Protective Effect of Human Amniotic Fluid Stem Cells in an Immunodeficient Mouse Model of Acute Tubular Necrosis

Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Childrens Hospital Los Angeles, Los Angeles, California, United States of America.
PLoS ONE (Impact Factor: 3.23). 02/2010; 5(2):e9357. DOI: 10.1371/journal.pone.0009357
Source: PubMed

ABSTRACT Acute Tubular Necrosis (ATN) causes severe damage to the kidney epithelial tubular cells and is often associated with severe renal dysfunction. Stem-cell based therapies may provide alternative approaches to treating of ATN. We have previously shown that clonal c-kit(pos) stem cells, derived from human amniotic fluid (hAFSC) can be induced to a renal fate in an ex-vivo system. Herein, we show for the first time the successful therapeutic application of hAFSC in a mouse model with glycerol-induced rhabdomyolysis and ATN. When injected into the damaged kidney, luciferase-labeled hAFSC can be tracked using bioluminescence. Moreover, we show that hAFSC provide a protective effect, ameliorating ATN in the acute injury phase as reflected by decreased creatinine and BUN blood levels and by a decrease in the number of damaged tubules and apoptosis therein, as well as by promoting proliferation of tubular epithelial cells. We show significant immunomodulatory effects of hAFSC, over the course of ATN. We therefore speculate that AFSC could represent a novel source of stem cells that may function to modulate the kidney immune milieu in renal failure caused by ATN.

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Available from: Stefano Giuliani, Sep 25, 2015
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    • "Human amniotic fluid stem cells, a novel class of broadly multipotent stem cells that exhibit characteristics of both embryonic and adult stem cells, have been regarded as a promising candidate for stem cell therapy [130]. Beneficial therapeutic effects of amniotic fluid stem cells have been shown in kidney injury models including acute kidney injury induced by glycerol [131, 132] or cisplatin [133], a mouse model of Alport syndrome [134], and a mouse unilateral ureteral obstruction (UUO) model [135]. "
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    ABSTRACT: The kidney has the capacity for regeneration and repair after a variety of insults. Over the past few decades, factors that promote repair of the injured kidney have been extensively investigated. By using kidney injury animal models, the role of intrinsic and extrinsic growth factors, transcription factors, and extracellular matrix in this process has been examined. The identification of renal stem cells in the adult kidney as well as in the embryonic kidney is an active area of research. Cell populations expressing putative stem cell markers or possessing stem cell properties have been found in the tubules, interstitium, and glomeruli of the normal kidney. Cell therapies with bone marrow-derived hematopoietic stem cells, mesenchymal stem cells, endothelial progenitor cells, and amniotic fluid-derived stem cells have been highly effective for the treatment of acute or chronic renal failure in animals. Embryonic stem cells and induced pluripotent stem cells are also utilized for the construction of artificial kidneys or renal components. In this review, we highlight the advances in regenerative medicine for the kidney from the perspective of renotropic factors, renal stem/progenitor cells, and stem cell therapies and discuss the issues to be solved to realize regenerative therapy for kidney diseases in humans.
    BioMed Research International 05/2014; 2014(3):595493. DOI:10.1155/2014/595493 · 3.17 Impact Factor
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    • "Evaluation of the myogenic effect of forced MYOD expression in vivo is needed for determination of its effect n muscle regeneration. A previous study using hAFS cells reported that transplantation of unstimulated hAFS cells into injured TA muscle had no detectable effect on regeneration [12,52], although hAFS cells show an immunomodulatory effect [53] and recruit host progenitor cells that help in the regeneration of the injured region [54]. In this report, we transplanted hAFS cells overexpressing MYOD into injured TA muscle, and found that muscle volume and myofiber size were increased by hAFS cells expressing MYOD (Figure 4). "
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    ABSTRACT: Human amniotic fluid stem (hAFS) cells have been shown to differentiate into multiple lineages, including myoblasts. However, molecular mechanisms underlying the myogenic differentiation of hAFS cells and their regenerative potential for muscle injury remain to be elucidated. In order to induce myogenic differentiation of hAFS cells, lentiviruses for MYOD were constructed and transduced into hAFS cells. Formation of myotube-like cells was analyzed by immunocytochemistry, and expression of molecular markers for myoblasts was analyzed by reverse transcription polymerase chain reaction and Western blotting. For in vivo muscle regeneration, MYOD transduced human AFS cells were injected into left tibialis anterior (TA) muscles injured with cardiotoxin, and muscle regeneration was analyzed using hematoxilin and eosin, immunocytochemistry, and formation of neuro-muscular junction. MYOD expression in hAFS cells successfully induced differentiation into multinucleated myotube-like cells. Consistently, significant expression of myogenic marker genes, such as MYOG, DES, DMD, and MYH, was induced by MYOD. Analysis of pre-myogenic factors showed that expression of PAX3, MEOX1, and EYA2 was significantly increased by MYOD. MYOD was phosphorylated and localized in the nucleus. These results suggest that in hAFS cells, MYOD is phosphorylated and localized in the nucleus, thus inducing expression of myogenic factors, resulting in myogenic differentiation of hAFS cells. To test regenerative potential of MYOD-transduced hAFS cells, we transplanted them into injured muscles of immunodeficient BALB/cSlc-nu mice. The results showed a substantial increase in the volume of TA muscle injected with MYOD-hAFS cells. In addition, TA muscle tissue injected with MYOD-hAFS cells has more neuro-muscular junction, indicating functional restoration of muscle injury by hAFS cells expressing by MYOD. Collectively, our data suggest that transduction of hAFS cells with MYOD lentiviruses induces skeletal myogenic differentiation in vitro and morphological and functional regeneration of injured muscle in vivo.
    Stem Cell Research & Therapy 12/2013; 4(6):147. DOI:10.1186/scrt358 · 3.37 Impact Factor
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    • "AFSC therapy, unlike previously published MSC based therapy, has yet to show deleterious secondary effects such as tumorogenesis or expression of fibrotic phenotypes in experimental models of chronic fibrotic injury [42], [44], [45], [73]. Furthermore, unlike specific CCL2 inhibitors, these studies coupled with our previously published findings demonstrate the plasticity of the mechanisms of action of AFSC, which are dependent on the type and location of injury. "
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    ABSTRACT: The potential for amniotic fluid stem cell (AFSC) treatment to inhibit the progression of fibrotic lung injury has not been described. We have previously demonstrated that AFSC can attenuate both acute and chronic-fibrotic kidney injury through modification of the cytokine environment. Fibrotic lung injury, such as in Idiopathic Pulmonary Fibrosis (IPF), is mediated through pro-fibrotic and pro-inflammatory cytokine activity. Thus, we hypothesized that AFSC treatment might inhibit the progression of bleomycin-induced pulmonary fibrosis through cytokine modulation. In particular, we aimed to investigate the effect of AFSC treatment on the modulation of the pro-fibrotic cytokine CCL2, which is increased in human IPF patients and is correlated with poor prognoses, advanced disease states and worse fibrotic outcomes. The impacts of intravenous murine AFSC given at acute (day 0) or chronic (day 14) intervention time-points after bleomycin injury were analyzed at either day 3 or day 28 post-injury. Murine AFSC treatment at either day 0 or day 14 post-bleomycin injury significantly inhibited collagen deposition and preserved pulmonary function. CCL2 expression increased in bleomycin-injured bronchoalveolar lavage (BAL), but significantly decreased following AFSC treatment at either day 0 or at day 14. AFSC were observed to localize within fibrotic lesions in the lung, showing preferential targeting of AFSC to the area of fibrosis. We also observed that MMP-2 was transiently increased in BAL following AFSC treatment. Increased MMP-2 activity was further associated with cleavage of CCL2, rendering it a putative antagonist for CCL2/CCR2 signaling, which we surmise is a potential mechanism for CCL2 reduction in BAL following AFSC treatment. Based on this data, we concluded that AFSC have the potential to inhibit the development or progression of fibrosis in a bleomycin injury model during both acute and chronic remodeling events.
    PLoS ONE 08/2013; 8(8):e71679. DOI:10.1371/journal.pone.0071679 · 3.23 Impact Factor
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