Overcoming the Limitations of Stem Cell-Derived Beta Cells

Abstract

Great advances in type 1 diabetes (T1D) and type 2 diabetes (T2D) treatment have been made to this day. However, modern diabetes therapy based on insulin injections and cadaveric islets transplantation has many disadvantages. That is why researchers are developing new methods to regenerate the pancreatic hormone-producing cells in vitro. The most promising approach is the generation of stem cell-derived beta cells that could provide an unlimited source of insulin-secreting cells. Recent studies provide methods to produce beta-like cell clusters that display glucose-stimulated insulin secretion-one of the key characteristics of the beta cell. However, in comparison with native beta cells, stem cell-derived beta cells do not undergo full functional maturation. In this paper we review the development and current state of various protocols, consider advantages, and propose ways to improve them. We examine molecular pathways, epigenetic modifications, intracellular components, and the microenvironment as a possible leverage to promote beta cell functional maturation. A possibility to create islet organoids from stem cell-derived components, as well as their encapsulation and further transplantation, is also examined. We try to combine modern research on beta cells and their crosstalk to create a holistic overview of developing insulin-secreting systems.

Keywords: GSIS; diabetes; insulin-producing cells; microenvironment; pancreas; stem cell-derived beta cells.

Figure 1

Further steps in cell-based diabetes treatment. Generation of fully mature insulin-producing cells that are functionally identical to native beta cells is the first stage. The next one could be the combination of beta cells with supporting cells and encapsulation of such islet organoids. The final stage would be finding the best transplantation method with minimal risks. GSIS—glucose-stimulated insulin secretion; ECM—extracellular matrix. Created with BioRender.com.

Figure 2

The microenvironment of beta cells includes many components such as pancreatic islet endocrine cells, endothelial cells, pericytes, neurons, macrophages, the extracellular matrix (ECM), and EVs (extracellular vesicles). All of them send different signals to beta cells, affecting their viability, proliferation, gene expression, and functions such as GSIS. These effects can be both negative and positive. Intracellular regulatory signals include genetic and epigenetic cues, cytoskeleton, and metabolic states. By intensifying some regulators and blocking others, it is possible to promote maturation, GSIS, and graft survival, which are all crucial for stem cell therapy of diabetes. LncRNAs-long non-coding RNAs; miRs-microRNAs. Created with BioRender.com.