significantly increased the heart rate, QRS voltage, the peak tension at the 15- and 30-min reperfusion time points and the peak tension per left ventricle at the 30-min reperfusion time point compared to the pre-ischaemia baseline. BM-MSCs resolve inter muscular oedema and lead to the re-appearance of normal cardiomyocytes. This improvement occurs with the observations of BM-MSCs in renal and heart tissues. Conclusions BM-MSCs can attenuate chronic kidney disease progression and the associated cardiac electrophysiological and inotropic dysfunction.
Collapse
Affiliation(s)
- Gehane M Hamed
- Department of Physiology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Wessam E Morsy
- Department of Physiology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Manal S Abd-El Hamid
- Department of Physiology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | | | - Fatma A Abu Zahra
- Department of Biochemistry, Medical Research Center, Ain Shams University, Cairo, Egypt
| |
Collapse
|
|
12
|
Villanueva S, González F, Lorca E, Tapia A, Valentina López G, Strodthoff R, Fajre F, Carreño JE, Valjalo R, Vergara C, Lecanda M, Bartolucci J, Figueroa FE, Khoury M. Adipose tissue-derived mesenchymal stromal cells for treating chronic kidney disease: A pilot study assessing safety and clinical feasibility. Kidney Res Clin Pract 2019; 38:176-185. [PMID: 31189223 PMCID: PMC6577210 DOI: 10.23876/j.krcp.18.0139] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 01/25/2019] [Accepted: 02/18/2019] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Chronic kidney disease (CKD) is a growing public health concern, and available treatments are insufficient in limiting disease progression. New strategies, including regenerative cell-based therapies, have emerged as therapeutic alternatives. Results from several groups, including our own, have reported evidence of a supportive role for mesenchymal stromal cells (MSCs) in functional recovery and prevention of tissue damage in murine models of CKD. Prompted by these data, an open pilot study was conducted to assess the safety and efficacy of a single injection of autologous adipose tissue-derived MSCs (AT-MSCs) for treatment of CKD. METHODS AT-MSCs were infused intravenously into six CKD patients at a dose of 1 million cells/kg. Patients were stabilized and followed for one year prior to MSC infusion and one year following infusion. RESULTS No patients presented with adverse effects. Statistically significant improvement in urinary protein excretion was observed in AT-MSCs transplanted patients, from a median of 0.75 g/day (range, 0.15-9.57) at baseline to 0.54 g/day (range, 0.01-2.66) at month 12 (P = 0.046). The glomerular filtration rate was not significantly decreased post-infusion of AT-MSCs. CONCLUSION Findings from this pilot study demonstrate that intravenous infusion of autologous expanded AT-MSCs into CKD patients was not associated with adverse effects and could benefit patients already undergoing standard medical treatment.
Collapse
Affiliation(s)
- Sandra Villanueva
- Laboratory of Molecular and Integrative Physiology, Faculty of Medicine, Universidad de Los Andes, Santiago,
Chile
| | | | - Eduardo Lorca
- Department of Nephrology, Hospital Salvador, Santiago,
Chile
| | - Andrés Tapia
- Laboratory of Nano-regenerative Medicine, Faculty of Medicine, Universidad de Los Andes, Santiago,
Chile
| | - G Valentina López
- Cells for Cells, Faculty of Medicine, Universidad de Los Andes, Santiago,
Chile
| | - Rocío Strodthoff
- Laboratory of Molecular and Integrative Physiology, Faculty of Medicine, Universidad de Los Andes, Santiago,
Chile
| | - Francisca Fajre
- Laboratory of Molecular and Integrative Physiology, Faculty of Medicine, Universidad de Los Andes, Santiago,
Chile
| | - Juan E. Carreño
- Laboratory of Molecular and Integrative Physiology, Faculty of Medicine, Universidad de Los Andes, Santiago,
Chile
| | - Ricardo Valjalo
- Department of Nephrology, Hospital Salvador, Santiago,
Chile
| | - César Vergara
- Laboratory of Molecular and Integrative Physiology, Faculty of Medicine, Universidad de Los Andes, Santiago,
Chile
| | - Manuel Lecanda
- Laboratory of Molecular and Integrative Physiology, Faculty of Medicine, Universidad de Los Andes, Santiago,
Chile
| | - Jorge Bartolucci
- Cells for Cells, Faculty of Medicine, Universidad de Los Andes, Santiago,
Chile
| | - Fernando E. Figueroa
- Laboratory of Nano-regenerative Medicine, Faculty of Medicine, Universidad de Los Andes, Santiago,
Chile
- Program for Translational Research in Cell Therapy, Universidad de Los Andes, Santiago,
Chile
- Consorcio Regenero, the Chilean Consortium for Regenerative Medicine, Faculty of Medicine, Universidad de Los Andes, Santiago,
Chile
| | - Maroun Khoury
- Laboratory of Nano-regenerative Medicine, Faculty of Medicine, Universidad de Los Andes, Santiago,
Chile
- Cells for Cells, Faculty of Medicine, Universidad de Los Andes, Santiago,
Chile
- Program for Translational Research in Cell Therapy, Universidad de Los Andes, Santiago,
Chile
| |
Collapse
|
|
13
|
Cai X, Wang L, Wang X, Hou F. miR-124a enhances therapeutic effects of bone marrow stromal cells transplant on diabetic nephropathy-related epithelial-to-mesenchymal transition and fibrosis. J Cell Biochem 2019; 121:299-312. [PMID: 31190436 DOI: 10.1002/jcb.29170] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 05/20/2019] [Accepted: 05/23/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Epithelial-to-mesenchymal transition (EMT) has been gradually considered as one of the major pathways that causes the production of interstitial myofibroblasts in diseased kidneys. MATERIALS AND METHODS The study was done to investigate the effect of a bone marrow stromal cell (BMSCs) transplant on rat podocytes and diabetic nephropathy (DN) rats in high-glucose concentration, and to explore the effect of miR-124a on BMSC therapy. High glucose-injured podocytes and streptozotocin-induced DN rats have been respectively used as injury models in in vitro and in vivo studies. Podocyte viability was measured using the Cell Counting Kit-8 assay. Renal pathological examination was observed by HE staining and Masson staining. The messenger RNA and protein levels were determined via real-time polymerase chain reaction and Western blotting, respectively. RESULTS By mediating the activation of caveolin-1 (cav-1) and β-catenin and affecting the expression levels of EMT biomarkers including p-cadherin, synaptopodin, fibroblast-specific protein-1, α-smooth muscle actin and snail, our in vitro study confirmed that miR-124a played a significant role in the treatment of high glucose-induced podocyte injury by BMSCs. The therapeutic effects of the BMSC transplant on DN rats were also proved to be further enhanced by miR-124a overexpression in BMSCs, and such a phenomenon was accompanied by the improvement of renal fibrosis and mitigation of DN-related kidney impairment. Regulation of fibronectin, collagen1, and EMT-related proteins was closely implicated with the mechanism, and the activation of cav-1 and β-catenin was also possibly involved. CONCLUSION The study demonstrated the pivotal effect of miR-124a on BMSC therapy for DN rats via mitigating EMT and fibrosis. Our results provide a novel insight into how therapeutic effects of BMSCs can be improved at the posttranscriptional level.
Collapse
Affiliation(s)
- Xiaojun Cai
- Department of Endocrinology, Heilongjiang Provincial Academy of Chinese Medical Science, Harbin, Heilongjiang, China
| | - Lei Wang
- Department of Endocrinology, Heilongjiang Provincial Academy of Chinese Medical Science, Harbin, Heilongjiang, China
| | - Xuling Wang
- Department of Endocrinology, Heilongjiang Provincial Academy of Chinese Medical Science, Harbin, Heilongjiang, China
| | - Fengyan Hou
- Department of Endocrinology, Heilongjiang Provincial Academy of Chinese Medical Science, Harbin, Heilongjiang, China
| |
Collapse
|
|
14
|
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.
Collapse
|
|
15
|
Cetinkaya B, Unek G, Kipmen-Korgun D, Koksoy S, Korgun ET. Effects of Human Placental Amnion Derived Mesenchymal Stem Cells on Proliferation and Apoptosis Mechanisms in Chronic Kidney Disease in the Rat. Int J Stem Cells 2019; 12:151-161. [PMID: 30595007 PMCID: PMC6457703 DOI: 10.15283/ijsc18067] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 08/21/2018] [Accepted: 11/20/2018] [Indexed: 12/20/2022] Open
Abstract
Background and Objectives The feature of chronic kidney failure (CKF) is loss of kidney functions due to erosion of healthy tissue and fibrosis. Recent studies showed that Mesenchymal stem cells (MSCs) differentiated into tubular epithelial cells thus renal function and structures renewed. Furthermore, MSCs protect renal function in CKF. Therefore, we aimed to investigate whether human amnion-derived mesenchymal stem cells (hAMSCs) can repair fibrosis and determine the effects on proliferation and apoptosis mechanisms in chronic kidney failure. Methods and Results In this study, rat model of CKF was constituted by applying Aristolochic acid (AA). hAMSCs were isolated from term placenta amnion membrane and transplanted into tail vein of rats. At the end of 30 days and 60 days of recovery period, we examined expressions of PCNA, p57 and Parp-1 by western blotting. Immunoreactivity of PCNA, Ki67, IL-6 and Collagen type I were detected by immunohistochemistry. Besides, apoptosis was detected by TUNEL. Serum creatinine and urea were measured. Expressions of PCNA and Ki67 increased in hAMSC groups compared with AA group. Furthermore, expressions of PARP-1 apoptosis marker and p57 cell cycle inhibitory protein increased in AA group significantly according to control, hAMSC groups and sham groups. IL-6 proinflammatory cytokine increased in AA group significantly according to control, hAMSCs groups and sham groups. Expressions of Collagen type I protein reduced in hAMSCs groups compared to AA group. After hAMSC treatment, serum creatinine and urea levels significantly decreased compared to AA group. After injection of hAMSC to rats, Masson’s Trichrome and Sirius Red staining showed fibrosis reduction in kidney. Conclusions According to our results hAMSCs can be ameliorate renal failure.
Collapse
Affiliation(s)
- Busra Cetinkaya
- Departments of Histology and Embryology.,Department of Histology and Embryology, Medical Faculty, Bulent Ecevit University, Zonguldak, Turkey
| | | | | | - Sadi Koksoy
- Medical Microbiology and Immunology, Medical Faculty, Akdeniz University, Antalya, Turkey
| | | |
Collapse
|
|
16
|
Abstract
Stem cell therapy has tremendous potential for clinical application in the treatment of a variety of diseases in veterinary medicine. Based on the known desirable immunomodulatory properties of mesenchymal stem cells, this therapy has potential for treatment of a variety of renal diseases. This review details our current understanding of stem cell biology and proposed mechanism of action as applicable to renal disease. Studies performed in chronic kidney disease clinical trials and models of acute kidney injury are summarized with the goal of providing an overview of the current status of this treatment modality and its potential for the future.
Collapse
Affiliation(s)
- Jessica M Quimby
- Department of Veterinary Clinical Sciences, The Ohio State University, 601 Vernon Tharp Road, Columbus, OH 43210, USA.
| |
Collapse
|
|
17
|
Wang XF, Zhang BH, Lu XQ, Wang P. Efficacy of different hemodialysis methods on dendritic cell marker CD40 and CD80 and platelet activation marker CD62P and P10 in patients with chronic renal failure. J Clin Lab Anal 2018; 33:e22713. [PMID: 30499177 DOI: 10.1002/jcla.22713] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Revised: 09/29/2018] [Accepted: 10/16/2018] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Chronic renal failure (CRF) has become a major public health concern, which increases the risk of stroke and systemic thromboembolism. Therefore, therapeutic strategies are in urgent requirement. This study was conducted for investigating efficacy of hemodialysis (HD), hemodiafiltration (HDF), and hemoperfusion (HP) in patients with CRF and the correlation with the presence of complications following HD therapy. METHODS The therapeutic effect, living quality, biochemical indicators, and dry weight were detected before and after the treatment regimens. Flow cytometry was conducted to detect expressions of dendritic cell markers (CD40 and CD80) and platelet activation markers (CD62P and P10), and the relationship between their expression and therapeutic effect as well as the association of these expressions with complications was analyzed. RESULTS After HD therapy, patients presented with decreased serum creatinine, serum phosphorus, triglyceride, parathyroid hormone, and β2 -MG expression; increased hemoglobin, plasma albumin expressions, and dry weight; and enhanced therapeutic effect and living quality. CD62P and P10 expressions decreased, while CD40 and CD80 expressions increased following HD therapy. The therapeutic effect improved in patients with low expressions of CD40 and CD80 and high expressions of CD62P and P10 following HP treatment and complications were lower after treatment of HDF and HP. CONCLUSION The aforementioned results indicated that CRF patients treated with HP exhibited higher expression of CD40 and CD80 and lower expression of CD62P and P10, suggesting that HP is conferred to have better efficacy than HDF and HD. Therefore, HP may be a promising clinical regimen for treatment of CRF patients.
Collapse
Affiliation(s)
- Xin-Fang Wang
- Department of Blood Purification, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Bei-Hao Zhang
- Department of Blood Purification, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiao-Qing Lu
- Department of Blood Purification, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Pei Wang
- Department of Blood Purification, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| |
Collapse
|
|
18
|
Yang RC, Zhu XL, Wang J, Wan F, Zhang HQ, Lin Y, Tang XL, Zhu B. Bone marrow mesenchymal stem cells attenuate the progression of focal segmental glomerulosclerosis in rat models. BMC Nephrol 2018; 19:335. [PMID: 30466397 PMCID: PMC6249725 DOI: 10.1186/s12882-018-1137-5] [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: 10/30/2017] [Accepted: 11/14/2018] [Indexed: 01/01/2023] Open
Abstract
Background Focal segmental glomerulosclerosis (FSGS) is the most common glomerular etiology of end-stage kidney disease (ESKD). Increasing evidence has indicated the reparative potential of mesenchymal stem cells (MSCs) in damaged diseased kidneys. However, the effect of bone marrow mesenchymal stem cells (BMSCs) on the FSGS progression remains unclear. This study aimed to investigate the protective effects of BMSCs on FSGS progression. Methods A rat model of FSGS was generated via unilateral nephrectomy plus adriamycin injection. Rat BMSCs were isolated and characterized on the basis of their differentiative potential towards adipocytes and osteoblasts and via flow cytometry analysis. Thereafter, rat BMSCs were transplanted into FSGS recipients through the caudal vein. After 8 weeks, 24-h proteinuria, serum creatinine, and urea nitrogen levels were determined. Renal morphology was assessed using a light and transmission electron microscope. MMP9 and TIMP-1 positive cells were detected via immunohistochemical analysis. Expression levels of proinflammatory cytokines IL-6 and TNF-α were examined via RT-PCR. Results The isolated adherent cells from the bone marrow of rats were phenotypically and functionally equivalent to typical MSCs. Clinical examination revealed that BMSC transplantation reduced the 24-h urinary protein excretion, and serum creatinine and urea nitrogen levels. Renal morphology was ameliorated in BMSCs-transplanted rats. Mechanistically, BMSC transplantation significantly downregulated TIMP-1 and upregulated MMP9, thereby increasing the renal MMP9/TIMP-1 ratio. Moreover, BMSC transplantation also downregulated IL-6 and TNF-α. Conclusions BMSC transplantation can attenuate FSGS progression in a rat model of FSGS, thereby providing a theoretical foundation for the application of autologous BMSCs in clinical FSGS therapy.
Collapse
Affiliation(s)
- Ru-Chun Yang
- Departmgent of Nephrology (Key laboratory of Zhejiang province, management of kidney disease), Hangzhou Hospital of Traditional Chinese Medicine, Tiyuchang Road 453, Hangzhou, 310007, People's Republic of China
| | - Xiao-Ling Zhu
- Departmgent of Nephrology (Key laboratory of Zhejiang province, management of kidney disease), Hangzhou Hospital of Traditional Chinese Medicine, Tiyuchang Road 453, Hangzhou, 310007, People's Republic of China.
| | - Jun Wang
- Departmgent of Nephrology (Key laboratory of Zhejiang province, management of kidney disease), Hangzhou Hospital of Traditional Chinese Medicine, Tiyuchang Road 453, Hangzhou, 310007, People's Republic of China
| | - Feng Wan
- Departmgent of Nephrology (Key laboratory of Zhejiang province, management of kidney disease), Hangzhou Hospital of Traditional Chinese Medicine, Tiyuchang Road 453, Hangzhou, 310007, People's Republic of China
| | - Hua-Qin Zhang
- Departmgent of Nephrology (Key laboratory of Zhejiang province, management of kidney disease), Hangzhou Hospital of Traditional Chinese Medicine, Tiyuchang Road 453, Hangzhou, 310007, People's Republic of China
| | - Yi Lin
- Departmgent of Nephrology (Key laboratory of Zhejiang province, management of kidney disease), Hangzhou Hospital of Traditional Chinese Medicine, Tiyuchang Road 453, Hangzhou, 310007, People's Republic of China
| | - Xuan-Li Tang
- Departmgent of Nephrology (Key laboratory of Zhejiang province, management of kidney disease), Hangzhou Hospital of Traditional Chinese Medicine, Tiyuchang Road 453, Hangzhou, 310007, People's Republic of China
| | - Bin Zhu
- Departmgent of Nephrology (Key laboratory of Zhejiang province, management of kidney disease), Hangzhou Hospital of Traditional Chinese Medicine, Tiyuchang Road 453, Hangzhou, 310007, People's Republic of China
| |
Collapse
|
|
19
|
Sattwika PD, Mustafa R, Paramaiswari A, Herningtyas EH. Stem cells for lupus nephritis: a concise review of current knowledge. Lupus 2018; 27:1881-1897. [PMID: 30099942 DOI: 10.1177/0961203318793206] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Lupus nephritis (LN), a common manifestation of systemic lupus erythematosus (SLE), accounts for significant morbidity and mortality in SLE patients. Since the available standard therapies and biologic agents for LN are yet to achieve the desired response and have considerable secondary effects, stem cell therapy has now emerged as a new approach. This therapy involves the transplantation of hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs). Our current review will highlight the progress of stem cell therapy for LN, along with the challenges encountered and the future direction of this approach.
Collapse
Affiliation(s)
- P D Sattwika
- 1 Department of Internal Medicine, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada/Dr Sardjito General Hospital, Indonesia
| | - R Mustafa
- 2 Clinical Epidemiology and Biostatistics Unit, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada/Dr Sardjito General Hospital, Indonesia
| | - A Paramaiswari
- 3 Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada/Dr Sardjito General Hospital, Indonesia
| | - E H Herningtyas
- 4 Department of Clinical Pathology and Laboratory Medicine, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Indonesia
| |
Collapse
|
|
20
|
Bozic M, Betriu A, Bermudez-Lopez M, Ortiz A, Fernandez E, Valdivielso JM. Association of FGF-2 Concentrations with Atheroma Progression in Chronic Kidney Disease Patients. Clin J Am Soc Nephrol 2018; 13:577-584. [PMID: 29519952 PMCID: PMC5969461 DOI: 10.2215/cjn.07980717] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 01/03/2018] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND OBJECTIVES Atherosclerosis is highly prevalent in CKD. The rate of progression of atherosclerosis is associated with cardiovascular events. Fibroblast growth factor 2 (FGF-2) is a member of the FGF family with potentially both protective and deleterious effects in the development of atherosclerosis. The role of circulating FGF-2 levels in the progression of atherosclerosis in CKD is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We used a multicenter, prospective, observational cohorts study of 481 patients with CKD. We determined the presence of atheroma plaque in ten arterial territories by carotid and femoral ultrasounds. Progression of atheromatosis was defined as an increase in the number of territories with plaque after 24 months. Plasma levels of FGF-2 were measured by multiplex analysis. A multivariable logistic regression analysis was performed to determine whether plasma FGF-2 levels were associated with atheromatosis progression. RESULTS Average age of the population was 61 years. The percentage of patients in each CKD stage was 51% in stage 3, 41% in stages 4-5, and 8% in dialysis. A total of 335 patients (70%) showed plaque at baseline. Atheromatosis progressed in 289 patients (67%). FGF-2 levels were similar between patients with or without plaque at baseline (79 versus 88 pg/ml), but lower in patients with atheromatosis progression after 2 years (78 versus 98 pg/ml; P<0.01). In adjusted analyses, higher plasma FGF-2 was associated with lower risk of atheromatosis progression (odds ratio [OR], 0.86; 95% confidence interval [95% CI], 0.76 to 0.96; per 50 pg/ml increment). Analysis of FGF-2 in tertiles showed that atheroma progression was observed for 102 participants in the lowest tertile of FGF-2 (reference group), 86 participants in the middle tertile of FGF-2 (adjusted OR, 0.70; 95% CI, 0.40 to 1.20), and 74 participants in the lowest tertile of FGF-2 (adjusted OR, 0.48; 95% CI, 0.28 to 0.82). CONCLUSIONS Low FGF-2 levels are independently associated with atheromatosis progression in CKD.
Collapse
Affiliation(s)
- Milica Bozic
- Vascular and Renal Translational Research Group, Institut de Recerca Biomedica de Lleida, Lleida, Spain; and
| | - Angels Betriu
- Vascular and Renal Translational Research Group, Institut de Recerca Biomedica de Lleida, Lleida, Spain; and
| | - Marcelino Bermudez-Lopez
- Vascular and Renal Translational Research Group, Institut de Recerca Biomedica de Lleida, Lleida, Spain; and
| | - Alberto Ortiz
- Instituto de Investigacion Sanitaria Fundación Jiménez Díaz, Autonomous University of Madrid, Red de Investigación Renal del Instituto de Salud Carlos III, Madrid, Spain
| | - Elvira Fernandez
- Vascular and Renal Translational Research Group, Institut de Recerca Biomedica de Lleida, Lleida, Spain; and
| | - Jose M. Valdivielso
- Vascular and Renal Translational Research Group, Institut de Recerca Biomedica de Lleida, Lleida, Spain; and
| | - on behalf of the NEFRONA investigators
- Vascular and Renal Translational Research Group, Institut de Recerca Biomedica de Lleida, Lleida, Spain; and
- Instituto de Investigacion Sanitaria Fundación Jiménez Díaz, Autonomous University of Madrid, Red de Investigación Renal del Instituto de Salud Carlos III, Madrid, Spain
| |
Collapse
|
|
21
|
Makhlough A, Shekarchian S, Moghadasali R, Einollahi B, Dastgheib M, Janbabaee G, Hosseini SE, Falah N, Abbasi F, Baharvand H, Aghdami N. Bone marrow-mesenchymal stromal cell infusion in patients with chronic kidney disease: A safety study with 18 months of follow-up. Cytotherapy 2018; 20:660-669. [PMID: 29580865 DOI: 10.1016/j.jcyt.2018.02.368] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2017] [Revised: 02/03/2018] [Accepted: 02/11/2018] [Indexed: 12/18/2022]
Abstract
BACKGROUND Chronic kidney disease (CKD) is a progressive loss of kidney function and structure that affects approximately 13% of the population worldwide. A recent meta-analysis revealed that cell-based therapies improve impaired renal function and structure in preclinical models of CKD. We assessed the safety and tolerability of bone marrow-mesenchymal stromal cell (MSC) infusion in patients with CKD. METHODS A single-arm study was carried out at one center with 18-month follow-up in seven eligible patients with CKD due to different etiologies such as hypertension, nephrotic syndrome (NS) and unknown etiology. We administered an intravenous infusion (1-2 × 106 cells/kg) of autologous cultured MSCs. The primary endpoint was safety, which was measured by number and severity of adverse events. The secondary endpoint was decrease in the rate of decrease in estimated glomerular filtration rate (eGFR). We compared kidney function during the follow-up visits to baseline and 18 months prior to the intervention. RESULTS Follow-up visits of all seven patients were completed; however, we have not observed any cell-related adverse events during the trial. Changes in eGFR (P = 0.10) and serum creatinine (P = 0.24) from 18 months before cell infusion to baseline in comparison with baseline to 18 months were not statistically significant. CONCLUSIONS We showed safety and tolerability of a single-dose infusion of autologous MSCs in patients with CKD.
Collapse
Affiliation(s)
- Atieh Makhlough
- Department of Nephrology, Gut and Liver Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Soroosh Shekarchian
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, The Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Reza Moghadasali
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, The Academic Center for Education, Culture and Research (ACECR), Tehran, Iran; Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, The Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Behzad Einollahi
- Nephrology and Urology Research Center, Baqiyatallah University of Medical Sciences, Baqiyatallah Hospital, Tehran, Iran
| | - Mona Dastgheib
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, The Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Ghasem Janbabaee
- Gastrointestinal Cancer Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Seyedeh Esmat Hosseini
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, The Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Nasrin Falah
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, The Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Fateme Abbasi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, The Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Hossein Baharvand
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, The Academic Center for Education, Culture and Research (ACECR), Tehran, Iran; Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, The Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Nasser Aghdami
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, The Academic Center for Education, Culture and Research (ACECR), Tehran, Iran.
| |
Collapse
|
|
22
|
Quimby JM, Borjesson DL. Mesenchymal stem cell therapy in cats: Current knowledge and future potential. J Feline Med Surg 2018; 20:208-216. [PMID: 29478398 PMCID: PMC10816289 DOI: 10.1177/1098612x18758590] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Practical relevance: Stem cell therapy is an innovative field of scientific investigation with tremendous potential for clinical application in veterinary medicine. Based on the known desirable immunomodulatory properties of mesenchymal stem cells, this therapy holds promise for the treatment of a variety of inflammatory diseases in cats. AIMS This review details our current understanding of feline stem cell biology and proposed mechanism of action. Studies performed in feline clinical trials for diseases including gingivostomatitis, chronic enteropathy, asthma and kidney disease are summarized, with the goal of providing an overview of the current status of this treatment modality and its potential for the future.
Collapse
Affiliation(s)
- Jessica M Quimby
- The Ohio State University, Department of Veterinary Clinical Sciences, Columbus, OH 43210, USA
| | - Dori L Borjesson
- University of California–Davis, Veterinary Institute for Regenerative Cures, and Department of Pathology, Microbiology and Immunology, Davis, CA 95616, USA
| |
Collapse
|
|
23
|
Li Y, Liu J, Liao G, Zhang J, Chen Y, Li L, Li L, Liu F, Chen B, Guo G, Wang C, Yang L, Cheng J, Lu Y. Early intervention with mesenchymal stem cells prevents nephropathy in diabetic rats by ameliorating the inflammatory microenvironment. Int J Mol Med 2018; 41:2629-2639. [PMID: 29484379 PMCID: PMC5846648 DOI: 10.3892/ijmm.2018.3501] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2016] [Accepted: 09/01/2017] [Indexed: 02/05/2023] Open
Abstract
Diabetic nephropathy (DN) is a major complication of diabetes and represents the leading cause of end-stage renal disease. Mesenchymal stem cell (MSC) treatment has been demonstrated to be effective in DN models by reducing albuminuria and attenuating glomerular injury; however, limited in-depth understanding of the underlying mechanism and a lack of clinical trials hinders its clinical use. Additionally, most of these experimental studies were conducted on the advanced stage of nephropathy, which is difficult to reverse and consequently showed limited therapeutic efficacy. We sought to evaluate whether early intervention by MSCs has the potential to prevent DN onset and progression as well as protect kidney function when intravenously administered to rats with diabetes. Diabetes was induced in adult male SD rats by streptozotocin (STZ) injection (55 mg/kg, i.p.). The diabetic rats were injected with or without bone marrow-derived MSCs (5×106 per rat), via tail vein at 2, 4, 5 and 7 weeks after diabetes onset. Fasting blood glucose (FBG), blood urea nitrogen (BUN) and serum creatinine (Scr) levels in serum samples and glycosuria (GLU), microalbumin (MAU), and albumin to creatinine ratio (ACR) in urine samples were determined. Renal pathology and immunohistochemistry (IHC) for CD68, MCP-1, fibronectin (FN), transforming growth factor-β (TGF-β) and pro-inflammatory cytokines were also performed. Expression levels of the above factors as well as interleukin-10 (IL-10), and epidermal growth factor (EGF) were assessed by qPCR and multiplex bead-based suspension array system, respectively. Additionally, MSC tracing in vivo was performed. Ex vivo, peritoneal macrophages were co-cultured with MSCs, and expression of inflammatory cytokines was detected as well. MSC treatment profoundly suppressed renal macrophage infiltration and inflammatory cytokine secretion in diabetic rats, resulting in prominently improved kidney histology, systemic homeostasis, and animal survival, although no significant effect on hyperglycemia was observed. Engrafted MSCs were primarily localized in deteriorated areas of the kidney and immune organs 48 h after infusion. MSC treatment upregulated serum anti-inflammatory cytokines IL-10 and EGF. Ex vivo, MSCs inhibited lipopolysaccharide (LPS)-stimulated rat peritoneal macrophage activation via the downregulation of inflammatory-related cytokines such as IL-6, MCP-1, tumor necrosis factor-α (TNF-α) and IL-1β. Our results demonstrated that early intervention with MSCs prevented renal injury via immune regulation in diabetic rats, which restored the homeostasis of the immune microenvironment, contributing to the prevention of kidney dysfunction and glomerulosclerosis.
Collapse
Affiliation(s)
- Yuanmin Li
- Key Laboratory of Transplant Engineering and Immunology, National Health and Family Planning Commission (NHFPC), West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Jingping Liu
- Key Laboratory of Transplant Engineering and Immunology, National Health and Family Planning Commission (NHFPC), West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Guangneng Liao
- Key Laboratory of Transplant Engineering and Immunology, National Health and Family Planning Commission (NHFPC), West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Jie Zhang
- Key Laboratory of Transplant Engineering and Immunology, National Health and Family Planning Commission (NHFPC), West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Younan Chen
- Key Laboratory of Transplant Engineering and Immunology, National Health and Family Planning Commission (NHFPC), West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Lan Li
- Key Laboratory of Transplant Engineering and Immunology, National Health and Family Planning Commission (NHFPC), West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Li Li
- Key Laboratory of Transplant Engineering and Immunology, National Health and Family Planning Commission (NHFPC), West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Fang Liu
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Bo Chen
- Key Laboratory of Transplant Engineering and Immunology, National Health and Family Planning Commission (NHFPC), West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Gang Guo
- Key Laboratory of Transplant Engineering and Immunology, National Health and Family Planning Commission (NHFPC), West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Chengshi Wang
- Key Laboratory of Transplant Engineering and Immunology, National Health and Family Planning Commission (NHFPC), West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Lichuan Yang
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Jingqiu Cheng
- Key Laboratory of Transplant Engineering and Immunology, National Health and Family Planning Commission (NHFPC), West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yangrong Lu
- Key Laboratory of Transplant Engineering and Immunology, National Health and Family Planning Commission (NHFPC), West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| |
Collapse
|
|
24
|
Effect of adipose-derived mesenchymal stem cell transplantation on vascular calcification in rats with adenine-induced kidney disease. Sci Rep 2017; 7:14036. [PMID: 29070880 PMCID: PMC5656613 DOI: 10.1038/s41598-017-14492-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Accepted: 10/11/2017] [Indexed: 12/29/2022] Open
Abstract
Previous studies have investigated the use of mesenchymal stem cells (MSCs) to treat damaged kidneys. However, the effect of adipose-derived MSCs (ASCs) on vascular calcification in chronic kidney disease (CKD) is still poorly understood. In the present study, we explored the potential of ASCs for the treatment of CKD and vascular calcification. CKD was induced in male Sprague-Dawley rats by feeding them a diet containing 0.75% adenine for 4 weeks. ASCs transplantation significantly reduced serum inorganic phosphorus (Pi) as compared to that in the control. The histopathology of the kidneys showed a greater dilation of tubular lumens and interstitial fibrosis in the control group. Calcium and Pi contents of the aorta in the ASCs transplantation group were lower than those in the control group. Von Kossa staining of the thoracic aorta media revealed that ASCs transplantation suppressed vascular calcification. Thus, this study revealed that autogenic ASCs transplantation inhibits kidney damage and suppresses the progression of vascular calcification in the CKD rat model, suggesting that autogenic ASCs transplantation is a novel approach for preventing the progression of CKD and vascular calcification.
Collapse
|
|
25
|
Uchida N, Kushida Y, Kitada M, Wakao S, Kumagai N, Kuroda Y, Kondo Y, Hirohara Y, Kure S, Chazenbalk G, Dezawa M. Beneficial Effects of Systemically Administered Human Muse Cells in Adriamycin Nephropathy. J Am Soc Nephrol 2017; 28:2946-2960. [PMID: 28674043 DOI: 10.1681/asn.2016070775] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Accepted: 05/08/2017] [Indexed: 01/24/2023] Open
Abstract
Multilineage-differentiating stress-enduring (Muse) cells are nontumorigenic endogenous pluripotent-like stem cells that can be collected from various organs. Intravenously administered Muse cells have been shown to spontaneously migrate to damaged tissue and replenish lost cells, but the effect in FSGS is unknown. We systemically administered human bone marrow-derived Muse cells without concurrent administration of immunosuppressants to severe combined immune-deficient (SCID) and BALB/c mouse models with adriamycin-induced FSGS (FSGS-SCID and FSGS-BALB/c, respectively). In FSGS-SCID mice, human Muse cells preferentially integrated into the damaged glomeruli and spontaneously differentiated into cells expressing markers of podocytes (podocin; 31%), mesangial cells (megsin; 13%), and endothelial cells (CD31; 41%) without fusing to the host cells; attenuated glomerular sclerosis and interstitial fibrosis; and induced the recovery of creatinine clearance at 7 weeks. Human Muse cells induced similar effects in FSGS-BALB/c mice at 5 weeks, despite xenotransplant without concurrent immunosuppressant administration, and led to improvement in urine protein, creatinine clearance, and plasma creatinine levels more impressive than that in the FSGS-SCID mice at 5 weeks. However, functional recovery in FSGS-BALB/c mice was impaired at 7 weeks due to immunorejection, suggesting the importance of Muse cell survival as glomerular cells in the FSGS kidney for tissue repair and functional recovery. In conclusion, Muse cells are unique reparative stem cells that preferentially home to damaged glomeruli and spontaneously differentiate into glomerular cells after systemic administration. Introduction of genes to induce differentiation is not required before Muse cell administration; thus, Muse cells may be a feasible therapeutic strategy in FSGS.
Collapse
Affiliation(s)
- Nao Uchida
- Departments of Stem Cell Biology and Histology and.,Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan
| | | | | | - Shohei Wakao
- Departments of Stem Cell Biology and Histology and
| | - Naonori Kumagai
- Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan
| | | | - Yoshiaki Kondo
- Department of Healthcare Services Management, Nihon University School of Medicine, Tokyo, Japan
| | - Yukari Hirohara
- Departments of Stem Cell Biology and Histology and.,Regenerative Medicine Division, Life Science Institute, Inc., Tokyo, Japan; and
| | - Shigeo Kure
- Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Gregorio Chazenbalk
- Department of Obstetrics and Gynecology, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California
| | - Mari Dezawa
- Departments of Stem Cell Biology and Histology and
| |
Collapse
|
|
26
|
Clinical Expectations for the New Bioactive Treatments: Greater Well-Being or Longer Survival? Int J Artif Organs 2017. [DOI: 10.5301/ijao.5000582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
|
|
27
|
Khanh VC, Ohneda K, Kato T, Yamashita T, Sato F, Tachi K, Ohneda O. Uremic Toxins Affect the Imbalance of Redox State and Overexpression of Prolyl Hydroxylase 2 in Human Adipose Tissue-Derived Mesenchymal Stem Cells Involved in Wound Healing. Stem Cells Dev 2017; 26:948-963. [PMID: 28537846 DOI: 10.1089/scd.2016.0326] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Chronic kidney disease (CKD) results in a delay in wound healing because of its complications such as uremia, anemia, and fluid overload. Mesenchymal stem cells (MSCs) are considered to be a candidate for wound healing because of the ability to recruit many types of cells. However, it is still unclear whether the CKD-adipose tissue-derived MSCs (CKD-AT-MSCs) have the same function in wound healing as healthy donor-derived normal AT-MSCs (nAT-MSCs). In this study, we found that uremic toxins induced elevated reactive oxygen species (ROS) expression in nAT-MSCs, resulting in the reduced expression of hypoxia-inducible factor-1α (HIF-1α) under hypoxic conditions. Consistent with the uremic-treated AT-MSCs, there was a definite imbalance of redox state and high expression of ROS in CKD-AT-MSCs isolated from early-stage CKD patients. In addition, a transplantation study clearly revealed that nAT-MSCs promoted the recruitment of inflammatory cells and recovery from ischemia in the mouse flap model, whereas CKD-AT-MSCs had defective functions and the wound healing process was delayed. Of note, the expression of prolyl hydroxylase domain 2 (PHD2) is selectively increased in CKD-AT-MSCs and its inhibition can restore the expression of HIF-1α and the wound healing function of CKD-AT-MSCs. These results indicate that more studies about the functions of MSCs from CKD patients are required before they can be applied in the clinical setting.
Collapse
Affiliation(s)
- Vuong Cat Khanh
- 1 Graduate School of Comprehensive Human Science, Laboratory of Regenerative Medicine and Stem Cell Biology, University of Tsukuba , Tsukuba, Japan
| | - Kinuko Ohneda
- 2 Takasaki University of Health and Welfare Laboratory of Molecular Pathophysiology , Takasaki, Japan
| | - Toshiki Kato
- 1 Graduate School of Comprehensive Human Science, Laboratory of Regenerative Medicine and Stem Cell Biology, University of Tsukuba , Tsukuba, Japan
| | - Toshiharu Yamashita
- 1 Graduate School of Comprehensive Human Science, Laboratory of Regenerative Medicine and Stem Cell Biology, University of Tsukuba , Tsukuba, Japan
| | - Fujio Sato
- 3 Department of Cardiovascular Surgery, University of Tsukuba , Tsukuba, Japan
| | - Kana Tachi
- 4 Department of Breast-Thyroid-Endocrine Surgery, University of Tsukuba , Tsukuba, Japan
| | - Osamu Ohneda
- 1 Graduate School of Comprehensive Human Science, Laboratory of Regenerative Medicine and Stem Cell Biology, University of Tsukuba , Tsukuba, Japan
| |
Collapse
|
|
28
|
Vidane AS, Pinheiro AO, Casals JB, Passarelli D, Hage MCFNS, Bueno RS, Martins DS, Ambrósio CE. Transplantation of amniotic membrane-derived multipotent cells ameliorates and delays the progression of chronic kidney disease in cats. Reprod Domest Anim 2016; 52 Suppl 2:316-326. [DOI: 10.1111/rda.12846] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- AS Vidane
- Department of Surgery; Faculty of Veterinary Medicine and Animal Science; University of São Paulo; São Paulo SP Brazil
| | - AO Pinheiro
- Department of Veterinary Medicine; Faculty of Animal Science and Food Engineering; University of São Paulo; Pirassununga SP Brazil
| | - JB Casals
- Department of Surgery; Faculty of Veterinary Medicine and Animal Science; University of São Paulo; São Paulo SP Brazil
| | - D Passarelli
- Department of Veterinary Medicine; Faculty of Animal Science and Food Engineering; University of São Paulo; Pirassununga SP Brazil
| | - MCFNS Hage
- Department of Veterinary Medicine; Faculty of Animal Science and Food Engineering; University of São Paulo; Pirassununga SP Brazil
| | - RS Bueno
- Department of Basic Science; Faculty of Animal Science and Food Engineering; University of São Paulo; Pirassununga SP Brazil
| | - DS Martins
- Department of Veterinary Medicine; Faculty of Animal Science and Food Engineering; University of São Paulo; Pirassununga SP Brazil
| | - CE Ambrósio
- Department of Veterinary Medicine; Faculty of Animal Science and Food Engineering; University of São Paulo; Pirassununga SP Brazil
| |
Collapse
|
|
29
|
Nassar W, El-Ansary M, Sabry D, Mostafa MA, Fayad T, Kotb E, Temraz M, Saad AN, Essa W, Adel H. Umbilical cord mesenchymal stem cells derived extracellular vesicles can safely ameliorate the progression of chronic kidney diseases. Biomater Res 2016; 20:21. [PMID: 27499886 PMCID: PMC4974791 DOI: 10.1186/s40824-016-0068-0] [Citation(s) in RCA: 346] [Impact Index Per Article: 38.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Accepted: 07/04/2016] [Indexed: 12/29/2022] Open
Abstract
Background Bio-products from stem/progenitor cells, such as extracellular vesicles, are likely a new promising approach for reprogramming resident cells in both acute and chronic kidney disease. Forty CKD patients stage III and IV (eGFR 15–60 mg/ml) have been divided into two groups; twenty patients as treatment group “A” and twenty patients as a matching placebo group “B”. Two doses of MSC-derived extracellular vesicles had been administered to patients of group “A”. Blood urea, serum creatinine, urinary albumin creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) have been used to assess kidney functions and TNF-α, TGF-β1 and IL-10 have been used to assess the amelioration of the inflammatory immune activity. Results Participants in group A exhibited significant improvement of eGFR, serum creatinine level, blood urea and UACR. Patients of the treatment group “A” also exhibited significant increase in plasma levels of TGF-β1, and IL-10 and significant decrease in plasma levels of TNF-α. Participants of the control group B did not show significant improvement in any of the previously mentioned parameters at any time point of the study period. Conclusion Administration of cell-free cord-blood mesenchymal stem cells derived extracellular vesicles (CF-CB-MSCs-EVs) is safe and can ameliorate the inflammatory immune reaction and improve the overall kidney function in grade III-IV CKD patients.
Collapse
Affiliation(s)
- Wael Nassar
- Department of Internal Medicine, Nephrology Section, Sahel Teaching Hospital, General Organization of Teaching Hospitals and Institutes (GOTHI), Cairo, Egypt ; Department of Internal medicine, Nephrology Section, Faculty of Medicine, October Six University, Cairo, Egypt
| | - Mervat El-Ansary
- Department of clinical pathology, stem cells Section, Faculty of medicine, Cairo University, Cairo, Egypt
| | - Dina Sabry
- Department of Biochemistry, Faculty of medicine, Cairo University, Cairo, Egypt
| | - Mostafa A Mostafa
- Department of Internal medicine, Nephrology Section, Faculty of Medicine, October Six University, Cairo, Egypt
| | - Tarek Fayad
- Department of Internal Medicine, Nephrology Section, Faculty of medicine, Cairo University, Cairo, Egypt
| | - Esam Kotb
- Department of Internal medicine, Nephrology Section, Faculty of Medicine, October Six University, Cairo, Egypt
| | - Mahmoud Temraz
- Department of Internal Medicine, Nephrology Section, Sahel Teaching Hospital, General Organization of Teaching Hospitals and Institutes (GOTHI), Cairo, Egypt
| | - Abdel-Naser Saad
- Department of Internal Medicine, Nephrology Section, Sahel Teaching Hospital, General Organization of Teaching Hospitals and Institutes (GOTHI), Cairo, Egypt
| | - Wael Essa
- Department of Internal Medicine, Nephrology Section, Sahel Teaching Hospital, General Organization of Teaching Hospitals and Institutes (GOTHI), Cairo, Egypt
| | - Heba Adel
- Department of clinical pathology, stem cells Section, Faculty of medicine, Cairo University, Cairo, Egypt
| |
Collapse
|
|
30
|
Rovira J, Diekmann F, Campistol JM, Ramírez-Bajo MJ. Therapeutic application of extracellular vesicles in acute and chronic renal injury. Nefrologia 2016; 37:126-137. [PMID: 27462016 DOI: 10.1016/j.nefro.2016.04.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Revised: 04/14/2016] [Accepted: 04/28/2016] [Indexed: 12/31/2022] Open
Abstract
A new cell-to-cell communication system was discovered in the 1990s, which involves the release of vesicles into the extracellular space. These vesicles shuttle bioactive particles, including proteins, mRNA, miRNA, metabolites, etc. This particular communication has been conserved throughout evolution, which explains why most cell types are capable of producing vesicles. Extracellular vesicles (EVs) are involved in the regulation of different physiological processes, as well as in the development and progression of several diseases. EVs have been widely studied over recent years, especially those produced by embryonic and adult stem cells, blood cells, immune system and nervous system cells, as well as tumour cells. EV analysis from bodily fluids has been used as a diagnostic tool for cancer and recently for different renal diseases. However, this review analyses the importance of EVs generated by stem cells, their function and possible clinical application in renal diseases and kidney transplantation.
Collapse
Affiliation(s)
- Jordi Rovira
- Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Centre de Recerca Biomèdica CELLEX, Fundació Clínic per la Recerca Biomèdica (FCRB), Barcelona, España; Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, España
| | - Fritz Diekmann
- Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Centre de Recerca Biomèdica CELLEX, Fundació Clínic per la Recerca Biomèdica (FCRB), Barcelona, España; Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, España; Departamento de Nefrología y Trasplante Renal, Institut Clínic de Nefrologia i Urologia (ICNU), Hospital Clínic, Barcelona, España.
| | - Josep M Campistol
- Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Centre de Recerca Biomèdica CELLEX, Fundació Clínic per la Recerca Biomèdica (FCRB), Barcelona, España; Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, España; Departamento de Nefrología y Trasplante Renal, Institut Clínic de Nefrologia i Urologia (ICNU), Hospital Clínic, Barcelona, España
| | - María José Ramírez-Bajo
- Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Centre de Recerca Biomèdica CELLEX, Fundació Clínic per la Recerca Biomèdica (FCRB), Barcelona, España
| |
Collapse
|
|
31
|
Messina M, Gallo E, Mella A, Pagani F, Biancone L. Update on the treatment of focal segmental glomerulosclerosis in renal transplantation. World J Transplant 2016; 6:54-68. [PMID: 27011905 PMCID: PMC4801805 DOI: 10.5500/wjt.v6.i1.54] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2015] [Revised: 12/22/2015] [Accepted: 01/22/2016] [Indexed: 02/05/2023] Open
Abstract
Focal segmental glomerulosclerosis (FSGS) represents one of the most severe glomerular diseases, with frequent progression to end-stage renal disease and a high rate of recurrence in renal allografts (30%-50%). Recurrent FSGS portends a negative outcome, with the hazard ratio of graft failure being two-fold higher then that of other glomerulonephritis. Two patterns of clinical presentations are observed: Early recurrence, which is characterized by massive proteinuria within hours to days after implantation of the renal graft, and late recurrence, which occurs several months or years after the transplantation. Many clinical conditions have been recognized as risk factors for recurrence, including younger age, rapid progression of the disease to end-stage renal disease on native kidneys, and loss of previous renal allografts due to recurrence. However, much less is known about the incidence and risk factors of the so-called “de novo” type of FSGS, for which sufferers are transplanted patients without disease on native kidneys; but, rapid development of allograft failure is frequently observed. Management of both forms is challenging, and none of the approaches proposed to date have been demonstrated as consistently beneficial or effective. In the present review we report an update on the available therapeutic strategies for FSGS in renal transplantation within the context of a critical overview of the current literature.
Collapse
|
|
32
|
Quimby JM, Webb TL, Randall E, Marolf A, Valdes-Martinez A, Dow SW. Assessment of intravenous adipose-derived allogeneic mesenchymal stem cells for the treatment of feline chronic kidney disease: a randomized, placebo-controlled clinical trial in eight cats. J Feline Med Surg 2016; 18:165-71. [PMID: 25784460 PMCID: PMC11149004 DOI: 10.1177/1098612x15576980] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/27/2024]
Abstract
OBJECTIVES Feline chronic kidney disease (CKD) is characterized by chronic tubulointerstitial nephritis, and inflammation contributes to the progression of renal fibrosis. Mesenchymal stem cells (MSCs) have demonstrated anti-inflammatory and antifibrotic effects in rodent CKD models. However, few randomized trials evaluating the effectiveness of MSC therapy for diseases in companion animals have been reported. The purpose of this study was to evaluate the effectiveness of allogeneic MSCs for the treatment of feline CKD using a randomized, placebo-controlled trial. METHODS MSCs were isolated from the cryopreserved adipose tissues of specific pathogen-free research cats and culture expanded. CKD cats were enrolled in a randomized, placebo-controlled, blinded one-way crossover clinical study. Four CKD cats were randomized to receive 2 × 10(6) MSCs/kg intravenously at 2, 4 and 6 weeks. Four CKD cats were randomized to receive placebo, with two cats crossing over to the MSC treatment group and one cat failing to complete the trial. Complete blood counts, chemistry and urinalysis were performed at weeks 0, 2, 4, 6 and 8. Glomerular filtration rate (GFR) via nuclear scintigraphy and urine protein:creatinine ratio (UPC) were determined at weeks 0 and 8. RESULTS Six cats received three doses of allogeneic MSC culture expanded from cryopreserved adipose without adverse effects. No significant change in serum creatinine, blood urea nitrogen, potassium, phosphorus, GFR by nuclear scintigraphy, UPC or packed cell volume was seen in cats treated with MSCs. Individual changes in GFR were 12%, 8%, 8%, 2%, -13% and -67% in treated cats compared with 16%, 36% and 0% in placebo-treated cats. CONCLUSIONS AND RELEVANCE While administration of MSC culture expanded from cryopreserved adipose was not associated with adverse effects, significant improvement in renal function was not observed immediately after administration. Long-term follow-up is necessary to determine whether MSC administration affects disease progression in cats with CKD.
Collapse
Affiliation(s)
- Jessica M Quimby
- Center for Immune and Regenerative Medicine, Department of Clinical Sciences, Colorado State University, Fort Collins, CO, USA
| | - Tracy L Webb
- Center for Immune and Regenerative Medicine, Department of Clinical Sciences, Colorado State University, Fort Collins, CO, USA
| | - Elissa Randall
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA
| | - Angela Marolf
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA
| | - Alex Valdes-Martinez
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA Current address: AV Veterinary Radiology, Denver, CO 80202, USA
| | - Steve W Dow
- Center for Immune and Regenerative Medicine, Department of Clinical Sciences, Colorado State University, Fort Collins, CO, USA Department of Microbiology, Immunology, and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
| |
Collapse
|
|
33
|
Al-Saikan B, Ding J, Tredget E, Metcalfe P. Benefits of mesenchymal stem cells after partial bladder outlet obstruction. Can Urol Assoc J 2016; 10:E1-E6. [PMID: 26858780 PMCID: PMC4729568 DOI: 10.5489/cuaj.3257] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Partial bladder outlet obstruction (pBOO) results in significant morbidity and mortality in the pediatric and adult populations. Mesenchymal stem cells (MSC) have been widely studied in many organ systems for the treatment and prevention of fibrotic and inflammatory conditions. Therefore, we hypothesize that systemic administration of MSC will demonstrate short-term biochemical, histological, and urodynamic benefits in an animal model for pBOO. METHODS After University ethics approval, 5 × 106 green fluorescent protein GFP-labeled MSC were intravenously injected concurrently with pBOO in adult Sprague-Dawley rats. Five groups (n=3/group) were analyzed: a) unobstructed controls; b) pBOO for seven days with intravenous MSC (7d+MSC); c) pBOO for seven days without intravenous MSC (7d-MSC); d) pBOO for 14 days with intravenous MSC (14d+MSC), e) pBOO for 14 days without MSC (14d-MSC). Urodynamics were performed at the end of the experimental period and bladders were weighed. Immunohistochemistry was performed for GFP detection and reverse transcription polymerase chain reaction (RT-PCR) to detect mRNA of: TGF-B, HIF-1a, RhoA, GRP-78, lumican, and decorin. RESULTS All animals remained healthy. GFP was detected in all treatment groups. MSC treatment resulted in a significant decrease in bladder capacity (0.91 cc vs. 2.15 cc, p=0.04). Treatment also resulted in significant decreases in mRNA levels of: TGF-B, HIF-1a, Rho-A, and GRP-78. CONCLUSIONS Systemic treatment with MSC was well tolerated and resulted in MSC accumulation after pBOO. Despite our low numbers, we were able to successfully demonstrate short-term urodynamic improvements and widespread, significant decreases in inflammatory mediators. We believe that this decreased inflammatory cascade will help prevent long-term detrusor deterioration.
Collapse
Affiliation(s)
- Bader Al-Saikan
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Jie Ding
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Edward Tredget
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Peter Metcalfe
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
| |
Collapse
|
|
34
|
Bi L, Hou R, Yang D, Zhao D, Li S, Zhao J, Zhang HE. Effect of bone marrow stem cell mobilisation on the expression levels of cellular growth factors in a rat model of acute tubular necrosis. Exp Ther Med 2015; 10:618-624. [PMID: 26622364 DOI: 10.3892/etm.2015.2574] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Accepted: 09/17/2014] [Indexed: 11/06/2022] Open
Abstract
The aim of the present study was to observe the mobilisation effects of stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) on bone marrow stem cells (BMSCs) in rats with renal ischaemia-reperfusion injury. In addition, the effects of the BMSCs on the expression levels of hepatocyte growth factor (HGF) and epidermal growth factor (EGF) were investigated, with the aim to further the understanding of the protective mechanisms of SCF and G-CSF in renal ischaemia-reperfusion injury. The model and treatment groups were established using a model of unilateral renal ischaemia-reperfusion injury, in which the treatment group and the treatment control group were subcutaneously injected once a day with 200 µg/kg SCF and 50 µg/kg G-CSF, 24 h after the modelling, for five consecutive days. The CD34+ cell count was measured in the peripheral blood using flow cytometry. The mRNA expression levels of HGF and EGF were determined using polymerase chain reaction analysis, while the protein expression levels of HGF and EGF were detected using immunohistochemistry. The CD34+ cell count in the peripheral blood of the treatment and treatment control groups was significantly higher compared with that in the model group (P<0.05). However, CD34 expression levels in the cells from the renal tissues of the model and treatment groups were significantly higher compared with that of the control and treatment control groups (P<0.05), with the greatest increase observed in the treatment group. The mRNA and protein expression levels of HGF and EGF in the treatment group were significantly higher compared with the model group (P<0.05). Therefore, the results indicated that a combination of SCF and G-CSF can promote the repair of acute tubular necrosis. This combination, which can mobilise sufficient numbers of BMSCs to migrate back to the injured site, is a key factor in promoting the repair of renal tubular injury. Upregulation of HGF and EGF was also shown to promote the repair of renal tubular injury.
Collapse
Affiliation(s)
- Lingyun Bi
- Department of Paediatrics, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Ruanling Hou
- Physiological Laboratory, Xinxiang Medical University, Xinxiang, Henan 453000, P.R. China
| | - Dasheng Yang
- Department of Paediatrics, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Dean Zhao
- Department of Paediatrics, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Shujun Li
- Department of Paediatrics, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Jingli Zhao
- Department of Paediatrics, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - H E Zhang
- Department of Paediatrics, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| |
Collapse
|
|
35
|
Moghadasali R, Hajinasrollah M, Argani H, Nassiri SM, Najarasl M, Sodeifi N, Baharvand H, Aghdami N. Autologous transplantation of mesenchymal stromal cells tends to prevent progress of interstitial fibrosis in a rhesus Macaca mulatta monkey model of chronic kidney disease. Cytotherapy 2015; 17:1495-505. [PMID: 26341479 DOI: 10.1016/j.jcyt.2015.06.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Revised: 05/09/2015] [Accepted: 06/11/2015] [Indexed: 12/17/2022]
Abstract
BACKGROUND AIMS Chronic kidney disease (CKD) attributed to cisplatin is well documented. Mesenchymal stromal cells (MSCs) are proven to be renotropic. Although they have been shown to improve function in CKD and reduce fibrosis in different experimental rodent models, their efficiency in primates is unknown. The present study aimed to evaluate the prevention of CKD and reduction of fibrosis in monkeys treated with MSCs after cisplatin nephrotoxicity. METHODS We induced CKD in adult rhesus Macaca mulatta monkeys by means of intravenous administration of cisplatin. Autologous MSCs were transplanted by means of intrarenal arterial injections to assess the adverse effects of cisplatin in two CKD models: preventative and stable. Preventative CKD monkeys (n = 3) underwent cell transplantation 4 days after the cisplatin injection. The stable CKD monkeys (n = 2) underwent cell transplantation 6 months after the cisplatin injection. Non-treated (n = 4) and normal saline-injected animals (n = 3) comprised the control and vehicle groups, respectively. We followed the animals for survival rate, serum biochemistry, urine analysis and histopathological indices. RESULTS In the preventive CKD model, MSC transplantation tended to improve some renal functions but significantly reduced the histopathologic score compared with the vehicle and control groups. In the stable CKD model, MSCs did not ameliorate renal function or pathological score. CONCLUSIONS These results suggest that MSCs tend to delay progression of CKD and fibrosis but do not reduce established interstitial fibrosis in this unique primate model of cisplatin-induced nephrotoxicity.
Collapse
Affiliation(s)
- Reza Moghadasali
- Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Mostafa Hajinasrollah
- Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Hassan Argani
- Urology and Nephrology Research Center, Modares Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Mahdi Nassiri
- Department of Clinical Pathology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Mostafa Najarasl
- Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Niloofar Sodeifi
- Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Hossein Baharvand
- Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; Department of Developmental Biology, University of Science and Culture, ACECR, Tehran, Iran
| | - Nasser Aghdami
- Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
| |
Collapse
|
|
36
|
Proregenerative Microenvironment Triggered by Donor Mesenchymal Stem Cells Preserves Renal Function and Structure in Mice with Severe Diabetes Mellitus. BIOMED RESEARCH INTERNATIONAL 2015; 2015:164703. [PMID: 26167475 PMCID: PMC4475763 DOI: 10.1155/2015/164703] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Revised: 04/30/2015] [Accepted: 05/14/2015] [Indexed: 02/06/2023]
Abstract
The aim of our work was to evaluate, in an animal model of severe diabetes mellitus, the effect of mesenchymal stem cells (MSCs) administration on diabetic nephropathy (DN) progression. After diabetes induction, one group of mice received the vehicle (DM) and other group received a single dose of MSCs (DM + MSCs). DM + MSCs mice showed a significant improvement in functional parameters of the kidney compared with untreated mice. While DM mice presented marked histopathological changes characteristics of advanced stages of DN (fibrosis, glomerulosclerosis, glomerular basement membrane thickening, capillary occlusion, decreased podocyte density, and effacement of foot processes), DM + MSCs mice showed only slight tubular dilatation. The renoprotection was not associated with an improvement in diabetic condition and very low number of donor cells was found in the kidney of DM + MSCs mice, suggesting that renoprotection could be mediated by paracrine effects. Indeed, DM + MSC mice presented increased renal proliferation index, decreased renal apoptotic index and the restoration of proregenerative factors, and anti-inflammatory cytokines levels. Moreover, macrophage infiltration and oxidative stress damage were also reduced in DM + MSCs mice. Our data demonstrate that MSC administration triggers a proregenerative microenvironment in DN kidney, which allows the preservation of the renal function even if diabetes was uncorrected.
Collapse
|
|
37
|
Novel treatment strategies for feline chronic kidney disease: A critical look at the potential of mesenchymal stem cell therapy. Vet J 2015; 204:241-6. [DOI: 10.1016/j.tvjl.2015.04.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Revised: 03/27/2015] [Accepted: 04/06/2015] [Indexed: 12/19/2022]
|
|
38
|
da Silva AF, Silva K, Reis LA, Teixeira VPC, Schor N. Bone Marrow-Derived Mesenchymal Stem Cells and Their Conditioned Medium Attenuate Fibrosis in an Irreversible Model of Unilateral Ureteral Obstruction. Cell Transplant 2015; 24:2657-66. [PMID: 25695732 DOI: 10.3727/096368915x687534] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The therapeutic potential of mesenchymal stem cells (MSCs) and their conditioned medium (MSC-CM) has been extensively studied. MSCs can repair tissue, reduce local inflammation, and modulate the immune response. Persistent renal tubular interstitial inflammation results in fibrosis and leads to chronic kidney disease (CKD). Unilateral ureteral obstruction (UUO) is a very well-accepted renal fibrosis model. In this study, we evaluated factors influenced by the administration of MSCs or MSC-CM in the UUO model. MSCs extracted from rat bone marrow were cultivated in vitro and characterized by flow cytometry and cellular differentiation. Eight groups of female rats were used in experiments (n = 7, each), including Sham, UUO, UUO + MSC (obstruction + MSC), and UUO + CM (obstruction + MSC-CM) for 7 days of obstruction and Sham, UUO, UUO + MSC, and UUO + CM for 14 days of obstruction. The MSCs or MSC-CM was administered via the abdominal vena cava after total ligation of the left ureter. After 7 or 14 days, rats were euthanized, and serum and obstructed kidney samples were collected. MSCs or MSC-CM decreased the expression of molecules, such as Col1a1, α-SMA, and TNF-α. We also observed reductions in the levels of caspase 3, α-SMA, and PCNA in treated animals by immunohistochemistry. Our results suggest that the intravenous administration of MSCs or MSC-CM improves fibrosis progression and factors involved in apoptosis, inflammation, cell proliferation, and epithelial-mesenchymal transition in Wistar rats subjected to UUO, indicating a potential tool for preventing CKD.
Collapse
Affiliation(s)
- Andrei F da Silva
- Nephrology Division, Department of Medicine, UNIFESP/EPM, São Paulo, Brazil
| | | | | | | | | |
Collapse
|
|
39
|
Papazova DA, Oosterhuis NR, Gremmels H, van Koppen A, Joles JA, Verhaar MC. Cell-based therapies for experimental chronic kidney disease: a systematic review and meta-analysis. Dis Model Mech 2015; 8:281-93. [PMID: 25633980 PMCID: PMC4348565 DOI: 10.1242/dmm.017699] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Cell-based therapy is a promising strategy for treating chronic kidney disease (CKD) and is currently the focus of preclinical studies. We performed a systematic review and meta-analysis to evaluate the efficacy of cell-based therapy in preclinical (animal) studies of CKD, and determined factors affecting cell-based therapy efficacy in order to guide future clinical trials. In total, 71 articles met the inclusion criteria. Standardised mean differences (SMD) and 95% confidence intervals (CI) were calculated for outcome parameters including plasma urea, plasma creatinine, urinary protein, blood pressure, glomerular filtration rate, glomerulosclerosis and interstitial fibrosis. Sub-analysis for each outcome measure was performed for model-related factors (species, gender, model and timing of therapy) and cell-related factors (cell type, condition and origin, administration route and regime of therapy). Overall, meta-analysis showed that cell-based therapy reduced the development and progression of CKD. This was most prominent for urinary protein (SMD, 1.34; 95% CI, 1.00–1.68) and urea (1.09; 0.66–1.51), both P<0.001. Changes in plasma urea were associated with changes in both glomerulosclerosis and interstitial fibrosis. Sub-analysis showed that cell type (bone-marrow-derived progenitors and mesenchymal stromal cells being most effective) and administration route (intravenous or renal artery injection) were significant predictors of therapeutic efficacy. The timing of therapy in relation to clinical manifestation of disease, and cell origin and dose, were not associated with efficacy. Our meta-analysis confirms that cell-based therapies improve impaired renal function and morphology in preclinical models of CKD. Our analyses can be used to optimise experimental interventions and thus support both improved preclinical research and development of cell-based therapeutic interventions in a clinical setting.
Collapse
Affiliation(s)
- Diana A Papazova
- Department of Nephrology and Hypertension, University Medical Centre Utrecht, 3508 GA Utrecht, The Netherlands
| | - Nynke R Oosterhuis
- Department of Nephrology and Hypertension, University Medical Centre Utrecht, 3508 GA Utrecht, The Netherlands
| | - Hendrik Gremmels
- Department of Nephrology and Hypertension, University Medical Centre Utrecht, 3508 GA Utrecht, The Netherlands
| | - Arianne van Koppen
- Department of Nephrology and Hypertension, University Medical Centre Utrecht, 3508 GA Utrecht, The Netherlands
| | - Jaap A Joles
- Department of Nephrology and Hypertension, University Medical Centre Utrecht, 3508 GA Utrecht, The Netherlands
| | - Marianne C Verhaar
- Department of Nephrology and Hypertension, University Medical Centre Utrecht, 3508 GA Utrecht, The Netherlands
| |
Collapse
|
|
40
|
Bruno S, Chiabotto G, Camussi G. Concise review: different mesenchymal stromal/stem cell populations reside in the adult kidney. Stem Cells Transl Med 2014; 3:1451-5. [PMID: 25355731 DOI: 10.5966/sctm.2014-0142] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
During fetal life, mesenchymal stromal/stem cells (MSCs) surround glomeruli and tubules and contribute to the development of the renal interstitium by secretion of growth factors that drive nephron differentiation. In the adult, an MSC-like population has been demonstrated in different compartments of human and murine nephrons. After injury, these cells might provide support for kidney regeneration by recapitulating the role they have in embryonic life. In this short review, we discuss the evidence of an MSC presence within the adult kidney and their potential contribution to the turnover of renal cells and injury repair.
Collapse
Affiliation(s)
- Stefania Bruno
- Departments of Molecular Biotechnology and Health Science and Medical Sciences, University of Torino, Torino, Italy
| | - Giulia Chiabotto
- Departments of Molecular Biotechnology and Health Science and Medical Sciences, University of Torino, Torino, Italy
| | - Giovanni Camussi
- Departments of Molecular Biotechnology and Health Science and Medical Sciences, University of Torino, Torino, Italy
| |
Collapse
|
|
41
|
Allogeneic mesenchymal stem cell transplantation for lupus nephritis patients refractory to conventional therapy. Clin Rheumatol 2014; 33:1611-9. [PMID: 25119864 DOI: 10.1007/s10067-014-2754-4] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Revised: 07/07/2014] [Accepted: 07/17/2014] [Indexed: 12/29/2022]
Abstract
Allogeneic mesenchymal stem cell transplantation (MSCT) has been shown to be clinically efficacious in the treatment of various autoimmune diseases. Here, we analyzed the role of allogeneic MSCT to induce renal remission in patients with active and refractory lupus nephritis (LN). This is an open-label and single-center clinical trial conducted from 2007 to 2010 in which 81 Chinese patients with active and refractory LN were enrolled. Allogeneic bone marrow- or umbilical cord-derived mesenchymal stem cells (MSCs) were administered intravenously at the dose of 1 million cells per kilogram of bodyweight. All patients were then monitored over the course of 12 months with periodic follow-up visits to evaluate renal remission, as well as possible adverse events. The primary outcome was complete renal remission (CR) and partial remission (PR) at each follow-up, as well as renal flares. The secondary outcome included renal activity score, total disease activity score, renal function, and serologic index. During the 12-month follow-up, the overall rate of survival was 95 % (77/81). Totally, 60.5 % (49/81) patients achieved renal remission during 12-month visit by MSCT. Eleven of 49 (22.4 %) patients experienced renal flare by the end of 12 months after a previous remission. Renal activity evaluated by British Isles Lupus Assessment Group (BILAG) scores significantly declined after MSCT (mean ± SD, from 4.48 ± 2.60 at baseline to 1.09 ± 0.83 at 12 months), in parallel with the obvious amelioration of renal function. Glomerular filtration rate (GFR) improved significantly 12 months after MSCT (mean ± SD, from 58.55 ± 19.16 to 69.51 ± 27.93 mL/min). Total disease activity evaluated by Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores also decreased after treatment (mean ± SD, from 13.11 ± 4.20 at baseline to 5.48 ± 2.77 at 12 months). Additionally, the doses of concomitant prednisone and immunosuppressive drugs were tapered. No transplantation-related adverse event was observed. Allogeneic MSCT resulted in renal remission for active LN patients within 12-month visit, confirming its use as a potential therapy for refractory LN.
Collapse
|
|
42
|
Westenfelder C. Does the greater omentum ("policeman of the abdomen") possess therapeutic utility in CKD? J Am Soc Nephrol 2014; 25:1133-5. [PMID: 24627351 DOI: 10.1681/asn.2014010127] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Affiliation(s)
- Christof Westenfelder
- Division of Nephrology, University of Utah, George E. Wahlen Department of Veterans Affairs Health Care System, Salt Lake City, Utah
| |
Collapse
|
|
43
|
Abstract
PURPOSE OF REVIEW Kidney transplantation has improved the life expectancy and quality of life for patients with end-stage renal failure. However, despite the impressive improvements in short-term outcome parameters because of better and more potent immunosuppressive drugs, the long-term survival of renal allografts has changed little over the last decades. Sustained inflammation in the areas of interstitial fibrosis and tubular atrophy (IFTA) is a strong predictor of allograft failure. Mesenchymal stromal cells (MSCs) have potent anti-inflammatory and reparative properties, and could thus play a role in controlling these processes. RECENT FINDINGS Local resident MSCs and exogenous MSCs have been implicated in the repair of the injured kidney, mostly by their paracrine functions. In the experimental models and clinical trials, first results with MSCs for the treatment of inflammation and IFTA suggest beneficial effects. SUMMARY Endogenously and exogenously administered MSCs might enhance the intrinsic reparative capabilities of the kidney in transplant recipients and maybe developed as a tool to control both inflammation and fibrosis.
Collapse
|
|
44
|
Bian XH, Zhou GY, Wang LN, Ma JF, Fan QL, Liu N, Bai Y, Guo W, Wang YQ, Sun GP, He P, Yang X, Su XS, Du F, Zhao GF, Miao JN, Ma L, Zheng LQ, Li DT, Feng JM. The role of CD44-hyaluronic acid interaction in exogenous mesenchymal stem cells homing to rat remnant kidney. Kidney Blood Press Res 2014; 38:11-20. [PMID: 24503496 DOI: 10.1159/000355749] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/19/2013] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND/AIMS The aim of our study was to reveal the role of CD44-Hyaluronic acid (HA) in the homing and improving renal function of systemically transplanted MSCs in chronic renal failure. METHODS First, a remnant kidney model was established in rats and the expression of HA was determined using immunohistochemistry (IHC) and western blotting. Next, chemotaxis assay using flow cytometry, and cell migration assay of MSCs were performed in vitro. Then, MSCs were transplanted into rats, thus, sprague-Dawley (SD) rats were randomly divided into sham group, 5/6 nephrectomy (5/6 Nx) group, MSC group and MSC/Anti-CD44 group (n = 8 for all groups). Migration of MSCs to the kidney in these rats was assessed by using cell tracking experiments, and tissue damage was evaluated by morphological analysis using Masson's trichrome staining and periodic acid Schiff staining. RESULTS HA was significantly observed in 5/6 Nx group, but not in sham group. Meanwhile, HA was discovered induced MSCs migration remarkably (p < 0.05) and anti-CD44 antibody inhibited the migration significantly (p < 0.05) in vitro. In vivo, the GFP-MSCs were observed in MSC group and the cells reduced in MSC/Anti-CD44 groups, especially, in the tubulointerstitium. CONCLUSION Our findings reveal that CD44-HA has the potential to induce MSCs homing to injured tissue, while its effect on the ability of MSCs, improving tissue function, is not significant.
Collapse
Affiliation(s)
- Xiao-Hui Bian
- Departments of Nephrology, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, China
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
45
|
Bian X, Zhang B, Guo W, Liu N, Bai Y, Miao J, Zhao G, Liu B, Wang S, Ma L, Zheng L, Zhao Y, Li D, Feng J. Effects of mesenchymal stem cells transplanted at different time points in a rat remnant kidney model. Am J Nephrol 2014; 39:75-84. [PMID: 24457259 DOI: 10.1159/000357870] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Accepted: 12/07/2013] [Indexed: 01/01/2023]
Abstract
AIMS The optimal time for mesenchymal stem cell (MSCs) transplantation remains an unresolved issue. We compared the effects of MSCs on a rat remnant kidney model. METHODS Male Sprague-Dawley rats were randomly divided and treated with a corresponding reagent at 4, 8, 12 and 16 weeks, respectively. A remnant kidney model was established and MSCs were injected into rats. The migration of MSCs was then assessed by using cell-tracking experiments. Renal function and histological analyses were performed 4 weeks after MSC transplantation. Immunohistochemistry, Western blotting and real-time polymerase chain reaction were used to detect the TGF-β1 and α-SMA levels. RESULTS Four weeks after MSC injection, MSCs were found to migrate to the injured kidney. Significant histological damage improvement was observed after the treatment of MSCs at 4 and 8 weeks. The functional benefits of MSC treatment were observed in the 5/6 nephrectomy (Nx) + MSC group and the benefits were significantly higher at 4 and 8 weeks than at other time points (p < 0.05). Meanwhile, serum creatinine and urea levels as well as glomerular sclerosis and tubulointerstitial injury indexes were decreased at 4 and 8 weeks. Compared with the 5/6 Nx + PBS group, TGF-β1 and α-SMA levels were decreased in the 5/6 Nx + MSC group. CONCLUSION These data can be used to optimize the MSC transplantation time point as a therapeutic modality.
Collapse
Affiliation(s)
- Xiaohui Bian
- Department of Nephrology, The First Affiliated Hospital, China Medical University, Shenyang, China
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Human umbilical mesenchymal stem cells attenuate the progression of focal segmental glomerulosclerosis. Am J Med Sci 2014; 346:486-93. [PMID: 23514668 DOI: 10.1097/maj.0b013e3182831777] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Previous studies have suggested the potential of mesenchymal stem cells (MSCs) to repair damaged kidney diseases. However, the effect of human umbilical cord MSCs (HuMSCs) on the progression of focal segmental glomerulosclerosis (FSGS) remains poorly understood. Adriamycin-induced nephropathy is a rodent model of chronic kidney disease that has been studied extensively and has enabled a greater understanding of the processes underlying the progression of FSGS. This study aimed to investigate the role of HuMSCs on the progression of kidney disease using a model of adriamycin-induced nephropathy. Human MSCs were labeled with 5-bromo-2'-deoxyuridine to track their localization to the kidneys after infusion. Clinical parameters and histology suggested amelioration of FSGS in MSC-treated animals at 12 weeks, especially in those that received repeated doses. These results were associated with reduced serum interleukin (IL)-6 and tumor necrosis factor-α, transforming growth factor-β levels, connective tissue growth factor messenger RNA expression and upregulated serum IL-10 levels. In short, this experiment found that HuMSCs improved kidney fibrosis and modulated the inflammatory response, suggesting that xenogenic transplantation of HuMSCs is a novel approach for improving the progression of FSGS and may be a promising therapeutic intervention in the future.
Collapse
|
|
47
|
Bioengineered kidneys: new sights on a distant horizon. Int Urol Nephrol 2013; 46:477-80. [DOI: 10.1007/s11255-013-0570-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2013] [Accepted: 09/17/2013] [Indexed: 10/26/2022]
|
|
48
|
Wang Y, He J, Pei X, Zhao W. Systematic review and meta-analysis of mesenchymal stem/stromal cells therapy for impaired renal function in small animal models. Nephrology (Carlton) 2013; 18:201-8. [PMID: 23217027 DOI: 10.1111/nep.12018] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/03/2012] [Indexed: 12/22/2022]
Abstract
AIM The meta-analysis of recent small animal experiments of mesenchymal stem/stromal cells (MSC) therapy for impaired kidney could provide significant clues to design large animal experiments as well as human clinical trials. METHOD A total of 21 studies was analyzed. These, were indexed from PubMed and Embase databases. All data were analyzed by RevMan 5.1 and SPSS 17.0. Pooled analysis and multivariable meta-regression were calculated by random effects models. Heterogeneity and publication bias across the studies were also explored. RESULTS Pooled analysis showed elevated serum creatinine (Scr) reduction in the animal models of renal failure following MSC therapy. By exploratory multivariable meta-regression, significant influence factors of Scr reduction were the time point of Scr measurement (early measurement showed greater reduction than the late (P = 0.005)) and the route of MSC delivery (arterial delivery of MSCs caused greater reduction in elevated Scr, when compared with the intra-renal delivery and intravenous injection (P = 0.040)). Subgroup analysis showed there tended to be greater reduction in Scr with higher MSC number (>10(6)), the renal ischemia-reperfusion injury (IRI) model, and late administration (>1 day) after injury. CONCLUSION The present meta-analysis confirmed that MSC therapy could improve impaired renal function. MSCs might get obvious effect in the early stage of renal injuries after arterial delivery. Further, this meta-analysis may provide important clues for animal experiments even for human clinical trials in MSC studies.
Collapse
Affiliation(s)
- Yan Wang
- Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | | | | | | |
Collapse
|
|
49
|
Lv SS, Liu G, Wang JP, Wang WW, Cheng J, Sun AL, Liu HY, Nie HB, Su MR, Guan GJ. Mesenchymal stem cells transplantation ameliorates glomerular injury in streptozotocin-induced diabetic nephropathy in rats via inhibiting macrophage infiltration. Int Immunopharmacol 2013; 17:275-82. [PMID: 23791972 DOI: 10.1016/j.intimp.2013.05.031] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2013] [Revised: 05/13/2013] [Accepted: 05/27/2013] [Indexed: 12/29/2022]
Abstract
Mesenchymal stem cells (MSCs) treatment has been shown to be effective in diabetic nephropathy (DN). However, the mechanisms involved in the renoprotective effects of MSCs have not been clearly demonstrated. Especially, there was no study on the relationship of MSCs and macrophages in diabetic kidney. To explore the effect of MSCs on macrophages in DN, streptozotocin-induced diabetes animals received no treatment or treatment with MSCs (2×10(6), via tail vein) for two continuous weeks. Eight weeks after treatment, physical, biochemical and morphological parameters were measured. Immunohistochemistry for fibronectin (FN), CollagenI, ED-1, monocyte chemoattractant protein-1 (MCP-1) was performed. Expressions of pro-inflammatory cytokines and hepatocyte growth factor (HGF) at gene level and protein level were determined by real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Blood glucose, urinary albumin excretion, creatinine clearance were significantly reduced after MSCs treatment. The glomerulosclerosis as revealed by periodic acid Schiff stain and expression of FN and CollagenI was also dramatically attenuated. Most importantly, the expression of MCP-1 and the number of infiltrated macrophages in kidney were effectively suppressed by MSCs treatment. The expression of HGF in MSCs group was up-regulated. Meanwhile, the expressions of IL-1β, IL-6 and TNFα were significantly down-regulated by MSCs treatment. Our study suggest that MSCs treatment ameliorates DN via inhibition of MCP-1 expression by secreting HGF, thus reducing macrophages infiltration, down-regulating IL-1β, IL-6, TNFα expression in renal tissue in diabetic rats.
Collapse
Affiliation(s)
- Sha-Sha Lv
- Shandong University, Jinan, Shandong, China
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
50
|
Human mesenchymal stem cells derived from adipose tissue reduce functional and tissue damage in a rat model of chronic renal failure. Clin Sci (Lond) 2013; 125:199-210. [PMID: 23480877 DOI: 10.1042/cs20120644] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Therapeutic approaches for CKD (chronic kidney disease) have been able to reduce proteinuria, but not diminish the disease progression. We have demonstrated beneficial effects by injection of BM (bone marrow)-derived MSCs (mesenchymal stem cells) from healthy donors in a rat model with CKD. However, it has recently been reported that BM-MSCs derived from uraemic patients failed to confer functional protection in a similar model. This suggests that autologous BM-MSCs are not suitable for the treatment of CKD. In the present study, we have explored the potential of MSCs derived from adipose tissue (AD-MSCs) as an alternative source of MSCs for the treatment of CKD. We have isolated AD-MSCs and evaluated their effect on the progression of CKD. Adult male SD (Sprague-Dawley) rats subjected to 5/6 NPX (nephrectomy) received a single intravenous infusion of 0.5×10(6) AD-MSCs or MSC culture medium alone. The therapeutic effect was evaluated by plasma creatinine measurement, structural analysis and angiogenic/epitheliogenic protein expression. AD-MSCs were detected in kidney tissues from NPX animals. This group had a significant reduction in plasma creatinine levels and a lower expression of damage markers ED-1 and α-SMA (α-smooth muscle actin) (P<0.05). In addition, treated rats exhibited a higher level of epitheliogenic [Pax-2 and BMP-7 (bone morphogenetic protein 7)] and angiogenic [VEGF (vascular endothelial growth factor)] proteins. The expression of these biomarkers of regeneration was significantly related to the improvement in renal function. Although many aspects of the cell therapy for CKD remain to be investigated, we provide evidence that AD-MSCs, a less invasive and highly available source of MSCs, exert an important therapeutic effect in this pathology.
Collapse
|