Development of insulin-producing cells from primitive biologic precursors

Abstract

Purpose of review: The differentiation of pluripotent and multipotent stem cells into insulin-producing cells has the potential to create a renewable supply of replacement beta cells with tremendous utility in the treatment of diabetes. The purpose of this review is to summarize recent advancements in the field, with emphasis on the limitations of this technology as it relates to the beta cell.

Recent findings: Multiple groups have developed successful in-vitro protocols to differentiate human embryonic stem cells and selected tissue specific stem cells into progenitors capable of insulin production and glucose-stimulated insulin secretion. The resulting cells are immature beta cell-like cells that coexpress multiple islet hormones and lack the full complement of genes necessary for normal function. Protocols that include in-vivo maturation in immune-compromised mice produce cells with a more mature phenotype.

Summary: Although tremendous progress has been made in differentiating stem cells into insulin-producing cells, there is still more research needed to produce a fully functional adult beta cell.

Figure 1. Four-step protocol for the differentiation of human embryonic stem cells into insulin producing cells

Depicted are the protocols used by Phillips et al (A) and Jiang et al (B). The factors used for differentiation are denoted above and below the arrows, and the relative stages of development are shown in boxes. The relevant genes expressed at each stage are shown above and below the boxes. Abbreviations: Bmp4, Bone morphogenetic protein 4; FGF18, Fibroblast growth factor 18; bFGF, basic Fibroblast growth factor; EGF, Epidermal growth factor; TGFα, Transforming growth factor α; IGF1, Insulin-like growth factor I; IGFII, Insulin-like growth factor II; VEGF, Vascular endothelial growth factor; HGF, Hepatocyte growth factor; PP, Pancreatic polypeptide; Gck, Glucokinase; Sur1, Sulfonylurea Receptor- 1; Gcg, glucagon; Sst, somatostatin. Adapted with permission from (A) Phillips et al. 2007. Stem Cells Dev; 16: 561–578 and (B) Jiang et al. 2007. Cell Res. 2007; 17: 333–344.

Figure 2. Expanded five-step protocol for the differentiation of human embryonicstem cells into insulin producing cells

Depicted are the protocols used by D’Amour et al (A) and Kroon et al (B). The factors used for differentiation are denoted above and below the arrows, and the relative stages of development are shown in boxes. The relevant genes expressed at each stage are shown within parentheses. Abbreviations: FGF10, Fibroblast growth factor 10; CYC, KAAD-cyclopamine; KGF, Keratinocyte growth factor; DAPT, γ-secretase inhibitor; IGFI, insulin-like growth factor I; HGF, Hepatocyte growth factor; Iapp; islet amyloid polypeptide; Gcg, glucagon; Sst, somatostatin; Ppy, pancreatic polypeptide; Ghrl, Ghrelin. Adapted with permission from (A) D'Amour et al. 2006. Nat Biotechnol; 24: 1392–1401 and (B) Kroon et al. 2008. Nat Biotechnol; 26: 443–452.