Recent Developments in β-Cell Differentiation of Pluripotent Stem Cells Induced by Small and Large Molecules

Abstract

Human pluripotent stem cells, including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), hold promise as novel therapeutic tools for diabetes treatment because of their self-renewal capacity and ability to differentiate into beta (β)-cells. Small and large molecules play important roles in each stage of β-cell differentiation from both hESCs and hiPSCs. The small and large molecules that are described in this review have significantly advanced efforts to cure diabetic disease. Lately, effective protocols have been implemented to induce hESCs and human mesenchymal stem cells (hMSCs) to differentiate into functional β-cells. Several small molecules, proteins, and growth factors promote pancreatic differentiation from hESCs and hMSCs. These small molecules (e.g., cyclopamine, wortmannin, retinoic acid, and sodium butyrate) and large molecules (e.g. activin A, betacellulin, bone morphogentic protein (BMP4), epidermal growth factor (EGF), fibroblast growth factor (FGF), keratinocyte growth factor (KGF), hepatocyte growth factor (HGF), noggin, transforming growth factor (TGF-α), and WNT3A) are thought to contribute from the initial stages of definitive endoderm formation to the final stages of maturation of functional endocrine cells. We discuss the importance of such small and large molecules in uniquely optimized protocols of β-cell differentiation from stem cells. A global understanding of various small and large molecules and their functions will help to establish an efficient protocol for β-cell differentiation.

Enhanced Differentiation of Human Embryonic Stem Cells Toward Definitive Endoderm on Ultrahigh Aspect Ratio Nanopillars

“…In published stem cell differentiation protocols, soluble molecules are added in different concentrations at different time points to mimic the stepwise embryonic development. [ 43 ] Likewise, the physical microenvironment changes during embryonic development, [ 44 ] and hereby the different differentiation steps may require different physical environments. Further the expression of the mechanical cell receptors integrins changes during stem cell differentiation.…”

Transcriptome landmarks of the functional maturity of rat beta-cells, from lactation to adulthood

“…Postnatal development of pancreatic beta-cells has become an important subject of research in recent years not only for the achievement of the capability to differentiate progenitor or reprogramed cells into insulin-secreting cells (Mayhew & Wells 2010, Schroeder 2012, Kumar et al 2014) but also to control beta-cell proliferation and maturation as a therapeutic approach in diabetes. Earlier work has suggested that cells that produce and secrete insulin can be generated using a variety of strategies (Sena et al 2010, Vetere et al 2014).…”

Chorionic and amniotic placental membrane‐derived stem cells, from gestational diabetic women, have distinct insulin secreting cell differentiation capacities

“…To explore induction further, we supplemented the culture medium with additional molecules to improve their maturation: GLP‐1, exendin‐4, and betacellulin. GLP‐1 was incorporated at Stage 3 of our original protocol to promote IPC maturation, whereas exendin‐4 and betacellulin have been widely used to promote the maturation and differentiation of MSCs into functional pancreatic cells (Kumar et al, ; Li, Lam, Xu, Lam, & Chung, ; Wong, ).…”