Single-Cell RNA-seq Reveals a Subpopulation of Cells Underlying β Cell Expansion in the Postnatal Islets

Abstract

Pancreatic β cells undergo significant expansion and maturation during human and rodent postnatal development. Here, we used single-cell RNA-seq to characterize gene expression patterns at various stages of mouse islet cell development and uncovered a population of cells that is most abundant during the early postnatal period. This cell population lacks expression of FLTP and expresses PDGF receptors. Each of these conditions have previously been associated with proliferative capacity in β cells suggesting that we have identified the proliferative competent of β cell mass expansion. The subpopulation co-express many endocrine lineage-specific genes and exhibits a downregulation of genes associated with mitochondrial oxidative phosphorylation and global protein synthesis. It has upregulated activity of genes in the Wnt, Hippo, PDGF, and Notch pathways and has a significantly higher proliferation potential than the more mature β population. We show that activity of the Notch pathway is required in postnatal β cell expansion where it serves to maintain an undifferentiated endocrine state in the polyhormonal cell population. Collectively, our study identifies a proliferative, progenitor-like cell subpopulation in the postnatal islet as the source of postnatal β cell expansion.

Mitogen Synergy: An Emerging Route to Boosting Human Beta Cell Proliferation

“…Yet, it might be critical to evaluate it in detail as for example different types of endocrine cells within islets regulate each other's physiology. Zhou et al (2008) were the first to demonstrate the successful redifferentiation of pancreatic exocrine cells in adult mice into cells closely resembling beta cells, through the ectopic expression of three key beta cell regulatory transcription factors -MafA, Pdx1, and Ngn3 -in acinar cells. In vitro transdifferentiation into beta cells has also been achieved with murine non-pancreatic cells, including endocrine cells in the intestine or stomach (Chen et al, 2014;Ariyachet et al, 2016;Baeyens et al, 2018).…”

“…These hub cells are relatively rare beta cells (<10% of total beta cells) acquired with pacemaker-like properties that orchestrate the activities of the remaining "follower" beta cells during the insulin response (Johnston et al, 2016). Second, as described above, there is a growing body of evidence to suggest that higher levels of proliferation are associated with a relatively immature beta cell profile both in mice (Bader et al, 2016;Klochendler et al, 2016;Zeng et al, 2017;Puri et al, 2018;Zhang et al, 2018) and humans (Klochendler et al, 2016;Xin et al, 2018;Rosado-Olivieri et al, 2020). Hub beta cells have also been described as less mature than other beta cells (Johnston et al, 2016).…”