Taking stock of pancreatic stem cells

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Taking Stock of Pancreatic Stem Cells

Xunlei Zhou, PhD and Peter Gruss, PhD, Max Planck Institute of Biophysical Chemistry, Göttingen Klinik & Forschung 2002; 8(2):51-52


Insulin-dependent (type1) diabetes is a widespread chronic disease affecting every age group. The symptoms can at least partially be treated by routine injections of insulin; even so, e.g. vascular complications are common and often a cause of early death. “Curing” the disease would ideally involve a permanent replacement of the beta-cell mass of the patients. Today, the sole sources are human pancreatea or islets of Langerhans. This obviously restricts the large-scale application of this therapy. Recently, progress in the field of stem cell biology opened new possibilities to generate large amounts of functional pancreatic endocrine cells in vitro, which could eventually be used for transplan­tation.


Embryonic stem cells

Stem cells have the potential to generate many types of differentiated cells. Since every tissue of the organism (be it skin, brain, muscle, pancreas or any other) will eventually be formed from the embryonic stem cells (ESC, the cells of the early embryo). These are the ultimate “stem cells”, which possess the ability to generate any kind of tissue. Stem cells of several species, including mouse and human, have been cultivated in vitro, passaged in culture and kept as “cell lines” which then can be maintained and grown circumventing the need of a permanent embryo supply. Outside their natural environment, ESC do not form an embryo but differentiate in a seemingly random manner into neurons, muscle cells, epithelial cells, etc. It has been demonstrated that they can also spontaneously become insulin-producing cells (see e.g.1). Moreover, ESC-derived insulin-producing cells have been shown to correct experimentally induced diabetes in mice 2. Now, in order to obtain reliable large numbers of these cells (for transplantation purposes), we have to be able to “guide” the ESC along the desired differentiating pathway (rather than relying on the unpredictable occurrence of insulin-producing cells in ESC culture dishes). Recently, Lumelsky and coworkers 3 have been able to coax mouse ESC into producing the types of cells, which express insulin and other pancreatic endocrine hormones. Moreover, the cells were able to assemble in culture and form clusters similar to normal pancreatic islets from every point of view. These in vitro-generated islets respond to glucose by secreting insulin, and, after being injected into diabetic mice, they receive vascularization and maintain their islet shape.

Pancreatic stem cells

A second source of stem cells is the pancreas itself. Pancreatic stem cells when compared to ESC have the advantage of being already primed to specifically produce pancreatic cell types. The endocrine cells of the rat pancreatic islets turn over every 40-50 days through the parallel processes of cell death (apoptosis) and cell proliferation (and differentiation). At least some of the new cells are born from progenitor epithelial cells in the pancreatic ducts 4.

An intermediate filament protein called nestin has been identified as a marker for multipotent stem cells in the central nervous system. Nestin-expressing cells have also been found in the pancreatic islet, suggesting that not only the ductal cells, but also some islet cells could have stem cell properties 5. This hypothesis is supported by the fact that the administration of islet trophic factors (e. g. glucose) to rats results in an increase of islet cell mass, which suggests that islet progenitor cells exist within the islets 4.

Nestin-positive islet cells can be isolated and grown in culture for several months, where they show ample proliferation and multipotential capacities 4. At least one additional group of potential pancreatic stem cells, expressing ngn3, has been described. The relation between these cells and the nestin-expressing cells is still unknown4. Finally, exocrine pancreatic cells have been shown to become endocrine cells by going through a process of dedifferentiation that would transform them into stem cells 6.

Reasonable amounts of human ductal cells can be obtained by cultivating pancreatic tissue under certain conditions. Moreover, human islets have been grown in vitro for more than one year. Under these conditions, islet cells are able to trans­differentiate into exocrine cells and also undif­ferentiated cells. The latter are presumably pancreatic stem cells 7,8.

These developments open the possibility of treating patients with “their own” islet cells, grown ex vivo from his/her own pancreas, then transplanted back. The concept has already been proven in the mouse model. Ramiya and coworkers have grown pancreatic ductal cells isolated from prediabetic adult non-obese diabetic mice, then induced them to produce functioning islets containing alpha, beta and delta cells. These islets were able to overcome the symptoms of insulin-dependent diabetes after being implanted into non-obese diabetic mice9.

Transcriptional complexity

Paradoxically, these cells which are attracting so much attention and inspiring so much hope are not very well understood at the molecular level. Detailed knowledge of the transcriptional control of the differentiated state would open a new door to therapy, namely the possibility to jump-start islet neogenesis at will by introducing appropriate regulator genes (or proteins) into the stem cells naturally present in the pancreas of patients.

Current research favors a complex network of regulation involving key players like Pdx1, Ngn3, NeuroD, Pax4 and Pax6 as responsible for pancreatic endocrine differentiation. Members of the Notch family of transcriptional activators would contribute to regulating the balance between differentiation and proliferation 10,11,12 13 ,14, 15, 16. The therapeutic prospects opened by this approach are tantalizingly underlined by recent results showing that ectopic expression of Ngn3 is sufficient to turn endodermal cells into endocrine cells able to form islets expressing glucagon and somatostatin 17.

Dietary modification

Also enticing are reports suggesting that pancreatic stem cells can be coaxed into producing new endocrine cells by dietary means. For instance, copper deprivation contributes to the neogenesis of alpha and beta cells in the pancreatic ducts 18, and hydrolyzed casein promotes islet neogenesis at least in certain strains of rat 19. Finding a way to exploit the relation between diet and pancreatic endocrine cells opens intriguing possibilities to therapy.

Stem cells and cancer

Finally, one more reason to study pancreatic stem cells is cancer research. Pancreatic cancer is very aggressive and difficult to treat, and is among the leading causes of death. It is very likely that most pancreatic cancer originates in stem cells. Insight into the molecular mechanisms of their proliferative and differentiative abilities could bring great rewards also in this area 20 ,21, 22.

References

1. Jacobson, L., Kahan, B., Djamali, A., Thomson, J. & Odorico, J. S. Differentiation of endoderm derivatives, pancreas and intestine, from rhesus embryonic stem cells. Transplant Proc 33, 674. (2001).

2. Soria, B. et al. Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice. Diabetes 49, 157-162. (2000).

3. Lumelsky, N. et al. Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science 292, 1389-1394. (2001).

4. Zulewski, H. et al. Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes. Diabetes 50, 521-533. (2001).

5. Hunziker, E. & Stein, M. Nestin-expressing cells in the pancreatic islets of Langerhans. Biochem Biophys Res Commun 271, 116-119. (2000).

6. Humphrey, R. K. et al. In vitro dedifferentiation of fetal porcine pancreatic tissue prior to transplantation as islet-like cell clusters. Cells Tissues Organs 168, 158-169 (2001).

7. Gmyr, V. et al. Human pancreatic ductal cells: large-scale isolation and expansion. Cell Transplant 10, 109-121. (2001).

8. Schmied, B. M. et al. Transdifferentiation of human islet cells in a long-term culture. Pancreas 23, 157-171. (2001).

9. Ramiya, V. K. et al. Reversal of insulin-dependent diabetes using islets generated in vitro from pancreatic stem cells. Nat Med 6, 278-282. (2000).

10. St-Onge, L., Sosa-Pineda, B., Chowdhury, K., Mansouri, A. & Gruss, P. Pax6 is required for differentiation of glucagon-producing alpha-cells in mouse pancreas. Nature 387, 406-409. (1997).

11. Sosa-Pineda, B., Chowdhury, K., Torres, M., Oliver, G. & Gruss, P. The Pax4 gene is essential for differentiation of insulin-producing beta cells in the mammalian pancreas. Nature 386, 399-402. (1997).

12. Artavanis-Tsakonas, S., Matsuno, K. & Fortini, M. E. Notch signaling. Science 268, 225-232. (1995).

13. Lammert, E., Brown, J. & Melton, D. A. Notch gene expression during pancreatic organogenesis. Mech Dev 94, 199-203. (2000).

14. Schwitzgebel, V. M. et al. Expression of neurogenin3 reveals an islet cell precursor population in the pancreas. Development 127, 3533-3542. (2000).

15. Jensen, J. et al. Independent development of pancreatic alpha- and beta-cells from neurogenin3-expressing precursors: a role for the notch pathway in repression of premature differentiation. Diabetes 49, 163-176. (2000).

16. Dutta, S. et al. PDX:PBX complexes are required for normal proliferation of pancreatic cells during development. Proc Natl Acad Sci U S A 98, 1065-1070. (2001).

17. Grapin-Botton, A., Majithia, A. R. & Melton, D. A. Key events of pancreas formation are triggered in gut endoderm by ectopic expression of pancreatic regulatory genes. Genes Dev 15, 444-454. (2001).

18. Al-Abdullah, I. H., Ayala, T., Panigrahi, D., Kumar, R. M. & Kumar, M. S. Neogenesis of pancreatic endocrine cells in copper-deprived rat models. Pancreas 21, 63-68. (2000).

19. Wang, G. S. et al. Hydrolysed casein diet protects BB rats from developing diabetes by promoting islet neogenesis. J Autoimmun 15, 407-416. (2000).

20. Mukherjee, P. et al. Mice with spontaneous pancreatic cancer naturally develop MUC-1- specific CTLs that eradicate tumors when adoptively transferred. J Immunol 165, 3451-3460. (2000).

21. Matsuzaki, H., Schmied, B. M., Ulrich, A., Batra, S. K. & Pour, P. M. In vitro induction of giant cell tumors from cultured hamster islets treated with N-Nitrosobis(2-Oxopropyl)amine. Am J Pathol 156, 439-443. (2000).

22. Regitnig, P., Spuller, E. & Denk, H. Insulinoma of the pancreas with insular-ductular differentiation in its liver metastasis—indication of a common stem-cell origin of the exocrine and endocrine components. Virchows Arch 438, 624-628. (2001).

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