Implantation of bFGF-treated islet progenitor cells ameliorates streptozotocin-induced diabetes in rats

Fudan-VARI Genetic Epidemiology Center, Fudan University, Shanghai, China.
Acta Pharmacologica Sinica (Impact Factor: 2.91). 11/2010; 31(11):1454-63. DOI: 10.1038/aps.2010.130
Source: PubMed


To examine whether implantation of islet preparation-derived proliferating islet cells (PIC) could ameliorate diabetes in rats.
PIC were expanded from rat islet preparation by supplementation of basic fibroblast growth factor (bFGF) and implanted into rats with streptozotocin (STZ)-induced diabetes through the portal vein. Body weight and blood glucose levels were measured. Serum insulin levels were measured by radioimmunoassay. The presence of insulin-positive cells was determined by hematoxylin and immunohistochemical staining.
Cultured islet cells (CIC) were demonstrated to dedifferentiate in vitro, and the apoptosis ratios reached more than 50% by the 15th day post-isolation. PIC cells treated with bFGF (20 ng/mL) continued growing within 30 days after isolation, and no apoptotic cells were detected. Implantation of PIC into diabetic rats was capable of ameliorating diabetes, in terms of the restoration of euglycemia, weight gain, improved glucose response and elevated serum insulin levels for up to 130 days. Livers derived from PIC-implanted rats were examined for insulin expression and single insulin-positive cells. In addition, most islets of PIC-implanted STZ-induced diabetic rats were intact at 130 days post-transplantation and comparable to those of normal rats.
Implantation of bFGF-treated proliferating islet cells is a promising cellular therapeutic approach for diabetes.

Download full-text


Available from: Ge Li, Feb 26, 2014
  • Source
    • "Changes in skeletal muscle PKC precede the skeletal muscle myopathy of diabetes mellitus (Given et al., 1998) and bFGF is necessary for regeneration and healing of skeletal muscle (Menetrey et al., 2000). PKC and bFGF also regulate factors that promote cells to differentiate into muscle fibers (Karpen et al., 1992; Hardy et al., 1993; Menetrey et al., 2000; Li et al., 2010). In addition, PKC activation closely associates with insulin resistance in skeletal muscle (Schmitz-Peiffer and Biden, 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: This study investigated the potential mechanisms that may underlie diabetes induced amyoatrophy. Sprague-Dawley rats were either injected intraperiotneally with STZ (test group; N=8) to induce diabetic-like symptoms (blood glucose level ≥16.65mmol/L) or with buffer (control group; N=8). Differences in muscle structure between the STZ-induced diabetic and control groups were evaluated by histochemistry. Protein and mRNA levels of basic FGF (bFGF), bax, bcl-2, and caspase 3 in skeletal muscle were compared between the 2 groups using immunohistochemistry and quantitative PCR, respectively. Serum level of insulin and protein kinase C (PKC) were measured by competitive RIA and ELISA, respectively. Unlike control animals, the skeletal muscle fibers from STZ-induced diabetic animals were broken and pyknotic, the sarcomeric structure disrupted, and mild hyperplasia of interstitial adipose tissues was detected. The serum level of PKC was higher (P=0.003) and the protein and mRNA levels of bFGF in skeletal muscle were lower (P=0.001) in STZ-induced diabetic versus control animals. Protein and mRNA levels of the apoptosis promoting genes caspase-3 and bax were higher in skeletal muscle from STZ-induced diabetic rats as compared to control animals (P<0.001 and P=0.037, respectively), while mRNA and protein levels of bcl-2, an inhibitor of apoptosis, was lower in STZ-induced diabetic rats versus control animals (P=0.026). Increasing apoptosis in skeletal muscle from STZ-induced diabetic rats was further demonstrated by TNNEL assay. Our findings suggest that enhanced PKC levels, reduction of bFGF expression, and increased in apoptosis might be associated with the development of diabetes-induced myoatrophy.
    Preview · Article · Sep 2013 · Tissue and Cell
  • [Show abstract] [Hide abstract]
    ABSTRACT: This study investigated the differentiation of human amniotic fluid-derived stem cells (hAFSCs) into insulin-producing clusters in vitro. Adenovirally-delivered mouse Pdx1 (Ad-Pdx1) induced human Pdx1 expression in hAFSCs and enhanced the coordinated expression of downstream β-cell markers. When Ad-Pdx1-transduced hAFSCs were sequentially treated with activin A, bFGF and nicotinamide and the culture plate surface coated with poly-l-ornithine, the expression of islet-associated human mRNAs for Pdx1, Pax6, Ngn3 and insulin was increased. C-peptide ELISA confirmed that Ad-Pdx1-transduced hAFSCs processed and secreted insulin in a manner consistent with that pathway in pancreatic β-cells. To sustain the β-cell-like phenotype and investigate the effect of three-dimensional (3D) conformation on the differentiation of hAFSCs, Pdx1-transduced cells were encapsulated in alginate and cultured long-term under serum-free conditions. Over 2 weeks, partially differentiated hAFSC clusters increased in size and increased insulin secretion. Taken together, these data demonstrate that ectopic Pdx1 expression initiates pancreatic differentiation in hAFSCs and that a β-cell-like phenotype can be augmented by culture conditions that mimic the stromal components and 3D geometry associated with pancreatic islets. Copyright © 2012 John Wiley & Sons, Ltd.
    No preview · Article · Oct 2012 · Journal of Tissue Engineering and Regenerative Medicine
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Diabetes mellitus, characterized by the impaired metabolism of insulin secretion in β cells, is becoming one of the most prevalent diseases around the world. Recently, cell replacement based on differentiation of various pluripotent stem cells, including embryonic stem cells, induced pluripotent stem cells and multipotent stem cells, such as bone marrow mesenchymal stem cells, adipose-derived stem cells and gnotobiotic porcine skin-derived stem cells, is becoming a promising therapeutic strategy. Cells derived from pancreatic tissues or other tissues that are relevant to β cell differentiation have also been used as cell source. However, in spite of hopeful experimental results, cell therapy in diabetes still confronts certain obstacles, such as purity of cells, functional differentiation of stem cells and possible tumorigenesis, which, in turn, lead to the seeking of new-generation tools, such as xenogenetic materials. In this review, we will summarize the current knowledge and future prospects of cell therapy in diabetes mellitus. © 2015, Science China Press and Springer-Verlag Berlin Heidelberg.
    Preview · Article · Jul 2015