The primary objective of the Institute of Diabetes and Regeneration Research (IDR) at the Helmholtz Zentrum München is to develop regenerative therapeutic approaches to treat diabetes mellitus. We provide an international environment and stimulating atmosphere in an institute dealing with various aspects of beta cell biology. Diabetes mellitus is one of the most prevalent metabolic disorders characterized by progressive loss or dysfunction of the insulin-producing β-cells in the pancreas. Currently, no treatments can stop or reverse the disease progression. Although daily doses of insulin save the lives of type 1 diabetic patients, they still suffer from fluctuating glucose levels that bear the risk of hypoglycemia, and eventually secondary complications and a shortened life span. Human islet transplantations reversed diabetes in type 1 diabetic patients, however compatible human islets are sparse and the
patients require lifelong immunosuppression. Therefore, a promising alternative to donor islets is the transplantation of human stem cell-derived islet-like clusters (SC-ILCs). Although recent differentiation protocols could improve the efficiency of generated β-cells, the SC-ILCs still consist of not only endocrine cells, but also other unwanted cell types. This heterogeneity impairs β-cell functionality and might be a risk for patients. We showed in our recent publication that the enrichment of a highly specified endodermal subpopulation results in a more homogenous differentiation with a higher yield of β-cells and improved functionality1. However, it is still not fully understood how the endoderm is formed and patterned and how an endocrine fate is induced especially during human pancreas development2–5. Therefore, unraveling biological processes during pancreas development will allow us to advance in vitro differentiation protocols and improve yield, purity and the functionality of SC-ILCs.
Generation of advanced stem cell-derived islet-like clusters for cell replacement therapy
The overall goal of the project is to generate SC-ILCs with superior functionality by modulating the patterning of the endoderm/foregut endoderm. The proposed project aims:
i. To decipher human endoderm/foregut formation and patterning in vitro.
ii. To screen small molecules that induce an anterior definitive endoderm/ pancreatic foregut endoderm fate that increases the yield of generated pancreatic progenitors and endocrine cells.
iii. To analyze the purity, functionality and maturation of the generated SC-ILCs in vitro and in vivo.
The PhD candidate will work with hPSCs and employ cutting edge technologies, such as in vitro differentiation, flow cytometry, insulin secretion assays, CRISPR/Cas9 genome editing, immunohistochemistry. This project will be a collaboration with the MacDonald Islet Biology laboratory at the Alberta Diabetes Institute (www.bcell.org), which will focus on the functional comparison of hPSC-derived islets and primary human islets.
1. Mahaddalkar, P. U., Scheibner K. et al. Generation of pancreatic β cells from CD177+ anterior definitive endoderm. Nat. Biotechnol. (2020) doi:10.1038/s41587-020-0492-5.
2. Scheibner, K., Bakhti, M., Bastidas-Ponce, A. & Lickert, H. Wnt signaling: implications in endoderm development and pancreas organogenesis. Current Opinion in Cell Biology (2019) doi:10.1016/j.ceb.2019.07.002.
3. Scheibner, K. et al. Epithelial cell plasticity drives endoderm formation during gastrulation. Nat. Cell Biol. 23, 692–703 (2021).
4. Bakhti, M., Scheibner K. et al. Establishment of a high-resolution 3D modeling system for studying pancreatic epithelial cell biology in vitro. Mol. Metab. (2019) doi:10.1016/j.molmet.2019.09.005.
5. Bastidas-Ponce, A., Scheibner, K., Lickert, H. & Bakhti, M. Cellular and molecular mechanisms coordinating pancreas development. Development 144, 2873–2888 (2017).