Production of pancreatic hormone–expressing endocrine cells from human embryonic stem cells

Abstract

Of paramount importance for the development of cell therapies to treat diabetes is the production of sufficient numbers of pancreatic endocrine cells that function similarly to primary islets. We have developed a differentiation process that converts human embryonic stem (hES) cells to endocrine cells capable of synthesizing the pancreatic hormones insulin, glucagon, somatostatin, pancreatic polypeptide and ghrelin. This process mimics in vivo pancreatic organogenesis by directing cells through stages resembling definitive endoderm, gut-tube endoderm, pancreatic endoderm and endocrine precursor--en route to cells that express endocrine hormones. The hES cell-derived insulin-expressing cells have an insulin content approaching that of adult islets. Similar to fetal beta-cells, they release C-peptide in response to multiple secretory stimuli, but only minimally to glucose. Production of these hES cell-derived endocrine cells may represent a critical step in the development of a renewable source of cells for diabetes cell therapy.

Murine Embryonic Stem Cell–Derived Pancreatic Acinar Cells Recapitulate Features of Early Pancreatic Differentiation

“…Via embryoid body (EB) formation, endodermal precursors can be specified into endocrine and exocrine lineages in a process that partially recapitulates early pancreatic development (25;26). Despite promising advances (27), this process is very inefficient. Here, we aimed at generating ES cells having activated a pancreatic acinar differentiation program in order to apply this knowledge to study exocrine pancreatic diseases.…”

Differentiation of Stem Cells into Insulin-Producing Cells: Current Status and Challenges

“…Two signaling pathways, the Wnt and transforming growth factor (TGF)-b are crucial to induce formation of the definitive endoderm. Differentiation of ESCs into definitive endoderm can be achieved via treatment with activin-A and Wnt3a and confirmed by expression of endodermal markers, including SOX17, FOXA2, GATA4, CXCR4, and cerberus (D'Amour et al 2006;Kroon et al 2008). Nodal, CHIR99021, IDE1 and IDE2 are another molecules that induce development of the definitive endoderm (Borowiak et al 2009;Takenaga et al 2007).…”

“…However, the percentage of insulin-positive cells generated using this protocol is relatively low around 7 % of total cell population. Moreover C-peptide release by these cells is marginal in response to glucose (D'Amour et al 2006). More recently the same group reported more efficient strategy to differentiate ESCs into IPCs.…”

Polymers to direct cell fate by controlling the microenvironment

“…Multiple factors can be delivered sequentially, simultaneously, or both, and these techniques can be combined with DNA or RNAi delivery to enable long-standing protein expression [35] or abrogation of expression [36]. The physiologic relevance of control over factors availability in time and space has been demonstrated by differentiation of stem cells [37], regulation over the extent of vascular network maturation with time [31], enhanced delivery and integration of transplanted cells [38], and the simultaneous formation of vascular networks at distinct stages of maturation in distinct spatial compartments [28].…”