Stepwise differentiation of functional pancreatic β cells from human pluripotent stem cells

Abstract

Pancreatic β cells differentiated from stem cells provide promise for cell replacement therapy of diabetes. Human pluripotent stem cells could be differentiated into definitive endoderm, followed by pancreatic progenitors, and then subjected to endocrinal differentiation and maturation in a stepwise fashion. Many achievements have been made in making pancreatic β cells from human pluripotent stem cells in last two decades, and a couple of phase I/II clinical trials have just been initiated. Here, we overview the major progresses in differentiating pancreatic β cells from human pluripotent stem cells with the focus on recent technical advances in each differentiation stage, and briefly discuss the current limitations as well.

Keywords: Diabetes mellitus; Human pluripotent stem cells; Pancreatic β cell; Stepwise differentiation.

Fig. 1

Stepwise differentiation of pancreatic β cells from human pluripotent stem cells. A Pancreatic islets are derived from the definitive endoderm, which is specified during gastrulation and then forms the primitive gut tube. During the development from the foregut to the pancreatic endoderm, pancreatic buds consisting of pancreatic progenitor cells emerge from the dorsal and ventral sides of the posterior foregut, following that the pancreatic epithelium expands and differentiates into endocrine progenitor cells, which finally give rise to β cells. B Through mimicking in vivo pancreatic development, human pluripotent stem cells (PSCs) are differentiated stepwise into pancreatic lineage and eventually to generate β cells. DE: Definitive Endoderm; PGT: Primitive Gut Tube; PF: Posterior Foregut; PE: Pancreatic Endoderm; EP: Endocrine Precursor

Fig. 2

Improvements to efficient differentiation of human PSC-derived pancreatic β cells. The current improvements of efficient differentiation mainly focus on exploring signal pathways. Key signal pathways and related molecules are shown in the graph. The top half of the figure depicts the commonly manipulated signaling pathways; the bottom half shows the recently reported signaling pathways or molecules improving differentiation efficiency

Fig. 3

Efforts on the functional maturation of human PSC-derived pancreatic β cells. The pancreatic β cells derived from human PSCs showed limited functional maturity. The expression of genes related to insulin transcription and secretion enables immature β cells to respond to high glucose levels with an appropriate insulin release, showing static GSIS with limited function. Dynamic GSIS with first- and second-phase insulin secretion has been achieved by regulating TGF-β signal pathway, reaggregation and/or metabolic regulation, but the amount of insulin secreted in the second stage is still low. Metabolic maturation of β cells, together with the microenvironment and islet structure considerations contribute to the functional maturity of human PSC-derived pancreatic β cells. GSIS: glucose-stimulated insulin secretion