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.
Highlights
The pancreas is an organ performing vital exocrine and endocrine roles in nutrient metabolism and glucose homeostasis
Quantitative analysis shows that endocrine differentiation is largely stochastic and that the probability of progenitor cell differentiation by the end of mid-gestation is about 20%
NEUROG3+ endocrine progenitors originate from pancreatic progenitors expressing PDX1/ SOX9/HNF1B during the early phases of multipotent pancreatic progenitor cells (MPCs) expansion and during the secondary transition spanning E12.5–15.5, with specific endocrine subtypes being specified during discrete time windows [10]
Summary
The pancreas is an organ performing vital exocrine and endocrine roles in nutrient metabolism and glucose homeostasis. Multipotent pancreatic progenitor cells (MPCs) emerge from the endoderm around embryonic day 9.0 (E9.0) [1]. This population, characterized by the expression of transcription factors PDX1 (GenBank NP_032840), SOX9 (GenBank NP_035578), and HNF1B (GenBank AAH25189), eventually gives rise to all three major cell lineages of the pancreas: endocrine, acinar, and ductal [2,3,4]. Whereas the majority of NEUROG3+ endocrine progenitors are post-mitotic [11] and unipotent, giving rise to only one endocrine subtype [12], we do not know whether individual PDX1/SOX9/HNF1B pancreatic progenitors give rise to both ductal and endocrine cells or are heterogeneous, encompassing cells with pre-specified lineage-restricted potentials. We ask how individual pancreas progenitors contribute to the population dynamics enabling organ expansion and endocrine differentiation
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
