Features

doi:10.1038/nindia.2009.160 Published online 25 June 2009

β-cells in the lab

Their new method to produce beta cells in the laboratory might just be the next big step in the hunt for a cure for diabetes, say Anandwardhan Awadhoot Hardikar and David Tosh.

Hardikar (left) and Tosh.

Diabetes is caused by the loss of the insulin-producing β-cells in the pancreas. A significant advance in treating diabetes has been the development of a protocol for islet transplantation from Dr James Shapiro and colleagues at the University of Alberta in Edmonton, Canada (the Edmonton protocol)1. However, lack of suitable organ donors for transplantation is still a major issue for the future.

A new way to overcome this problem is to try and produce β-cells in the laboratory for transplantation into patients2. Fresh research demonstrates that the gallbladder contains a potential source of β-cells for transplantation into diabetics.

India has the largest number of diabetics at over 60 million. According to the International Diabetes Federation, there are more than 246 million people worldwide with diabetes (WHO). This figure is projected to rise significantly to 380 million by 2020. Although treating diabetes with insulin injections is reasonably successful, this does not precisely mimic the function of a normal β-cell. Therefore complications such as kidney failure, blindness and heart disease develop. These complications reduce life expectancy, quality of life and more pressure is placed on medical time and healthcare budgets.

Cell Therapy

Cell therapy means treating diseases with the body's own cells. The main objective of cell therapy for diabetes is to replace the functional β-cells in the body that are lost in the disease. One way to do this is through transplantation of pancreatic islets (the islands of cells in the pancreas that contain β-cells) into diabetics.

Islet transplantation procedures have recently improved considerably but one of the main problems is the lack of donor supply of β-cells since demand far outweighs availability. An alternative to donors is making β-cells in the laboratory. Being able to create β-cells is one of the 'holy grails' of diabetes research. It may eventually become possible to make β-cells from different cell sources. Currently, many groups around the world are working on ways to recreate β-cells in the lab from a variety of sources3, 4, 5, 6, 7, 8. Perhaps one of the interesting sources is from the endodermal cells outside the pancreas.

β-cells from non-pancreatic tissues

One tissue generating enormous interest is the liver. There are two good reasons for this intense interest. First, liver and pancreas are 'next door neighbours' during embryonic development suggesting that it may be possible to convert one cell into another cell type in the adult 9, 10. Second, the liver has the unique ability to regenerate following removal of part of the tissue. In the future, it may be possible that a patient could have part of the liver removed, cells separated in a culture lab, converted into β-cells and transplanted back into the patient. While this is potentially interesting, removing part of the liver is not without risk. So, the question is whether β-cells can be made from other tissues associated with the liver, for example the gallbladder11.

Recently, the gall bladder removed from a patient expressed several pancreatic hormones including insulin. This was surprising because until recently, it was thought that insulin was only produced in pancreatic cells. This study provided proof that β-like cells do occur outside the pancreas. It therefore becomes interesting to study the development of such hormone-producing cells in the gallbladder and compare them with β-cells in the pancreas.

Implications for the future

Cholecystectomy (removal of gall bladder) is generally carried out in individuals who develop gall stones. The lining cells of the gallbladder (the epithelial cells) can be isolated and grown in the lab. Recent work carried out in mouse models12, 13. suggests that it may be possible to induce differentiation of such gallbladder cells into insulin-producing cells.

In comparison to stem cells, such cells are believed to be easy candidates for differentiation into insulin-producing cells as they are obtained from cells that can produce insulin. If this is achieved in the laboratory, it may well be possible to derive, expand, differentiate and transplant insulin-producing cells using the patient's own gallbladder cells. Though other immunological issues need to be addressed, the discovery of such hormone-containing cells in gallbladder opens up another potential source of cells that can be used for cell replacement therapy in diabetes.

Hardikar is a senior scientist in the stem cells and diabetes section of the National Centre for Cell Science, Pune, India and Tosh a reader at the Center for Regenerative Medicine, University of Bath, UK.


References

  1. Shapiro, A. M. et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N. Engl. J. Med. 343, 230-238 (2000) | Article |
  2. Sahu, S. et al. Islet-like cell clusters occur naturally in human gall bladder and are retained in diabetic conditions. J. Cell Mol. Med. 13, 999-10002008)  | Article |
  3. Zhou, Q. et al. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 455, 627-632 (2008)  | Article | ADS |
  4. Gershengorn, M. C. et al. Epithelial-to-mesenchymal transition generates proliferative human islet precursor cells. Science 306, 2261-2264 (2004) | Article | ADS |
  5. Meivar-Levy, I. et al. New organs from our own tissues: liver-to-pancreas transdifferentiation. Trends Endocrinol. Metab. 14, 460-466 (2003) | Article |
  6. D'Amour, K. A. et al. Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat. Biotechnol. 24, 1392-1401 (2006) | Article |
  7. Bonner-Weir, S. et al. In vitro cultivation of human islets from expanded ductal tissue. Proc. Natl. Acad. Sci. U S A 97, 7999-8004 (2000) | Article | ADS |
  8. Tayaramma, T. et al. Chromatin-remodeling factors allow differentiation of bone marrow cells into insulin-producing cells. Stem Cells 24, 2858-2867 (2006) | Article |
  9. Sumitran-Holgersson, S. et al. Generation of hepatocyte-like cells from in vitro transdifferentiated human fetal pancreas. Cell Transplant 18, 183-193 (2009) | Article |
  10. Shen, C. N. et al. Molecular basis of transdifferentiation of pancreas to liver. Nat. Cell Biol. 2, 879-887 (2000) | Article |
  11. Sahu, S. et al. New sources of beta-cells for treating diabetes. J. Endocrinol. doi: 10.1677/JOE-09-0097(2009)
  12. Dutton, J. R. et al. Beta cells occur naturally in extrahepatic bile ducts of mice. J. Cell Sci. 120, 239-245 (2007) | Article | 
  13. Nagaya, M. et al. Adult mouse intrahepatic biliary epithelial cells induced in vitro to become insulin-producing cells. J. Endocrinol. 201, 37-47 (2009) | Article |