Cell Cycle–Dependent Differentiation Dynamics Balances Growth and Endocrine Differentiation in the Pancreas

Abstract

Organogenesis relies on the spatiotemporal balancing of differentiation and proliferation driven by an expanding pool of progenitor cells. In the mouse pancreas, lineage tracing at the population level has shown that the expanding pancreas progenitors can initially give rise to all endocrine, ductal, and acinar cells but become bipotent by embryonic day 13.5, giving rise to endocrine cells and ductal cells. However, the dynamics of individual progenitors balancing self-renewal and lineage-specific differentiation has never been described. Using three-dimensional live imaging and in vivo clonal analysis, we reveal the contribution of individual cells to the global behaviour and demonstrate three modes of progenitor divisions: symmetric renewing, symmetric endocrinogenic, and asymmetric generating a progenitor and an endocrine progenitor. Quantitative analysis shows that the endocrine differentiation process is consistent with a simple model of cell cycle–dependent stochastic priming of progenitors to endocrine fate. The findings provide insights to define control parameters to optimize the generation of β-cells in vitro.

Feedback control of growth, differentiation, and morphogenesis of pancreatic endocrine progenitors in an epithelial plexus niche

“…We estimate ∼12 h for both the cell cycle period and Ngn3 protein-positive period in vivo. Consistent with recent reporter-based single-cell live-imaging analyses in explants (Kim et al 2015), the rapid EdU acquisition in Ngn3 + populations indicates that a large portion of endocrinecommitting cells acquire Ngn3 immunoreactivity shortly after a division event (Fig. 4).…”

Cycling through developmental decisions: how cell cycle dynamics control pluripotency, differentiation and reprogramming

“…This principle also broadly applies to mammalian embryogenesis. During pancreatic development, for example, endocrine progenitor cells adopt different fates depending on whether they are exposed to differentiation signals in early or late G1 phase (Kim et al, 2015). If exposure to signals occurs in early G1 phase, cells differentiate and exit the cell cycle through an asymmetric cell division.…”

Precommitment low-level Neurog3 expression defines a long-lived mitotic endocrine-biased progenitor pool that drives production of endocrine-committed cells

“…4A,B (Puri and Hebrok 2007;Kim et al 2015). To determine whether the observed division events produced Neurog3…”

“…Recently, Kim et al (2015) published a real-time analysis of mitotic Pdx1 GFP -and Neurog3 RFP -expressing cells. They reported division events for Pdx1-expressing cells that were symmetric (for both progenitor renewal and terminal differentiation) and asymmetric (producing one Pdx1 + Sox9 + daughter and one Neurog3 + daughter).…”