Implementation of different signaling pathways for the full conversion of human pluripotent stem cells into functional β cells
PhD Student: Manuj Bandral
Supervisor at TUD: Anthony Gavalas
Supervisor at KCL: Aileen King
Start Date: 01.01.2020
Type 1 diabetes is an autoimmune disease arises due to the destruction of pancreatic beta cells, responsible for insulin production. Absence of insulin paves the way for conditions like hyperglycemia and ketoacidosis that could be very risky for human health and could eventually cause death. Hence, the lack of sufficient endogenous insulin makes a person dependent on external sources of insulin, delivered through injections or insulin pumps, for the rest of their life.
One of the current avenues of the research to tackle type 1 diabetes is the generation of insulin-producing beta cells from human pluripotent stem cells (hPSC). In the recent past, numerous attempts have made significant progress but the conversion rate of hPSC to endocrine cells are still insufficient and the generated beta cells are immature. The lack of signalling information at later stages of differentiation is one of the major reasons for limited information pertaining to beta cell development. Therefore, our lab has investigated the signal pathways S1pr2 and Glp1r hat could be involved at these later steps.
We have established the role of S1p in the lineage allocation and specification of the pancreas development. The S1p signalling through S1pr2 promotes the survival of pancreatic progenitors as well as the specification of acinar and endocrine lineages through the stabilization of YAP and attenuation of Notch signalling5. Lack of S1pr2 resulted in the developmental delay of acinar and endocrine lineage. Glp1r is a GPCR receptor protein largely expressed in beta cells and plays an important role in maintaining blood glucose level by mediating insulin secretion through the adenylyl cyclase pathway. Glp1r signalling through Ex4, a Glp1r agonist, in 14.5 dpc pancreatic explants enhanced alpha and beta cells specification by 50% at the expense of acinar cells whereas treatment with Ex9-39, a Glp1r antagonist, reduced endocrine specification by almost 40%.
Both, S1pr2 and Glp1r signalling are conveyed through Gα subunits. Selective blocking of Gα subunits during mouse pancreas development revealed remarkable effects on endocrine and acinar specification.
These findings disseminate the unsuspected relevance of Gα subunit function in generating various pancreatic lineages and together with the discoveries regarding the involvement of S1p signalling in the same process, encouraged further means to manipulate later stages of differentiation.
Publication:
A Ca(2+)-ATPase Regulates E-cadherin Biogenesis and Epithelial-Mesenchymal Transition in Breast Cancer Cells. D.K. Dang, M.R. Makena, J.P. Llongueras, H. Prasad, M. Ko, M. Bandral, R. Rao. Mol Cancer Res. 2019;17:1735-1747.