Abstract
The identification of secreted factors that can selectively stimulate the generation of insulin producing β-cells from stem and/or progenitor cells represent a significant step in the development of stem cell-based β-cell replacement therapy. By elucidating the molecular mechanisms that regulate the generation of β-cells during normal pancreatic development such putative factors may be identified. In the mouse, β-cells increase markedly in numbers from embryonic day (e) 14.5 and onwards, but the extra-cellular signal(s) that promotes the selective generation of β-cells at these stages remains to be identified. Here we show that the retinoic acid (RA) synthesizing enzyme Raldh1 is expressed in developing mouse and human pancreas at stages when β-cells are generated. We also provide evidence that RA induces the generation of Ngn3+ endocrine progenitor cells and stimulates their further differentiation into β-cells by activating a program of cell differentiation that recapitulates the normal temporal program of β-cell differentiation.
Highlights
The identification of secreted signal(s) that promotes the selective generation of b-cells from stem and/or progenitor cells represent a significant step in the development of stem cell-based b-cell replacement therapy for type 1 diabetes
Expression of Raldh1 in embryonic mouse pancreas was restricted to the branching ductal and acinar epithelium flanking the differentiating endocrine cells (Fig. S1b). qRT-PCR revealed that RALDH1 expression overlapped temporally with that of INSULIN in the developing human pancreas, whereas expression of RALDH 2, 3, and 12 was distinctly lower and/or barely detectable (Fig. 1b and data not shown)
We show that the retinoic acid (RA) synthesizing enzyme Raldh1 is expressed in the developing mouse and human pancreas at stages when b-cells are predominantly generated
Summary
The identification of secreted signal(s) that promotes the selective generation of b-cells from stem and/or progenitor cells represent a significant step in the development of stem cell-based b-cell replacement therapy for type 1 diabetes. Such signals may be identified by studying how b-cells are normally generated during pancreas development. No secreted signal has been identified that selectively promotes the generation of b-cells during pancreas development. Ngn3+ endocrine progenitor cells give rise to different endocrine cell types at different stages of mouse embryonic development [1,2,5]. Extra-cellular signals may induce distinct classes of Ngn3+ endocrine progenitor cells at different developmental stages
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