Delayed Treatment With Human Umbilical Cord Blood-Derived Stem Cells Attenuates Diabetic Renal Injury

Department of Bioinspired Science, Division of Life and Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea.
Transplantation Proceedings (Impact Factor: 0.98). 05/2012; 44(4):1123-6. DOI: 10.1016/j.transproceed.2012.03.044
Source: PubMed


Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide. Excess accumulation of extracellular matrix and the epithelial-to-mesenchymal transition contribute to renal fibrosis, which is associated with DKD. The present study examined whether delayed treatment with human umbilical cord blood-derived stem cells (hUCB-SC) showed a therapeutic effect on DKD progression. Experimental diabetes was induced by intraperitoneal injection of streptozotocin (STZ; 50 mg/kg) into 6-week-old male Sprague-Dawley rats. Age-matched control rats received an equivalent volume of sodium citrate buffer alone. At 4 weeks after the STZ injection when diabetic renal injury had developed, hUCB-SC were administered (1 × 10(6) cells/rat) through the tail vein. Four weeks after administering the hUCB-SC, rats were sacrificed and we measured indices of DKD, including urinary protein excretion as well as fibronectin, α-smooth muscle actin (α-SMA), and E-cadherin mRNA, and protein expression. Diabetic rats developed significantly increased urinary protein excretion and renal hypertrophy compared to those in control rats. Renal expression of fibronectin and α-SMA mRNA, and protein were increased significantly in diabetic rats compared to those in the controls. E-cadherin protein expression in diabetic kidneys decreased significantly. Intravenously administered hUCB-SC effectively reduced proteinuria, renal fibronectin, and α-SMA up-regulation, as well as renal E-cadherin down-regulation in diabetic rats without a significant effect on blood glucose. Engrafted hUCB-SC in diabetic kidneys were confirmed by human DNA PKcs. The results demonstrated that delayed treatment with hUCB-SC attenuated the progression of diabetic renal injury.

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    • "In both pre-clinical and clinical settings, MSCs have been studied to treat a various diseases. Pre-clinically, UCB-MSCs have been used to treat neonatal brain injury [21], fibrocartilaginous embolic myelopathy [22], spinal cord injury [23,24], diabetic renal injury [25,26], bone loss [27], ischemia [28,29], hearing loss [30], damaged corneal endothelium [31], Alzheimer’s disease [32], graft-versus-host disease (GVHD) [33], acute hepatic necrosis [34], diabetes mellitus [35], and liver cirrhosis [36]. Clinically, UCB-MSCs have been transplanted for treatment of autism [37], hereditary spinocerebellar ataxia [38], foot disease in patients with type 2 diabetes mellitus [39], and basilar artery dissection [40]. "
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    ABSTRACT: Mesenchymal stem cells (MSCs) are an attractive source of stem cells for clinical applications. These cells exhibit a multilineage differentiation potential and strong capacity for immune modulation. Thus, MSCs are widely used in cell therapy, tissue engineering, and immunotherapy. Because of important advantages, umbilical cord blood-derived MSCs (UCB-MSCs) have attracted interest for some time. However, the applications of UCB-MSCs are limited by the small number of recoverable UCB-MSCs and fetal bovine serum (FBS)-dependent expansion methods. Hence, this study aimed to establish a xenogenic and allogeneic supplement-free expansion protocol. UCB was collected to prepare activated platelet-rich plasma (aPRP) and mononuclear cells (MNCs). aPRP was applied as a supplement in Iscove modified Dulbecco medium (IMDM) together with antibiotics. MNCs were cultured in complete IMDM with four concentrations of aPRP (2, 5, 7, or 10%) or 10% FBS as the control. The efficiency of the protocols was evaluated in terms of the number of adherent cells and their expansion, the percentage of successfully isolated cells in the primary culture, surface marker expression, and in vitro differentiation potential following expansion. The results showed that primary cultures with complete medium containing 10% aPRP exhibited the highest success, whereas expansion in complete medium containing 5% aPRP was suitable. UCB-MSCs isolated using this protocol maintained their immunophenotypes, multilineage differentiation potential, and did not form tumors when injected at a high dose into athymic nude mice. This technique provides a method to obtain UCB-MSCs compliant with good manufacturing practices for clinical application.
    Journal of Translational Medicine 02/2014; 12(1):56. DOI:10.1186/1479-5876-12-56 · 3.93 Impact Factor
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    ABSTRACT: Aims: The present study examined renoprotective effect of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSC) in diabetes. NRK-52E cells were utilized to determine the paracrine effect of hUCB-MSC. Methods: hUCB was harvested with the mother's consent. MSC obtained from the hUCB were injected through the tail vein. Growth arrested and synchronized NRK-52E cells were stimulated with transforming growth factor-β1 (TGF-β1) in the presence of hUCB-MSC conditioned media. Results: At 4 weeks after the streptozotocin (STZ) injection, diabetic rats showed significantly increased urinary protein excretion, renal and glomerular hypertrophy, fractional mesangial area, renal expression of TGF-β1 and α-smooth muscle actin, and collagen accumulation but decreased renal E-cadherin and bone morphogenic protein-7 expression, confirming diabetic renal injury. hUCB-MSC effectively prevented diabetic renal injury except renal and glomerular hypertrophy without a significant effect on blood glucose. CM-DiI-labeled hUCB-MSC and immunostaining of PKcs, a human nuclei antigen, confirmed a few engraftment of hUCB-MSC in diabetic kidneys. hUCB-MSC conditioned media inhibited TGF-β1-induced extracellular matrix upregulation and epithelial-to-mesenchymal transition in NRK-52E cells in a concentration-dependent manner. Conclusions: These results demonstrate the renoprotective effect of hUCB-MSC in STZ-induced diabetic rats possibly through secretion of humoral factors and suggest hUCB-MSC as a possible treatment modality for diabetic renal injury.
    Diabetes research and clinical practice 09/2012; 98(3). DOI:10.1016/j.diabres.2012.09.034 · 2.54 Impact Factor
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    ABSTRACT: Mesenchymal stem cells (MSCs) are self-renewing cells with multipotent differentiation characteristics and capability for the regulation of immune response. Accordingly, in the context of diabetes research, the ability of MSC to generate insulin-producing cells and to enhance islet engraftment and survival makes them attractive as new therapeutic agents for treatment of diabetes and related complications. In this chapter we emphasized the role of MSCs in the repair of β cell mass and function and we described the capacity of MSCs to modulate the autoimmune response during the pathogenesis of diabetes mellitus. In addition, we also presented here the mechanisms, promises and potential obstacles for MSC therapy of diabetic complications: cardiomyopathy, critical limb ischemia, nephropathy, polyneuropathy, retinopathy and diabetic wounds.
    Essentials of Mesenchymal Stem Cell Biology and Its Clinical Translation, 01/2013: pages 207-227; , ISBN: 978-94-007-6715-7
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