The pancreas is a little organ behind the stomach and has two main functions – digestion and blood sugar regulation. How the human pancreas develops has been relatively unexplored for ethical and practical reasons. Researchers from the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden, Germany, the Novo Nordisk Foundation Center for Stem Cell Biology (DanStem) in Copenhagen, Denmark, and several other international collaborators, including CIC bioGUNE in Bilbao, Spain, were now able to establish a human pancreas miniature organ in cell culture. Another result of the study is also an atlas of single cells in the human fetal pancreas, which allows researchers to see which genes are expressed in the different cell types during development. This miniature organ and the atlas could offer insights into human syndromes impairing pancreas development and can help in generating replacement beta cells for diabetes therapy.
Even though the pancreas is a little organ, sitting behind the stomach, it is an essential organ producing digestive enzymes and hormones, notably insulin and glucagon. To study the development of this vital organ, Anne Grapin-Botton, a director of the MPI-CBG and former professor at the DanStem, developed in past studies culture methods that allow mouse pancreas cells to grow in three-dimensional conditions, forming tree-like structures that resemble a miniature mouse pancreas. Those miniature organs are also referred to as organoids. The development of the human pancreas in embryos has been challenging to research and there was little information available on how its cells develop in 3D.
Carla Gonçalves, a doctoral student in the research lab of Anne Grapin-Botton, worked together with colleagues in both DanStem and MPI-CBG to develop a similar culture system for human pancreas cells in order to study the developing human pancreas. The researchers then compared these newly generated human pancreas organoids and human pancreas cells in traditional flat cell culture to a reference single cell transcriptome of the human fetal pancreas. This single cell transcriptome atlas shows all the genes expressed in each cell during development, as only a subset of the genetic code is converted into RNA molecules and then proteins. “When comparing the two cell culture systems, we found that the pancreatic progenitor cells in the three-dimensional cell culture system are more similar to the cells in the human fetal pancreas. The method to generate the miniature human pancreas is very robust, so it will allow us to explore many questions related to human pancreas biology in the future,” explains Carla Gonçalves. “Indeed, organoids can be observed with microscopes as they develop and easily subjected to experiments, which we are doing at the MPI-CBG,” adds Anne Grapin-Botton. The labs of Antonio del Sol at CIC bioGUNE and the LCSB – Luxembourg Centre for Systems Biomedicine used the data generated from the human fetal pancreas in a cell-cell communication network model to study how cells communicate by tracing which cells produce which signal and which ones receive it.
“Our cell culture system enables us to study human pancreas development in three-dimensions. Diseases like diabetes can have their origin already during the development of a fetus. With this new three-dimensional miniature organ, we can get more insight into the human pancreas development,” says Anne Grapin-Botton. “We now have a benchmark how a normal human pancreas should develop and study how diabetes may occur when development goes wrong. We can also study how the beta cells that make insulin are formed to produce them more efficiently for future cell therapies of diabetes.”
Carla A. Gonçalves, Michael Larsen, Sascha Jung, Johannes Stratmann, Akiko Nakamura, Marit Leuschner, Lena Hersemann, Rashmiparvathi Keshara, Signe Perlman, Lene Lundvall, Lea Langhoff Thuesen, Kristine Juul Hare, Ido Amit, Anne Jørgensen, Yung Hae Kim, Antonio del Sol, Anne Grapin-Botton: A 3D system to model human pancreas development and its reference single cell transcriptome atlas identify signaling pathways required for progenitor expansion. Nature Communications, 25. May 2021, Doi: 10.1038/s41467-021-23295-6