Abstract
NEUROGENIN3+ (NEUROG3+) cells are considered to be pancreatic endocrine progenitors. Our current knowledge on the molecular program of NEUROG3+ cells in humans is largely extrapolated from studies in mice. We hypothesized that single-cell RNA-seq enables in-depth exploration of the rare NEUROG3+ cells directly in humans. We aligned four large single-cell RNA-seq datasets from postnatal human pancreas. Our integrated analysis revealed 10 NEUROG3+ epithelial cells from a total of 11,174 pancreatic cells. Noticeably, human NEUROG3+ cells clustered with mature pancreatic cells and epsilon cells displayed the highest frequency of NEUROG3 positivity. We confirmed the co-expression of NEUROG3 with endocrine markers and the high percentage of NEUROG3+ cells among epsilon cells at the protein level based on immunostaining on pancreatic tissue sections. We further identified unique genetic signatures of the NEUROG3+ cells. Regulatory network inference revealed novel transcription factors including Prospero homeobox protein 1 (PROX1) may act jointly with NEUROG3. As NEUROG3 plays a central role in endocrine differentiation, knowledge gained from our study will accelerate the development of beta cell regeneration therapies to treat diabetes.
Highlights
Neurogenin 3 (Neurog3) encodes a basic helix-loop-helix transcription factor considered to be the master regulator of pancreatic endocrine differentiation
We identified a total of ten cell clusters including all the major pancreatic cell types, together with one cluster of potential doublets displaying a mixture of Molecular Profiling of NEUROG3+ Cells B
To investigate the regulatory framework of NEUROG3, we focused on transcription factors (TFs)
Summary
Neurogenin 3 (Neurog3) encodes a basic helix-loop-helix transcription factor considered to be the master regulator of pancreatic endocrine differentiation. Neurog deficient mice do not have any pancreatic endocrine cells, develop diabetes, and die shortly after birth [1]. NEUROG3 expression is biphasic [5]. It is first detected at embryonic day (E) 8.5 during the primary transition and the expression declines to near zero at E11.5. NEUROG3 expression becomes detectable again during the secondary transition and peaks at E15.5 [5]. NEUROG3+ cells are considered multipotent endocrine progenitor cells: They never co-express mature hormone markers; instead, they have the potential to differentiate into different endocrine lineages in vivo and in vitro [6]. In the adult mouse pancreas, under normal homeostasis, a small number of NEUROG3+ cells can be detected
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