Abstract
Spatiotemporal balancing of cellular proliferation and differentiation is crucial for postnatal tissue homoeostasis and organogenesis. During embryonic development, pancreatic progenitors simultaneously proliferate and differentiate into the endocrine, ductal and acinar lineages. Using in vivo clonal analysis in the founder population of the pancreas here we reveal highly heterogeneous contribution of single progenitors to organ formation. While some progenitors are bona fide multipotent and contribute progeny to all major pancreatic cell lineages, we also identify numerous unipotent endocrine and ducto-endocrine bipotent clones. Single-cell transcriptional profiling at E9.5 reveals that endocrine-committed cells are molecularly distinct, whereas multipotent and bipotent progenitors do not exhibit different expression profiles. Clone size and composition support a probabilistic model of cell fate allocation and in silico simulations predict a transient wave of acinar differentiation around E11.5, while endocrine differentiation is proportionally decreased. Increased proliferative capacity of outer progenitors is further proposed to impact clonal expansion.
Highlights
Spatiotemporal balancing of cellular proliferation and differentiation is crucial for postnatal tissue homoeostasis and organogenesis
Population-based lineage tracing has demonstrated the multipotency of the early pancreatic progenitors by virtue of their capability to give rise to progeny in the three major pancreatic lineages[12, 15,16,17, 21] (Fig. 1a), no study has addressed the clonal contribution of the proposed multipotent pancreatic progenitors (MPCs) to pancreas organogenesis
In this study, using clonal analysis of E9.5 pancreatic progenitors, when the pancreatic primordium has just been specified, we demonstrate that individual pancreatic progenitors contribute heterogeneously to pancreas organogenesis both in progeny size and fate composition
Summary
Spatiotemporal balancing of cellular proliferation and differentiation is crucial for postnatal tissue homoeostasis and organogenesis. In contrast to postnatal tissue homoeostasis, embryonic development of most organs occurs at a state of system disequilibrium, as a population of progenitors expands while simultaneously giving rise to differentiating progeny. While some progenitors are multipotent per se, giving rise to acinar, endocrine and ductal progeny, we demonstrate the existence of bipotent ducto-endocrine and unipotent endocrine cells forming half of the primordium. This population represents cells at different stages of progression on the endocrine differentiation path, including proliferative endocrinecommitted cells, and exhibits undetectable to low levels of PTF1A. We show that clonal expansion and fate heterogeneity are compatible with a simple model of probabilistic cell fate acquisition operating downstream of spatially controlled proliferative and fate-biasing patterning cues
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