Promotion of β-Cell Differentiation in Pancreatic Precursor Cells by Adult Islet Cells

Abstract

It is thought that differentiation of beta-cell precursors into mature cells is largely autonomous, but under certain conditions differentiation can be modified by external factors. The factors that modify beta-cell differentiation have not been identified. In this study, we tested whether adult islet cells can affect the differentiation process in mouse and human pancreatic anlage cells. We assessed beta-cell proliferation and differentiation in mouse and human pancreatic anlage cells cocultured with adult islet cells or betaTC3 cells using cellular, molecular, and immunohistochemical methods. Differentiation of murine anlage cells into beta-cells was induced by mature islet cells. It was specific for beta-cells and not a general feature of endodermal derived cells. beta-Cell differentiation required cell-cell contact. The induced cells acquired features of mature beta-cells including increased expression of beta-cell transcription factors and surface expression of receptor for stromal cell-derived factor 1 and glucose transporter-2 (GLUT-2). They secreted insulin in response to glucose and could correct hyperglycemia in vivo when cotransplanted with vascular cells. Human pancreatic anlage cells responded in a similar manner and showed increased expression of pancreatic duodenal homeobox 1 and v-maf musculoaponeurotic fibrosarcoma oncogene homolog A and increased production of proinsulin when cocultured with adult islets. We conclude that mature beta-cells can modify the differentiation of precursor cells and suggest a mechanism whereby changes in differentiation of beta-cells can be affected by other beta-cells.

A factor(s) secreted from MIN-6 β-cells stimulates differentiation of definitive endoderm enriched embryonic stem cells towards a pancreatic lineage

“…This confirms and extends previous findings that pancreatic extracts [23,24] and adult islets cells [25] may provide signals to precursor cells that affect differentiation to endocrine pancreatic lineages.…”

Extracellular CADM1 interactions influence insulin secretion by rat and human islet β-cells and promote clustering of syntaxin-1

“…There is evidence to suggest that similar transcellular interactions help direct the formation of the insulin exocytic machinery. This evidence includes the dependence of ␤-cell function and maturation on contact between ␤-cells as well as the tendency for exocytic complexes to form beneath the ␤-cell plasma membrane at sites where such cell-to-cell contact occurs (12,16,27).…”

“…␤-CELLS REQUIRE CONTACT WITH OTHER ␤-CELLS to mature and function normally (12,19,27). This contact gives rise to transcellular protein interactions that drive the maturation and help regulate the function of the insulin secretory machinery (19,27,31,40,50).…”

Co-culture with Mature Islet Cells Augments the Differentiation of Insulin-Producing Cells from Pluripotent Stem Cells

“…In conditioned medium (CM) experiments, mature islet cells were cultured in 12-well plates (100 islets/well) using only DF12 medium, and islet cell-derived CM was collected after 3 days of culture. Co-culture studies involving cell-cell contact were performed as described previously [20]. Briefly, isolated islets were used intact or dissociated into single cells using enzyme-free dissociation buffer (Invitrogen).…”

“…External factors derived from fetal pancreatic tissues have also been reported to induce the growth and differentiation of islet cells [9,10]. Chen et al induced the pancreatic anlage to differentiate into mature β-cells in vitro by providing direct contact with adult islet cells [20]. In this context, factors derived from adult islet cells could affect β-cell differentiation under certain conditions, such as pancreatectomy.…”