Islet- contains the insulin producing β-cells of the islets of Langerhans in the pancreas. The abnormality and the loss of these cells is the cause of the development of diabetes mellitus. Diabetes is considered to be an epidemic of 21st century. There are two main types of diabetes - type-1 and type-2. Type-1 diabetes has two forms-type 1A results from progressive autoimmune destruction or programmed cell death of insulin producing β-cell and type-1B which shows impaired β-cell function and the reason for this abnormality is not known. In type-2 diabetes, disease is caused by insulin resistance at its target cells. Because of this lack of insulin, affected insulin action or complete dysfunction diabetes patients suffer from increased concentration of glucose in blood plasma and these chronically raised blood glucose concentration creates micro vascular complication such as retinopathy, nephropathy, and neuropathy with high rates of mortality. Islet cell transplantation with the aid of stem cell science and tissue engineering has a huge potential to replace lost β-cells in restoring glucose homeostasis in type-1 diabetes. [1, 2, 3]
In the era before the discovery of insulin by Canadian surgeon Frederick G Banting and his student assistant Charles H Best at the University of Toronto in 1921 Diabetes-1 was a fatal disease with certain death. Until now the administration of insulin by injection into the blood stream has been the primary treatment for type-1 diabetes. Although insulin therapy has enabled millions of diabetes patients to live and survive but this therapy is not able to recreate body's need specific real-time variation of blood glucose for metabolism. And diabetes transformed as a chronic illness with substantial risk of premature death and long-term intolerable morbidity with no cure [1, 2]. To re-establish and maintain long-term glucose homeostasis, two possible treatments are being considered, either artificial tissue engineered pancreas implantation or donor pancreas transplantation, or islet replacement of β-cell by transplantation or stem cell engineering [3].
First transplantation of pancreatic extract was performed by Watson-Williams and Harsant at the Bristol Royal Infirmary in the UK in 1893. After that, several times clinical islet transplantation attempts had been taken but initial success rates were low. Over the years many studies have been done to get a better understanding of the islet isolation techniques, integration of implanted tissue within the hepatic microenvironment, tackling the rejection of islet tissue by immune system and improvement of surgical techniques in general [5]. Recently there has been an unprecedented success of islet transplantation program in Edmonton at the University of Alberta, Canada where James Shapiro and his colleagues have shown a 100% cure rate with their new improved technique, called Edmonton protocol. Below is a brief overview of the procedure-
Before transplantation, islets have to be separated from pancreas tissue. Protein collagen holds the tissue together which can be broken down using a solution of collagenase. So collagenase is injected into the pancreas of cadaver organ donor, which will break it into smaller fragments and islets. This tissue is further processed and purified by complex technique to obtain viable, well characterized islets. This islet is then injected into the portal vein where islets are integrated with the hepatic environment to survive and produce insulin. But these transplanted cells are subjected to attack by immune system which is programmed to attack any foreign cells and could cause rejection of the implanted cells. So this protocol uses a unique steroid- free anti-rejection drugs which suppress the immune system's attack on the transplanted cells [4, 5, 6].
Figure 1: Islet transplantation from donor to recipient [8].
This procedure has given a result of 100% success in seven patients who were able to achieve independence from insulin therapy for more than one year. Success of the Edmonton protocol has caused a great enthusiasm and thought to be the first standardized reproducible protocol. Huge efforts have been made to replicate this protocol successfully worldwide with positive outcomes from seven international trial centres [7]. Unfortunately, despite this success and enthusiasm there are two major problems associated with the clinical islet transplantation-1) Limited availability of transplantable islets and 2) complications from lifelong immunosuppressive drugs which causes some serious side effects on some patients. Because of these reasons less than 0.5% of type-1 diabetes patients could access this treatment [2, 9].
To overcome these problems of scarcity of islet cell and immune incompatibility, production of islet cell from stem cell based tissue engineering could be the solution. To do these two approach could be taken, either culturing stem cell into differentiated desired tissue or tissue engineered artificial universal donor living tissue which also could be made from stem cell [10]. There are two types of stem cells-1) Embryonic stem cell 2) Adult stem cell.
Embryonic stem cell from the inner mass of the blastocyst become specialised into all adult tissue in the course of normal development of embryo. They are called pluripotent as they have the highest proliferation ability into every type of adult cell. These cells could be signalled to be differentiated into insulin producing β- cell in the culture. Studies have done which support this could be possible. But there is a critical issue- is controlling of the differentiation process of stem-cell as proliferation in uncontrolled fashion would give rise to tumorous tissue. This problem needs to be overcome. And rejection by body's immune system of transplanted cells (even in the case of embryonic stem cell source) still exists. There are several possible ways these can be dealt with. Immunomodulation, immunoisolation and induction of donor specific tolerance is being evaluated. Immunomodulation and immunoisolation methods can modify implantable cell by masking the histocompatibility protein which recognizes non-self. Induction of donor cell specific tolerance manipulates the T-cell generation which detects non self antigens. Also there are ethical issues about the embryonic stem cell. To obtain embryonic stem cell human embryo will be destroyed in the process which is controversial and needs to be addressed to find out solution [2, 11].
Another type of stem cell is adult stem cell which was thought to be vanished after birth, but research has showed that they do exist. For example-red blood cell which originates from bone marrow contains haematopoietic and mesenchymal stem cell. Mesenchymal stem cell has the ability to proliferate into all kinds of differentiated form including insulin producing β-cell. There are also other sources of adult stem cell-liver, pancreas. Testing on animal has showed positive results but some problem associated with it in human context, e.g. - finding exact location of the stem cell, their limited ability to proliferate. By genetic manipulation proliferation could be increased and could be controlled. If it is possible, use of adult stem cell in sourcing β-cell for islet cell transplantation would solve the problem of immune system rejection of implanted tissue, unregulated differentiation of stem cell population and the ethical issue concerning human embryo destruction. Further studies and research is needed in this area of stem cell science [2, 9].
Tissue engineering also can be used to develop artificial living replacement tissue, organ and in the case of diabetes patients-islet cell and pancreas. This way making of complex vascularised tissues and organs will be possible in near future. Replacement islet tissue made by tissue engineering can eliminate some of the problems associated with isolation and purification process. During extraction period islets experience cellular stress which does affect its function, adaptation in the hepatic microenvironment and above all survival. Tissue engineering uses a three dimensional extra cellular matrix along with implanted cell in vivo so that they can integrate with the patient's body. This is a new technology with huge potential [10].
Transplantation of islets to cure type-1 diabetes gives real hope to the millions of patients. Finding sources of islet cell or alternative insulin producing cell from stem cell or by tissue engineering offers exciting perspectives. It is challenging and complex, and involves some controversial aspects and should not be underestimated. Lot of study and research is required by combined interdisciplinary cooperation before any practical applicable success is achieved in clinical arena. Also to prevent diabetes at the first place by vaccination or some other measurements needs to be sought and fully explored.
