Dr. Long Jun Dai

James D. Johnson, Ziliang Ao, Longjun Dai,  Zehua He,  May Tee, Kathryn J. Potter,  Agnieszka M. Klimek, Mark Meloche, David M. Thompson, Bruce Verchere, Garth L. Warnock: Different effects of FK506, rapamycin, and MMF on glucose-stimulated insulin release and apoptosis in human islets. Cell Transplantation 18: 833-845, 2009.

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Abstract  Pancreatic islet transplantation has the potential to be an effective treatment for type 1 diabetes mellitus. While recent improvements have improved 1-year outcomes, follow-up studies show a persistent loss of graft function/survival over 5 years. One possible cause of islet transplant failure is the immunosuppressant regimen required to prevent alloimmune graft rejection. Although there is evidence from separate studies, mostly in rodents and cell lines, that FK506 (tacrolimus), rapamycin (sirolimus), and mycophenolate mofetil (MMF; CellCept) can damage pancreatic β-cells, there have been few side-by-side, multiparameter comparisons of the effects of these drugs on human islets. In the present study, we show that 24-h exposure to FK506 or MMF impairs glucose-stimulated insulin secretion in human islets. FK506 had acute and direct effects on insulin exocytosis, whereas MMF did not. FK506, but not MMF, impaired human islet graft function in diabetic NOD.scid mice. All of the immunosuppressants tested in vitro increased caspase-3 cleavage and caspase-3 activity, whereas MMF induced ER-stress to the greatest degree. Treating human islets with the GLP-1 agonist exenatide ameliorated the immunosuppressant-induced defects in glucosestimulated insulin release. Together, our results demonstrate that immunosuppressants impair human β-cell function and survival, and that these defects can be circumvented to a certain extent with exenatide treatment. Pancreatic islet transplantation has the potential to be an effective treatment for type 1 diabetes mellitus. While recent improvements have improved 1-year outcomes, follow-up studies show a persistent loss of graft function/survival over 5 years. One possible cause of islet transplant failure is the immunosuppressant regimen required to prevent alloimmune graft rejection. Although there is evidence from separate studies, mostly in rodents and cell lines, that FK506 (tacrolimus), rapamycin (sirolimus), and mycophenolate mofetil (MMF; CellCept) can damage pancreatic β-cells, there have been few side-by-side, multiparameter comparisons of the effects of these drugs on human islets. In the present study, we show that 24-h exposure to FK506 or MMF impairs glucose-stimulated insulin secretion in human islets. FK506 had acute and direct effects on insulin exocytosis, whereas MMF did not. FK506, but not MMF, impaired human islet graft function in diabetic NOD.scid mice. All of the immunosuppressants tested in vitro increased caspase-3 cleavage and caspase-3 activity, whereas MMF induced ER-stress to the greatest degree. Treating human islets with the GLP-1 agonist exenatide ameliorated the immunosuppressant-induced defects in glucosestimulated insulin release. Together, our results demonstrate that immunosuppressants impair human β-cell function and survival, and that these defects can be circumvented to a certain extent with exenatide treatment.

Dong-Sheng Li, Ya-Hong Yuan, Hang-Jun Tu, Qing-Le Liang, Long-Jun Dai: A protocol for islet isolation from mouse pancreas. Nature Protocols. 4:1649-1652, 2009.

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Abstract The recent era of islet transplantation research began more than four decades ago. In 1967, Lacy’s group described a new collagenase-based method to isolate islets, paving the way for future islet experiments both in vitro and in vivo, and eventually leading to a successful islet transplantation to treat patients with type 1 diabetes; since then it has been referred to as the Edmonton protocol. Islet isolation has been a fundamental technique in the field of diabetic research for almost half a century. Achieving good islet isolation is one of the most important factors for reliable islet transplantation studies.

Dong-Sheng Li, Garth L. Warnock, Han-Jun Tu, Ziliang Ao, Zehua He, Hong Lu,  Long-Jun Dai: Do immunotherapy and β cell replacement play a synergistic role in the treatment of type 1 diabetes? Life Sciences. 85:549-556, 2009.

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Abstract Type 1 diabetes (T1D) is the result of the autoimmune response against pancreatic insulin-producing ß-cells. Its ultimate consequence is β-cell insufficiency-mediated dysregulation of blood glucose control. In terms of T1D treatment, immunotherapy addresses the cause of T1D, mainly through re-setting the balance between autoimmunity and regulatory mechanisms. Regulatory T cells play an important role in this immune intervention. An alternative T1D treatment is β-cell replacement, which can reverse the consequence of the disease by replacing destroyed β-cells in the diabetic pancreas. The applicable insulin-producing cells can be directly obtained from islet transplantation or generated from other cell sources such as autologous adult stem cells, embryonic stem cells, and induced pluripotent stem cells. In this review, we summarize the recent research progress and analyze the possible advantages and disadvantages of these two therapeutic options especially focusing on the potential synergistic effect on T1D treatment. Exploring the optimal combination of immunotherapy and β-cell replacement will pave the way to the most effective cure for this devastating disease.

Long-Jun Dai, Hong-Ying Li, Li-Xue Guan, Gordon Ritchie, Jeff X. Zhou: The therapeutic potential of bone marrow-derived mesenchymal stem cells on hepatic cirrhosis. Stem Cell Research 2:16-25, 2009.

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Abstract Hepatic cirrhosis is the end-stage of chronic liver diseases. The majority of patients with hepatic cirrhosis die from life-threatening complications occurring at their earlier ages. Liver transplantation has been the most effective treatment for these patients. Since liver transplantation is critically limited by the shortage of available donor livers, searching for an effective alternative therapy has attracted great interest in preclinical studies. The transplantation of autologous bone marrow-derived mesenchymal stem cells holds great potential for treating hepatic cirrhosis. Mesenchymal stem cells can differentiate to hepatocytes, stimulate the regeneration of endogenous parenchymal cells, and enhance fibrous matrix degradation. Experimental and clinical studies have shown promising beneficial effects. This review is intended to translate the bench study results to the patients’ bedside. The potential interventions of mesenchymal stem cells on cirrhosis are illustrated in terms of the cellular and molecular mechanisms of hepatic fibrogenesis.