Single-cell resolution analysis of the human pancreatic ductal progenitor cell niche

Abstract

We have described multipotent progenitor-like cells within the major pancreatic ducts (MPDs) of the human pancreas. They express PDX1, its surrogate surface marker P2RY1, and the bone morphogenetic protein (BMP) receptor 1A (BMPR1A)/activin-like kinase 3 (ALK3), but not carbonic anhydrase II (CAII). Here we report the single-cell RNA sequencing (scRNA-seq) of ALK3bright+-sorted ductal cells, a fraction that harbors BMP-responsive progenitor-like cells. Our analysis unveiled the existence of multiple subpopulations along two major axes, one that encompasses a gradient of ductal cell differentiation stages, and another featuring cells with transitional phenotypes toward acinar tissue. A third potential ducto-endocrine axis is revealed upon integration of the ALK3bright+ dataset with a single-cell whole-pancreas transcriptome. When transplanted into immunodeficient mice, P2RY1+/ALK3bright+ populations (enriched in PDX1+/ALK3+/CAII− cells) differentiate into all pancreatic lineages, including functional β-cells. This process is accelerated when hosts are treated systemically with an ALK3 agonist. We found PDX1+/ALK3+/CAII− progenitor-like cells in the MPDs of types 1 and 2 diabetes donors, regardless of the duration of the disease. Our findings open the door to the pharmacological activation of progenitor cells in situ.

Spatial drivers and pre-cancer populations collaborate with the microenvironment in untreated and chemo-resistant pancreatic cancer

“…However, this is based on mouse models and the actual role this cell state plays in the development of PDAC remains unknown (Storz, 2017). A major hurdle has been the small numbers of acinar and ADM cells sampled from patients at single cell resolution (Peng et al, 2019; Qadir et al, 2020). We detected ADM populations in 20/21 cases, but focused our analyses to the two cases with the most substantial proportion of ADM cells in our cohort: HT122P1 and HT168P1 ( Figure 4A) .…”

Generation of a Single-Cell RNAseq Atlas of Murine Salivary Gland Development

“…Single-cell RNA sequencing (scRNAseq) has made it possible to discover new and rare cell types, explore cellular heterogeneity, and identify cell-fate-determining factors during developmental trajectories ( Hedlund and Deng, 2018 ; Zappia, et al., 2018 ). Recently, scRNAseq analyses in branching organs including the kidney ( Combes, et al., 2019 ), lung ( Angelidis, et al., 2019 ; Reyfman, et al., 2019 ), pancreas ( Qadir, et al., 2020 ; Byrnes, et al., 2018 ; Sznurkowska, et al., 2018 ), mammary gland ( Bach, et al., 2017 ), and many others have helped characterize tissue-specific heterogeneity and cell lineages during specific developmental stages or physiological conditions (i.e., embryonic development, aging, or injury). scRNAseq offers a unique opportunity to investigate acinar and duct development in salivary glands to identify cells that may be primed to produce acinar cells and define key transcription factors (TFs) involved in cell-fate decisions.…”

Multiomics single-cell analysis of human pancreatic islets reveals novel cellular states in health and type 1 diabetes

“…It is possible that these Hybrid cells in adulthood are multihormonal cells retained from early development or are formed when monohormonal cells differentiate into another cell type during adulthood. Most recently, it has been suggested that multipotent progenitor-like cells in humans defined as PDX1 + /ALK3 + /CAII − cells can differentiate into all pancreatic lineages including endocrine cells ( 44 ). While cells annotated as Hybrid cells in our study did not show high expression levels of ALK3 ( BMPR1A ) (fig.…”