Kallikrein-Modified Mesenchymal Stem Cell Implantation Provides Enhanced Protection Against Acute Ischemic Kidney Injury by Inhibiting Apoptosis and Inflammation

Hagiwara, Makoto; Shen, Bo; Chao, Lee; Chao, Julie

doi:10.1089/hum.2008.016

Cited by 94 publications

(31 citation statements)

References 49 publications

(60 reference statements)

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“…Transplantation of MSCs has proven to be an effective treatment for tissue injuries, including myocardial infarction, 5) hind limb ischemia, 6) acute renal failure 7) and liver transplantation. 8) However, progress in stem cell therapy is hampered by the poor survival of the implanted cells.…”

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confidence: 99%

Berberine Protects Mesenchymal Stem Cells against Hypoxia-Induced Apoptosis in Vitro

Zhang

Gao

et al. 2009

Biological & Pharmaceutical Bulletin

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Bone marrow mesenchymal stem cells (MSCs) have the potential to be used in the cellular therapy of solid organs. However, tissue regeneration is limited by the death of transplanted cells. One of the main mechanisms of stem cell death in transplanted organs is through ischemia. In the present study, we sought to investigate whether a plant-derived antioxidant, berberine (BBR), could protect MSCs against MSCs apoptosis in a model of ischemia consisting of serum deprivation-and hypoxia-induced apoptosis in vitro. We also investigated the potential mechanism(s) that may mediate the action of berberine. We found that berberine significantly attenuated hypoxia-induced MSC apoptosis. Further study revealed that berberine could scavenger the reactive oxygen species (ROS), inhibit the c-jun NH(2)-terminal kinase (JNK), the loss of mitochondrial membrane potential and the release of cytochrome c (Cyt C) and caspase-3. In addition, we also showed that berberine could activate phosphoinositide-3 kinase (PI3K)/Akt and that pretreatment with PI3K/Akt inhibitors prevented berberineinduced inhibition of ROS, JNK and subsequent apoptosis, suggesting that the protective effects of berberine were PI3K/Akt-dependent. Taken together, these findings reveal that berberine protects against MSC apoptosis by preventing ROS-dependent and JNK-driven cell apoptosis in a PI3K/Akt-dependent manner. These data indicate that berberine is a promising anti-apoptotic agent for improving MSC survival during cell transplantation.

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confidence: 99%

Berberine Protects Mesenchymal Stem Cells against Hypoxia-Induced Apoptosis in Vitro

Zhang

Gao

et al. 2009

Biological & Pharmaceutical Bulletin

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“…This was due to an increase in cell proliferation due to differentiation of some transplanted BMMNC into renal tubular epithelial cells in addition to an increase in biological activity, due to release of various growth factors and trophic factors. Hagiwara et al [57] similarly showed that using kallikrein-modified MSC (TK-MSC; combined SC and kallikrein gene approach) led to the migration and homing ability as well as paracrine effect, thereby enhanced renal protection and advanced benefits in healing the injured kidney. The expression of human tissue kallikrein in the rat kidney after TK-MSC implantation exhibited enhanced protection against renal injury by inhibiting apoptosis and inflammatory cell infiltration.…”

Section: Evidence Favouring Sc In Renal Irimentioning

confidence: 99%

“…Thus TK-MSC secreted recombinant human tissue kallikrein into culture medium and significantly improved stem cell survival during oxidative stress via activation of the phosphatidylinositol 3-kinases/protein kinase B (PI3K-Akt) pathway. At 48 h after IRI, TK-MSC inhibited interstitial neutrophil and monocyte/macrophage infiltration and decreased the myeloperoxidase activity, superoxide formation, p38 mitogen-activated protein kinase phosphorylation and expression of TNF-α, monocyte chemoattractant protein-1 and ICAM-1 [57]. Wang et al [58] showed improved renal function when SC of neural origin (neural precursor cells, NPC) were administered in the rat IRI model.…”

Section: Evidence Favouring Sc In Renal Irimentioning

confidence: 99%

Stem Cells and Their Role in Renal Ischaemia Reperfusion Injury

Bagul

Frost

Drage³

2012

Am J Nephrol

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Background: Ischaemia-reperfusion injury (IRI) remains one of the leading causes of acute kidney injury (AKI). IRI is an underlying multifactorial pathophysiological process which affects the outcome in both native and transplanted patients. The high morbidity and mortality associated with IRI/AKI and disappointing results from current available clinical therapeutic approaches prompt further research. Stem cells (SC) are undifferentiated cells that can undergo both renewal and differentiation into one or more cell types which can possibly ameliorate IRI. Aim: To carry out a detailed literature analysis and construct a comprehensive literature review addressing the role of SC in AKI secondary to IRI. Methods: Evidence favouring the role of SC in renal IRI and evidence showing no benefits of SC in renal IRI are the two main aspects to be studied. The search strategy was based on an extensive search addressing MESH terms and free text terms. Results: The majority of studies in the field of renal IRI and stem cell therapy show substantial benefits. Conclusions: Studies were mostly conducted in small animal models, thus underscoring the need for further pre-clinical studies in larger animal models, and results should be taken with caution. SC therapy may be promising though controversy exists in the exact mechanism. Thorough scientific exploration is required to assess mechanism, safety profile, reproducibility and methods to monitor administered SC.

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“…Kallikrein is a renoprotective molecule due its anti-inflammatory, -apoptotic and -dilation activities. When delivered to kidneys of rats in a renal ischemia/reperfusion injury model by modified MSCs caused a decrease in blood urea nitrogen and creatine levels and the number of apoptotic kidney cells and inflammatory cells within the kidney [152] . While these studies demonstrate the various and numerous potential factors for the enhancement of MSC-dependent treatment of acute myocardial infarctions and other ischemic injuries, it seems likely the best approach will be a combination of molecules that target the cells appropriately and regulate both the paracrine stimulation of surrounding cells and the differentiation of the transplanted MSCs.…”

Section: Cardiovascular and Ischemic Diseasementioning

confidence: 99%

Mesenchymal stem cells at the intersection of cell and gene therapy

Myers¹,

Granero‐Moltó²,

Longobardi³

et al. 2010

Expert Opinion on Biological Therapy

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Importance Mesenchymal stem cells have the ability to differentiate into osteoblasts, chondrocytes and adipocytes. Along with differentiation, MSCs can modulate inflammation, home to damaged tissues and secret bioactive molecules. These properties can be enhanced through genetic-modification that would combine the best of both cell and gene therapy fields to treat monogenic and multigenic diseases. Areas covered A review of the findings demonstrating the immunomodulation, homing and paracrine activities of MSCs followed by a summary of the current research utilizing MSCs as a vector for gene therapy, focusing on skeletal disorders, but also cardiovascular disease, ischemic damage and cancer. What the reader will gain MSCs are a possible therapeutic for many diseases, especially those related to the musculoskeletal system, as a standalone treatment, or in combination with factors that enhance the abilities of these cells to migrate, survive or promote healing through anti-inflammatory and immunomodulatory effects, differentiation, angiogenesis, delivery of cytolytic or anabolic agents. Take home message Genetically-modified MSCs are a promising area of research that would be improved by focusing on the biology of MSCs that could lead to identification of the natural and engrafting MSC-niche and a consensus on how to isolate and expand MSCs for therapeutic purposes.

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Kallikrein-Modified Mesenchymal Stem Cell Implantation Provides Enhanced Protection Against Acute Ischemic Kidney Injury by Inhibiting Apoptosis and Inflammation

Cited by 94 publications

References 49 publications

Berberine Protects Mesenchymal Stem Cells against Hypoxia-Induced Apoptosis in Vitro

Berberine Protects Mesenchymal Stem Cells against Hypoxia-Induced Apoptosis in Vitro

Stem Cells and Their Role in Renal Ischaemia Reperfusion Injury

Mesenchymal stem cells at the intersection of cell and gene therapy

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