CXC-chemokine receptor 4 antagonist prevents acute kidney injury potentially through recruiting bone marrow-derived stem cells

2015 ◽  
Vol 2 (1) ◽  
pp. 12
Author(s):  
Duo Guo ◽  
Yan Chen ◽  
Dan Gao ◽  
Xiuying Zhang
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Acute Kidney Injury ◽  
Renal Function ◽  
Stem Cell ◽  
Kidney Injury ◽  
Cxc Chemokine Receptor 4 ◽  
Cxc Chemokine ◽  
Cell Mobilization ◽  
Chemokine Receptor 4

Background: Existing literature suggests that stromal-cell derived factor 1 (SDF-1) interacts with CXC-chemokine receptor 4 (CXCR4) in regulating the homing of stem cells derived from bone marrow. The CXCR4 antagonist, AMD3100, disrupts this SDF-1/CXCR4 interaction and triggers stem cell mobilization. We investigated whether AMD3100 could ameliorate renal ischemia reperfusion (I/R) injury via recruiting circulating stem cells to injured kidneys. Methods: We divided Sprague-Dawley rats into four groups, Sham, Sham + AMD3100, I/R, and I/R + AMD3100. All groups were treated with single subcutaneous injections of AMD3100 (5 mg/kg) or saline after sham surgery or I/R injury. Serum and renal tissues were harvested 12 hours and 3 days after treatment. We assessed survival, renal function changes, and histopathological alterations. TUNEL staining and caspase-3 expression levels were harnessed to measure tubular cell apoptosis, and circulating CXCR4 and CD34 positive mononuclear cells were identified by flow cytometry. Results: The I/R + AMD3100 group displayed significantly higher survival, lower serum creatinine, less prominent renal damage upon histopathological examination, and a lower degree of apoptosis than the I/R group. In addition, the AMD3100 treated group showed a significantly higher degree of CXCR4 and CD34 positive cell mobilization in the circulation and increased recruitment of these cells into the injured kidneys. Conclusions: AMD3100 promotes bone marrow stem cell mobilization and improves the recovery of renal function after I/R injury, and this effect may offer a promising therapeutic approach for acute kidney injury.  

CXCR4-overexpressing bone marrow-derived mesenchymal stem cells improve repair of acute kidney injury

2013 ◽  
Vol 305 (7) ◽  
pp. F1064-F1073 ◽  
Author(s):  
Nanmei Liu ◽  
Andreas Patzak ◽  
Jinyuan Zhang
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Acute Kidney Injury ◽  
Cell Death ◽  
Mesenchymal Stem Cells ◽  
Renal Function ◽  
Caspase 3 ◽  
Kidney Injury ◽  
Nuclear Antigen ◽  
Tubular Cells

Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) can repair acute kidney injury (AKI), but with limited effect. We test the hypothesis that CXCR4 overexpression improves the repair ability of BMSCs and that this is related to increased homing of BMSCs and increased release of cytokines. Hypoxia/reoxygenation-pretreated renal tubular epithelial cells (HR-RTECs) were used. BMSCs, null-BMSCs, and CXCR4-BMSCs were cocultured with HR-RTECs. The number of migrating BMSCs was counted. Proliferating cell nuclear antigen (PCNA) expression, cell death, and expressions of cleaved caspase-3 and Bcl-2 in cocultured HR-RTECs were measured. Cytokeratin 18 (CK18) expression and cytokine secretions of the BMSCs cultured with HR-RTEC supernatant were detected. BMSC homing, renal function, proliferation, and cell death of tubular cells were assayed in the AKI mouse model. CXCR4-BMSCs showed a remarkable expression of CXCR4. Stromal cell-derived factor-1 in the HR-RTEC supernatant was increased. Migration of BMSCs was CXCR4-dependent. Proportions of CK18+ cells in BMSCs, null-BMSCs, and CXCR4-BMSCs showed no difference. However, CXCR4 overexpression in BMSCs stimulated secretion of bone morphogenetic protein-7, hepatocyte growth factor, and interleukin 10. The neutralizing anti-CXCR4 antibody AMD3100 abolished this. In cocultured HR-RTECs the proportions of PCNA+ cells and Bcl-2 expression were enhanced; however, the proportion of annexin V+ cells and expression of cleaved caspase-3 were reduced. The in vivo study showed increased homing of CXCR4-BMSCs in kidneys, which was associated with improved renal function, reduced acute tubular necrosis scoring, accelerated mitogenic response of tubular cells, and reduced tubular cell death. The enhanced homing and paracrine actions of BMSCs with CXCR4 overexpression suggest beneficial effects of such cells in BMSC-based therapy for AKI.

scholarly journals The combination of G-CSF and AMD3100 mobilizes bone marrow-derived stem cells to protect against cisplatin-induced acute kidney injury in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhi Chen ◽  
Xiang Ren ◽  
Ruimin Ren ◽  
Yonghong Wang ◽  
Jiwen Shang
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Acute Kidney Injury ◽  
Renal Function ◽  
Tissue Injury ◽  
Therapeutic Option ◽  
Kidney Injury ◽  
Saline Group ◽  
Inflammatory Factors ◽  
Tissue Samples

Abstract Background Several studies have confirmed that mobilizing bone marrow-derived stem cells (BMSCs) ameliorates renal function loss following cisplatin-induced acute kidney injury (AKI). The aim of this study was to explore whether the combination of granulocyte-colony stimulating factor (G-CSF) and plerixafor (AMD3100) exerts beneficial effects on renal function recovery in a model of cisplatin-induced nephrotoxicity. Methods C57BL/6J mice received intraperitoneal injections of G-CSF (200 μg/kg/day) for 5 consecutive days. On the day of the last injection, the mice received a single subcutaneous dose of AMD3100 (5 mg/kg) 1 h before cisplatin 20 mg/kg injection. Ninety-six hours after cisplatin injection, the mice were euthanized, and blood and tissue samples were collected to assess renal function and tissue damage. Cell mobilization was assessed by flow cytometry (FCM). Results Mice pretreated with G-CSF/AMD3100 exhibited longer survival and lower serum creatinine and blood urea nitrogen (BUN) levels than mice treated with only G-CSF or saline. Combinatorial G-CSF/AMD3100 treatment attenuated tissue injury and cell death, enhanced cell regeneration, and mobilized a higher number of stem cells in the peripheral blood than G-CSF or saline treatment. Furthermore, the mRNA expression of proinflammatory factors was lower, whereas that of anti-inflammatory factors was higher, in the G-CSF/AMD3100 group than in the G-CSF or saline group (all P < 0.05). Conclusions These results suggest that combinatorial G-CSF/AMD3100 therapy mobilizes BMSCs to accelerate improvements in renal functions and prevent cisplatin-induced renal tubular injury. This combinatorial therapy may represent a new therapeutic option for the treatment of AKI and should be further investigated in the future.

scholarly journals Bone marrow mesenchymal stem cells protect against folic acid- induced acute kidney injury

2012 ◽  
Vol 15 (2) ◽  
pp. 1661-1665
Author(s):  
Marina Burgos-Silva ◽  
Cassiano Donizetti-Oliveira ◽  
Marco Antonio Cenedeze ◽  
Denise Maria Avancini Costa Malheiros ◽  
Marlene Antônia dos Reis ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Acute Kidney Injury ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Folic Acid ◽  
Kidney Injury ◽  
Bone Marrow Stem Cells ◽  
Mrna Levels ◽  
Marrow Mesenchymal Stem Cells

Acute kidney injury constitutes a syndrome responsible by a major percentage of acute kidney failures and it continues being associated to high mortality rates. Induced mainly by ischemia-reperfusion injury and nephrotoxic drugs, this condition is marked by a decrease in organ function and histopathological pattern of acute tubular necrosis. In search of more efficient therapies, a great deal of attention has been given to the therapeutic use of stem cells to treat kidney injuries. Bone marrow stem cells in particular have received a great attention due to its immunomodulatory properties, and its therapeutic mechanisms are intensely being studied in the literature. Purpose: In view of recent findings, the aim of our research was to get a better understanding on the potential role of bone marrow mesenchymal stem cells in a murine model of acute nephotoxicity induced by folic acid. Methods: C57Bl/6j mice (8 weeks) were submitted to acute kidney injury by folic acid (200mg/kg) administered intraperitoneally. After 24 hours, mice received mesenchymal stem cells (5.105 cells per animal) through retro-orbital intravenous injection. Mice were sacrificed after 24 hours and blood and kidneys were harvested for analysis. Results: Stem cell treatment conferred functional improvement seen through lower creatinine and urea serum levels in 8 week old C57Bl/6j mice in comparison to mice treated only with folic acid (200mg/kg body weight). This amelioration are also correlated to down regulation of kidney pro-inflammatory cytokine mRNA levels as TNF-a, IL-6 and IL-1b in stem cell treated mice. In addition, treated mice demonstrated higher levels of immunostaining for proliferating cell nuclear antigen and a tendency towards a higher Bcl-2/Bax mRNA ratio, indicating higher tissue regeneration and protection against injury-induced apoptosis. Conclusion: These results indicate bone marrow stem cells as an efficient tool in nephrotoxic kidney injury treatment.  

scholarly journals The Combination of G-CSF/AMD3100 Mobilizes Bone Marrow-Derived Stem Cells to Rescue Mice from Cisplatin-Induced Acute Kidney Injury

2021 ◽  
Author(s):  
Zhi Chen ◽  
Xiang Ren ◽  
Ruimin Ren ◽  
Yonghong Wang ◽  
Jiwen Shang
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Acute Kidney Injury ◽  
Renal Function ◽  
Bone Marrow Cells ◽  
Tissue Injury ◽  
Therapeutic Option ◽  
Kidney Injury ◽  
Inflammatory Factor ◽  
Tissue Samples

Abstract Background: Several studies have confirmed that mobilizing bone marrow-derived stem cells (BMSCs) ameliorates renal function loss following cisplatin-induced acute kidney injury (AKI). The aim of this study was to explore whether the combination of G-CSF/AMD3100 exerts beneficial effects with respect to renal function recovery in a mouse model of cisplatin-induced nephrotoxicity. Methods: C57BL/6J mice received intraperitoneal injections of G-CSF (200 μg/kg/d) for 5 consecutive days. On the day of the last injection, the mice received a single subcutaneous dose of AMD3100 (5 mg/kg) 1 hour before cisplatin 20 mg/kg injection. 96 hours after cisplatin injection, the mice were euthanized, blood and tissue samples were collected to assess renal function and tissue damage. Cell mobilization was assessed by flow cytometry. Results: Mice pretreated with G-CSF/AMD3100 exhibited longer survival and significantly lower serum creatinine and BUN levels than mice treated with only G-CSF or saline, exhibited attenuated tissue injury and cell death and enhanced tissue repair and cell regeneration. C57BL/6J mice pretreated with G-CSF/AMD3100 exhibited higher numbers of stem cells in peripheral blood than mice treated with only G-CSF or saline. Furthermore, G-CSF/AMD3100 administration prevented increases in the expression of proinflammatory factors, such as IL-6 and TNF-α, and increased the expression of the anti-inflammatory factor IL-10. Conclusions: These results suggest that G-CSF/AMD3100 mobilizes bone marrow cells to improve renal function and prevent cisplatin-induced renal tubular injury and that the combination of G-CSF/AMD3100 is superior to G-CSF alone for preventing AKI. This combination may represent a new therapeutic option for the treatment of AKI and warrants further investigation.

scholarly journals The Phenotypic Fate of Bone Marrow-Derived Stem Cells in Acute Kidney Injury

2013 ◽  
Vol 32 (5) ◽  
pp. 1517-1527 ◽  
Author(s):  
Guowei Feng ◽  
Duo Mao ◽  
Yongzhe Che ◽  
Weijun Su ◽  
Yuebing Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Acute Kidney Injury ◽  
Kidney Injury

Abstract 253: The Presence of Coronary Artery Disease Influences Number and Function of Stem Cells in the Bone Marrow

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Evelien Nollet ◽  
Dina De Bock ◽  
Inez R Rodrigus ◽  
Vicky Y Hoymans ◽  
Christiaan J Vrints ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Stem Cells ◽  
Bone Marrow ◽  
Renal Function ◽  
Stem Cell ◽  
Coronary Artery ◽  
Therapeutic Benefits ◽  
Migratory Capacity ◽  
Artery Disease ◽  
And Function

Purpose: Despite the observed therapeutic benefits of autologous bone marrow (BM)-derived stem cell transplantation in patients with ischemic heart disease, the efficacy of this approach could be hampered by BM dysfunction. We investigated whether BM cellularity and function is affected by coronary artery disease (CAD). Methods & Results: BM samples were obtained peri-operatively from 26 CAD patients, undergoing coronary artery bypass surgery (LVEF 54±16%), and 6 controls, undergoing mitral valve surgery (LVEF 50±12%; age 59±10yrs). CAD patients were stratified according to their Syntax score (mild ≤15, age 61±10yrs; and moderate CAD >15, age 63±8yrs; stratification based on median score), which is used to assess complexity of coronary lesions. In vitro functional analysis of isolated BM-derived mononuclear cells (BM-MNC) revealed a significant impairment of migratory capacity towards SDF-1α and VEGF in patients with moderate CAD (25.71±7.3%) compared to controls (33.82±8.3%; p=0.042) and patients with mild CAD (34.76±7.8%; p=0.007). Hematopoetic stem cells (HSC, CD45dimCD34+SSClow) were reduced in patients with moderate CAD (8178±5530 HSC/106 BM-MNC; p=0.014) and mild CAD (10655±5489 HSC/106 BM-MNC; p=0.054) compared to controls (16220±6126 HSC/106 BM-MNC). An inverse correlation was found between age and the number of granulocyte-macrophage colony forming units (r= −0.408; p=0.048), burst forming units erythroid (r= −0.458; p=0.028) and HSC (r=-0.356; p=0.046). Furthermore, our data revealed a relation between reduced renal function (CKD-EPI eGFR, 81.2±19 ml/min) and reduced number of HSC (r=0.480; p=0.011) and endothelial progenitor cells (EPC, CD45dimCD34+KDR+; r=0.522; p=0.008). Conclusions: Migratory capacity of BM-MNC and the number of HSC are reduced in patients with CAD, which is more pronounced in more complex CAD. In addition, age and renal function emerge as relevant determinants on BM function and stem cell populations. Therefore, these factors should be taken into account when assessing benefits of autologous stem cell therapy.

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