Deconstructing pancreas development to reconstruct human islets from pluripotent stem cells

Abstract

There is considerable excitement about harnessing the potential of human stem cells to replace pancreatic islets that are destroyed in type 1 diabetes mellitus. However, our current understanding of the mechanisms underlying pancreas and islet ontogeny has come largely from the powerful genetic, developmental, and embryological approaches available in nonhuman organisms. Successful islet reconstruction from human pluripotent cells will require greater attention to "deconstructing" human pancreas and islet developmental biology and consistent application of conditional genetics, lineage tracing, and cell purification to stem cell biology.

Figure 1. Schematic Summarizing Two General Strategies to Assess and Improve the Quality of Progeny Produced from Pluripotent Stem Cell Cultures

(A) Marking of embryonic stem cell (ESC) or induced pluripotent stem cell (iPSC) progeny via Cre recombinase-based methods to induce expression of probes signaling sequential passage through a SOX17⁺, then NGN3⁺ and INSULIN⁺ fates. n1, n2, and n3 represent numbers of indicated, undifferentiated, or partially differentiated cells in cultures, where n1 < n2 ≪ n3. (B) Sequential flow cytometry-based enrichment to reduce heterogeneity of ESC or iPSC progeny at discrete stages of differentiation toward SOX17⁺, then NGN3⁺ and INSULIN⁺ fates.