Department of Surgery

Wang Laboratory

Islet Cell Transplantation Research

Islet Cell Transplantation Research Lab
Left to right: Hongjun Wang, PhD; Tanisha Hutchinson, Summer Research Student; Xinxu Yun, PhD; Dustin Baker, Summer Research Student; Huansheng Dong, PhD

Islet cell transplantation is the most potent therapy for patients with type 1 diabetes. However, there are two major problems besetting this process. First, there are not enough islets available for transplant. Second, islets after transplantation are often undergoing apoptosis due to the stresses encountered during islet harvest and after transplantation. The ongoing projects in the Islet Cell Transplantation lab led by Dr. Hongjun Wang are focused on solving these problems.

The areas of investigation in the Wang lab include:

(i) Generation of insulin-secreting cells from adipose stem cells to expand the source of transplanted islets

(ii) Mechanisms that lead to islet death after allogeneic and autologous islet transplantation

(iii) Interventional approaches that can protect islets from apoptosis and immune rejection by induction of protective genes or encapsulating islets with nanoparticles

(iv) the role of HO-1 in obesity and insulin resistance

(v) a translational approach that can prevent the onset of surgical diabetes after total pancreatectomy and islet autotransplantation for patients with chronic pancreatitis.

Principal Investigator:

Hongjun Wang, PhD

Lab Members:

Huansheng Dong, Ph.D, Postdoctoral fellow

Xinxu Yun, Ph.D: Postdoctoral fellow

Yong Zhang, Ph.D, Visiting scholar

Do-Sung Kin, Ph.D: Postdoctoral fellow

Research Focus:

The Wang lab focuses on pancreatic islet cell biology and transplantation immunology in the treatment of type 1 and type 2 diabetes and chronic pancreatitis.

Type 1 diabetes: Islet cell transplantation is the most potent therapy for patients with type 1 diabetes. However, there are two major problems besetting this process. First, there are not enough islets available for transplant. Second, islets after transplantation are often undergoing apoptosis due to the stresses encountered during islet harvest and after transplantation and the consequent immune rejection response, thus their function are compromised. Ongoing projects in the Wang lab focus on solving these problems. Major areas of investigation include:

(i)   The roles of a protective gene, heme oxygenase-1 (HO-1) and its products, carbon monoxide and bilirubin in islet transplantation;

(ii)  Generation of insulin-secreting cells from adult stem cells (e.g., adipose stem cells, umbilical cord stem cells) to expand source of transplanted islets;

(iii) Developing novel encapsulation methods using FDA approved nanoparticles to protect islets from apoptosis and immune rejection;

(iv) Understanding the role of the Regulator of G Protein Signaling 2 (RGS2) in islet regeneration.

Chronic Pancreatitis (CP):  CP is a long-standing inflammation of the pancreas that alters its normal structure and functions. Current therapies for CP patients focus on pain relief medically, endoscopically and surgically (by resection of diseased parenchyma and drainage of obstructed ducts). In patients with intractable pain and those with diffuse small duct diseases, total pancreatectomy with islet autotransplantation (TP-IAT) can be an ideal treatment option. Compared to other treatment options for CP, TP-IAT has a higher potential to eliminate pancreatic pain without total sacrifice of the endocrine function of the pancreas. Together with Drs. David B Adams and Katherine A Morgan, we are developing interventional procedures including induction of protective genes, nano-encapsulation, and co-transplantation with mesenchymal stem cells to improve islet yield quantity and quality in order to prevent onset of surgical diabetes after TP-IAT in patients with chronic pancreatitis.

Type 2 diabetes:  Prevalence of obesity has become a social and economic burden for health care today. In addition, obesity is a major cause for insulin resistance and type 2 diabetes (T2D). We have found that HO-1 induction or bilirubin administration reduce hyperglycemia, increases insulin sensitivity in both the leptin-receptor deficient (db/db) mice and the diet-induced obese mice. The goal of our study is to further understand the molecular mechanisms of HO-1 and bilirubin, and to develop clinical applicable therapies to improve obesity and insulin resistance.

Major Publications:

1.       Dong H, Morgan KA, Adams DB and Wang, H. Prevention of Beta Cell Death in Chronic Pancreatitis. Advances in Bioscience and Biotechnology. In press.

2.       Dong H, Famhy T, Metcalfe S, Gao W and Wang H. Islet Encapsulation with Nanoparticles Leads to Allograft Long-term Survival. PLoS One. In press.

3.       Wang H, Desai K, Dong H, Owzarski S, Romagnuolo J, Morgan KA and Adams DB. Prior Surgery Determines Islet Yield and Insulin Requirement in Patients with Chronic Pancreatitis. Transplantation. In press.

4.       Bones, R, Icyuz M, Zhang Y, Zhang Y, Cui W, Wang, H, Peng J, Matthews Q, Siegal G, and Wu, H. Gene transfer of active Akt1 by an infectivity-enhanced adenovirus impacts β-cell survival and proliferation differentially in vitro and in vivo. Islets. In press.

5.       Zhang Y, Zhang Y, Bone RN, Cui W, Peng JB, Siegal GP, Wang H, Wu H. Regeneration of Pancreatic Non-β Endocrine Cells in Adult Mice following a Single Diabetes-Inducing Dose of Streptozotocin. PLoS One. 2012;7(5):e36675.

6.       Wang H, Wu, H, Rocuts, F, Gu Z2, Bach FH, Otterbein L. Activation of Peroxisome Proliferator activated Receptor γ Prolongs Islet Allograft Survival. Cell Transplant, 2012 Mar 28. [Epub ahead of print].

7.       Wang H, Ferran, C, Attanasio C, Calise F and Otterbein L. Induction of Protective Genes Leads to Islets Survival and Function. Journal of Transplantation, 2011:141898.

8.       Rocuts, F, Ma, Y, Zhang, X, Gao W, Yue, Y, Vartanian, T and Wang H. Carbon Monoxide Suppresses Membrane Expression of TLR4 via MD-2. J. Immunology, 2010 Aug 15;185(4):2134-9. Epub 2010 Jul 14.

9.       Yan J, Wang H, Jain N, Toxavidis, V, Tigges, J, Yang, H, Yue, G and Gao W. Signal Sequence is still Required in Genes Downstream of “auto-cleaving” 2A Peptide for Secretary or Membrane-anchored Expression. Analytical Biochemistry. Epub: December 10, 2009.

10.    Rocuts, F, Zhang, X, Yan, J, Yue, Y. Thomas, M, Bach FH, Csizmadia E and Wang H. Bilirubin Promotes de novo Generation of T Regulatory Cells”. Cell Transplant. Epub: December 18, 2009.

11.    Wang H, Öllinger, R. Yamashita K, Wegiel B, Thomas M, Margreite, and Bach FH. Therapeutic Applications of Bilirubin and Biliverdin in Transplantation. Antioxidants & Redox Signaling, review. Antioxid Redox Signal. 2007 Dec;9(12):2175-85.

12.    Lee SS, Gao W, Mazzola S, Thomas MN, Csizmadia E, Otterbein LE, Bach FH, Wang H. Hemeoxygenase-1, Carbon Monoxide, and Bilirubin Induce Tolerance in Recipients Toward Islet Allografts by Modulating T Regulatory Cells. FASEB J. 2007 Nov;21(13):3450-7.

13.    Goldberg, A, Parolini M, Chin, BY, Lee SS, Csizmadia E, Otterbein LE, Bach FH and Wang H. Toll-like receptor 4 suppression leads to islet allograft survival. FASEB J. 2007 Sep;21(11):2840-8.

14.    Chin BY, Jiang G, Wegiel B, Wang H, Lee SS, Bilban, M, Gallo D, Czimadia E, Bach FH, Lee PJ and Otterbein LE. Hypoxia-inducible factor 1alpha stabilization by carbon monoxide results in cytoprotective preconditioning. Proc Natl Acad Sci U S A. 2007. Mar 20;104(12):5109-14.

15.    Wang H, Lee S, McDaid J, Ollinger R, Czismadia E, Gao W, Yamashita K and Bach FH. Bilirubin can induce islet allograft survival and tolerance. Endocrinology. 2006 Feb;147(2):762-8.

16.    Wang H*, Lee SS, Gao W, Czismadia E, McDaid J, Ollinger R, Soares MP, Yamashita K, Bach FH. Donor treatment with carbon monoxide can yield islet allograft survival and tolerance. Diabetes. 2005 May;54(5):1400-6.

 
 
 

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