Regeneration Research in Diabetes: Future Application Areas

Therapies with stem cells

Stem cells are the hope of modern medicine. On the one hand they possess a high self-renewal rate and on the other hand the ability to develop (differentiate) into any type of body cell. Therefore, approaches are being investigated to replace diseased/defective tissue of the pancreas with stem cells. Stem cells are therefore also an alternative to the limited donor organs. Therapy with the body's own stem cells (such as progenitor cells of beta cells or dopaminergic neurons for Parkinson's therapy) also significantly reduces the risk of a rejection reaction. Stem cell therapies can, however, entail other risks, in particular the formation of tumors.

Stem cells can be obtained in different ways. Pluripotent human embryonic stem cells are one possible option. They are obtained from undifferentiated cells of the embryo at an early stage of development and are then multiplied in cell cultures almost indefinitely. However, many legal and ethical hurdles still have to be overcome on the way to clinical application.

In brief:

Tissues developed from stem cells could in future be an alternative to scarce donor organs such as the pancreas.

Adult stem cells

In principle, stem cell therapy could also be possible with adult bone marrow stem cells. These progenitor cells form certain cell types as substitutes for damaged tissue. Compared to embryonic stem cells, adult bone marrow stem cells have a lower division rate and thus limited differentiation possibilities. They migrate into injured or destroyed tissue and support the action of the immune system, stimulate blood vessel formation and cell growth.

Induced pluripotent stem cells (iPS cells) are another possible option. They are produced by artificial reprogramming from adult tissue-specific stem cells, in the case of diabetes from the pancreas, and are functionally similar to embryonic stem cells. Scientists are currently placing great hopes in these iPS cells: They could be used to circumvent the ethical problems of human embryonic stem cells as well as to develop individual, tailor-made therapies. The 2012 Nobel Prize in Medicine was awarded for the discovery that mature cells can be converted back into embryonic stem cells.

Tissue regeneration through stem cells

Current stem cell research is dedicated to the key molecular mechanisms that enable stem cells to mature into tissue-specific functional cells. The aim is to artificially stimulate stem cells to undergo such maturation to produce cells as tissue replacement or to regenerate remaining cells.

Overall, however, the potential for tissue regeneration by stem cells is still poorly understood. After all, in the mouse model of diabetes, the blood glucose levels of the animals improve when they are injected with adult bone marrow stem cells. Damage to nerves and kidneys, for example, is not as severe as it would otherwise be. The research is still at an early stage.

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Regenerative Therapies give opportunities for cure - for Type-1- and also for Type-2-Diabetes. Prof. Heiko Lickert, head of the Institute of Diabetes and Regeneration Research at Helmholtz Zentrum München, explains the different strategies in a video-interview. Length: 2.33 Minutes

The role of the immune system

In type 1 diabetes the insulin-producing beta cells of the pancreas are destroyed by antibodies of the immune system (so-called autoantibodies). In various therapy studies, approaches are being tested to stop this immune reaction.

Stem cells of the immune system

Stem cells of the immune system can be obtained from umbilical cord blood or alternatively from bone marrow. Treatment with these cells is intended to prevent the immune system from reacting incorrectly.ms gewinnen. Eine Behandlung mit diesen Zellen soll die Fehlreaktion des Immunsystems verhindern.

Good to know:

Umbilical cord blood has not proved successful for treating children with type 1 diabetes.

Umbilical cord blood for the immune system

The body's own umbilical cord blood can be deep-frozen for years in order to serve as a stem cell source for therapy in the event of disease as an adult.

Umbilical cord blood has already been successfully used to treat cancer and immunodeficiencies. In diabetes, the treatment approach is still new; it is intended to improve blood glucose control and regenerate the destroyed beta cells. One approach to treating type 1 diabetes was to use autologous umbilical cord blood to increase the immune system's tolerance to beta cells.

Unfortunately, various clinical studies have shown no relevant effect on the metabolism and immune status of children. There was no evidence that the development of type 1 diabetes could be positively influenced by the therapy.

Immune stem cells from bone marrow

In another study led by Brazilian scientists, immune stem cells were taken from the bone marrow of patients with type 1 diabetes. They were then given strong drugs that killed the immune cells in the body. The stem cells were then administered again by infusion. In twelve of the fifteen participants, the immune destruction of the beta cells was stopped, but relapses were also reported. In addition, immunosuppression by the strong drugs harbors a high risk of side effects, in particular severe infections and germ cell disorders.

Immunomodulation

Immunomodulatory approaches try to intervene in the immune reaction by blocking specific cell receptors or neurotransmitters. This stops the destruction of beta cells and halts the disease. So far, however, all these methods are still the subject of research and not available for clinical treatment. One reason for this is, among other things, that the long-term effects of immunotherapeutics have not yet been sufficiently studied.

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References

  • Tritschler, S. et al.: Systematic single-cell analysis provides new insights into heterogeneity and plasticity of the pancreas. In: Mol Metab., 2017, 6(9):974-990. doi: 10.1016/j.molmet.2017.06.021. eCollection 2017 Sep. Review.
  • Bastidas-Ponce, A. et al.: Cellular and molecular mechanisms coordinating pancreas development. In: Development. 2017 Aug 15;144(16):2873-2888. doi: 10.1242/dev.140756.
  • Bastidas-Ponce, A.: Foxa2 and Pdx1 cooperatively regulate postnatal maturation of pancreatic β-cells. In: Mol Metab., 2017, 6(6):524-534. doi: 10.1016/j.molmet.2017.03.007. eCollection 2017 Jun.
  • Lickert, H., Kaestner, K.H.: Islet biology. In: Mol Metab., 2017, 6(9):vi. doi: 10.1016/j.molmet.2017.06.005. eCollection 2017 Sep 
  • Kleinert, M. et al.: Animal models of obesity and diabetes mellitus. In: Nat Rev Endocrinol., 2018, 14(3):140-162. doi: 10.1038/nrendo.2017.161.
  • Wang, X. et al: Genome-wide analysis of PDX1 target genes in human pancreatic progenitors. In: Mol Metab., 2018, 9:57-68. doi: 10.1016/j.molmet.2018.01.011.
  • Wang, X. et al.: Generation of a human induced pluripotent stem cell (iPSC) line from a patient with family history of diabetes carrying a C18R mutation in the PDX1 gene. In: Stem Cell Res., 2016, 17(2):292-295. doi: 10.1016/j.scr.2016.08.005.
  • Wang, X. et al: Generation of a human induced pluripotent stem cell (iPSC) line from a patient carrying a P33T mutation in the PDX1 gene. In: Stem Cell Res., 2016, 17(2):273-276. doi: 10.1016/j.scr.2016.08.004. Epub 2016 Aug 5.
  • Roscioni, S.S. et al.: Impact of islet architecture on β-cell heterogeneity, plasticity and function. In: Nat Rev Endocrinol., 2016, 12(12):695-709. doi: 10.1038/nrendo.2016.147. Epub 2016 Sep 2.
  • Migliorini, A. et al.: Targeting insulin-producing beta cells for regenerative therapy. In: Diabetologia. 2016 Sep;59(9):1838-42. doi: 10.1007/s00125-016-3949-9.
  • Bader, E. et al: Identification of proliferative and mature β-cells in the islets of Langerhans. In: Nature. 2016 Jul 21;535(7612):430-4. Epub 2016 Jul 11.
  • Willmann S.J. et al.: The global gene expression profile of the secondary transition during pancreatic development. In: Mech Dev. 2016 Feb;139:51-64. doi: 10.1016/j.mod.2015.11.004. 

Scientific advice: Prof. Dr. Heiko Lickert

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December, 13, 2018

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