Investigating development and impairments in pancreas using human embyronic stem cell-derived organoid models
PhD Student: Rashmiparvathi Keshara
Supervisor at TUD: Anne Grapin-Botton
Supervisor at KCL: Rocio Sancho
Start Date: 01.09.2019
The pancreas is an organ with exocrine as well as endocrine functions in nutrient metabolism and glucose homeostasis. Islets of Langerhans constitute the endocrine part of the pancreas and secrete hormones such as insulin, glucagon, and somatostatin, the key regulators of glucose homeostasis. Any error in the differentiation or function of these cells leads to severe physiological disorders, notably diabetes. Mmost cases of diabetes have a strong lifestyle component, mutations in genes such as HLA class II, PPARg, GCK, IER3IP1 have been reported to induce severe conditions of permanent neonatal diabetes mellitus, whereas mutations in ABCC8/KCNJ11 leads to persistent hyperinsulinemic hypoglycemia in childhood as well as diabetes type 2 in adults. Aim of this study is to investigate cell fate decisions in pancreas development in normal conditions and in the context of mutations leading to neonatal diabetes using human embryonic stem (hES) cell-derived organoid models.
We aim to investigate and characterize how the mutations in IER3IP1 affect the differentiation and function of pancreatic cells. During development, pancreatic progenitor cells undergo proliferation as well as differentiation to form all the endocrine, ductal, and acinar cells of the pancreas. Many human pancreatic differentiation protocols based on mouse pancreas development can generate pancreatic progenitors with high efficiency even in 2-D cultures. Insulin secreting beta cells have been efficiently generated from human pancreatic progenitors derived from hES cells. However, most of the protocols focus on producing insulin-producing cells and the efficiency of endocrine differentiation is substantially lower than that of the pancreatic progenitor generation. Using organoid models derived from human ES cell lines, we want to understand how the multipotent progenitor cells decide to undergo differentiation not only into endocrine cells but also exocrine cells, and what molecular signals are involved in regulating these processes as well as controlling their spatial arrangements in 3D.
Overall, this project will contribute to a more comprehensive understanding of human pancreas development. Knowledge of the mechanisms involved in endocrine cell formation can help to improve therapies for the treat-ment of diabetes and pancreatic disorders.
Publications:
Self-organization of organoids from endoderm-derived cells. A. Lewis, R. Keshara, Y.H. Kim, A. Grapin-Botton. J Mol Med. 2020; 99:449-462.
A 3D system to model human pancreas development and its reference single-cell transcriptome atlas identify signaling pathways required for progenitor expansion. C.A. Gonçalves, M. Larsen, S. Jung, J. Stratmann, A. Nakamura, M. Leuschner, L. Hersemann, R. Keshara, S. Perlman, L. Lundvall, L.L. Thuesen, K.J. Hare, I. Amit, A. Jørgensen, Y.H. Kim, A. Del Sol, A. Grapin-Botton. Nat Commun. 2021;12(1):3144.