Bulk and single-cell RNA-seq of human fetal pancreatic organoids

The mammalian pancreas consists of three epithelial compartments: the
acini and ducts of the exocrine pancreas and the endocrine islets of
Langerhans. Murine studies indicate that these three compartments derive
from a transient, common pancreatic progenitor. Here, we report the
derivation of 18 human fetal pancreas organoid (hfPO) lines from
gestational week 8-17 (8-17GW) fetal pancreas samples. Four of these
lines, derived from 15-16GW samples, generate acinar-, ductal- and
endocrine lineage cells while expanding exponentially for >2 years
under optimized culture conditions. Single-cell RNA sequencing identifies
rare LGR5+ cells in the fetal pancreas and hfPOs as the root of the
developmental hierarchy. These LGR5+ cells share multiple markers with
adult gastrointestinal tract stem cells. Organoids derived from single
LGR5+ organoid-derived cells recapitulate this tri-potency in vitro. We
describe a human fetal tri-potent stem/progenitor cell, capable of
long-term expansion in vitro and of generating all three pancreatic cell
lineages.