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 a complex and multifactorial disease characterized by progressive loss or dysfunction of the insulin-producing beta cells in the pancreas. Nowadays, no current treatments can stop or reverse the disease progression except bariatric surgery and islet transplantation. However, donor shortage and risks associated with life-long immunosuppression demand the development of alternative therapies. Therefore, intensive efforts in the field of diabetes research are put into the development of novel therapeutic approaches. In vitro differentiation of ß cells from human pluripotent stem cells in one of the most promising approach of cell replacement therapy in diabetes. To achieve such an ambitious goal, the differentiation programs of all islet cells (endocrine, endothelial, mesenchymal), and the way in which islets are formed during pancreas development in their body niche, need to be fully understood and translated to the cell culture dish (Bader, Migliorini et al., Nature, 2016; Bakthi et al., Nat Rev Endocrinol, 2019; Theis and Lickert, Nature, 2019).
Generation of stem cell-derived islet-like clusters for cell replacement therapies
The overall goal of this project is the is the in vitro generation of the main endocrine islet cell types, glucagon-secreting α-cells and insulin-secreting β cells, from human pluripotent stem cells with defined differentiation protocols. Our lab is at the forefront in developing improved protocols for α- and β-cell differentiation by reducing the numbers of required differentiation factors and applying an enrichment strategy of intermediate cells to reduce the heterogeneity of differentiation (Mahaddalkar et al., in revision; Nat Biotech). Despite this forthcoming, the in vitro generated β-like cells still resemble fetal β-cells and are not fully mature. Moreover, pluripotent stem cell (PSC)-derived islet-like clusters are heterogenous mixtures of cells, including pancreatic progenitors, gut endocrine cell types and different ratios of α- and β-like cells.
The proposed project aims:
i) to improve the protocols for the generation, isolation and purification of PSC-derived islet cell types with therapeutic activity comparable to that of human islet cells
ii) to re-aggregate PSC-derived islet cells into defined 3D micro-organs with defined cell-type composition and improved functionality
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 PSC-derived islets and primary human islets. The PhD candidate will work with pluripotent stem cells (hESC and iPSCs) and employ cutting edge technologies such as in vitro differentiation protocols, flow cytometry, CRISPR/Cas9 genome editing, single-cell RNAseq, single-molecule RNA FISH and live cell imaging.