Single-Cell Analysis Uncovers Clonal Acinar Cell Heterogeneity in the Adult Pancreas

Wollny, Damian; Zhao, Sheng; Everlien, Isabelle; Lun, Xiao-Kang; Brunken, Jan; Brune, D.; Ziebell, Frederik; Tabansky, Inna; Weichert, Wilko; Marciniak–Czochra, Anna; Martín-Villalba, Ana

doi:10.1016/j.devcel.2016.10.002

Cited by 91 publications

(89 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Progenitor Cell Signature and Early Differentiation Routes. Identification of a stem/progenitor cell population based solely on single-cell RNA sequencing (scRNA-seq) results is extremely difficult, particularly in tissues with rare such cells (36,37). Our FACS analysis indicated that Aldh1b1-expressing adult pancreatic cells represent just 0.5% of the cells in the adult organ.…”

Section: Aldh1b1-expressing Cells Are Necessary and Sufficient To Genmentioning

confidence: 89%

Aldh1b1 expression defines progenitor cells in the adult pancreas and is required for Kras-induced pancreatic cancer

Mameishvili

Serafimidis

Iwaszkiewicz

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The presence of progenitor or stem cells in the adult pancreas and their potential involvement in homeostasis and cancer development remain unresolved issues. Here, we show that mouse centroacinar cells can be identified and isolated by virtue of the mitochondrial enzyme Aldh1b1 that they uniquely express. These cells are necessary and sufficient for the formation of self-renewing adult pancreatic organoids in an Aldh1b1-dependent manner. Aldh1b1-expressing centroacinar cells are largely quiescent, self-renew, and, as shown by genetic lineage tracing, contribute to all 3 pancreatic lineages in the adult organ under homeostatic conditions. Single-cell RNA sequencing analysis of these cells identified a progenitor cell population, established its molecular signature, and determined distinct differentiation pathways to early progenitors. A distinct feature of these progenitor cells is the preferential expression of small GTPases, including Kras, suggesting that they might be susceptible to Kras-driven oncogenic transformation. This finding and the overexpression of Aldh1b1 in human and mouse pancreatic cancers, driven by activated Kras, prompted us to examine the involvement of Aldh1b1 in oncogenesis. We demonstrated genetically that ablation of Aldh1b1 completely abrogates tumor development in a mouse model of KrasG12D-induced pancreatic cancer.

show abstract

Section: Aldh1b1-expressing Cells Are Necessary and Sufficient To Genmentioning

confidence: 89%

Aldh1b1 expression defines progenitor cells in the adult pancreas and is required for Kras-induced pancreatic cancer

Mameishvili

Serafimidis

Iwaszkiewicz

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Short-lived progenitors are able to interconvert into stem-like cells after tissue damage,10, 23, 24 but it remains unclear whether such interconverted cells can develop into cancer. In organs such as pancreas and liver that do not frequently divide in the normal state, cancers may arise from more differentiated acinar and hepatocyte compartments, but recent evidence has suggested the existence within these compartments of specific facultative reserve stem-like cells, which preferentially may contribute to regeneration and give rise to cancer 25, 26, 27, 28, 29, 30. In any case, although it may be possible for non–stem cells to contribute to gastric regeneration and cancer, chronic inflammation associated with H pylori infection typically induces a regenerative and reparative response orchestrated by tissue resident stem cells, 31 which are activated and expand as part of an injury response, predisposing to the acquisition of genetic and epigenetic alterations (Figure 1).…”

mentioning

confidence: 99%

The Origins of Gastric Cancer From Gastric Stem Cells: Lessons From Mouse Models

Hayakawa

Fox

Wang

2017

Cellular and Molecular Gastroenterology and Hepatology

View full text Add to dashboard Cite

The cellular origin of digestive cancers has been a long-standing question in the cancer field. Mouse models have identified long-lived stem cells in most organ systems, including the luminal gastrointestinal tract, and numerous studies have pointed to tissue resident stem cells as the main cellular origin of cancer. During gastric carcinogenesis, chronic inflammation induces genetic and epigenetic alterations in long-lived stem cells, along with expansion of stem cell niches, eventually leading to invasive cancer. The gastric corpus and antrum have distinct stem cells and stem cell niches, suggesting differential regulation of cancer initiation at the 2 sites. In this short review, we discuss recent experimental models and human studies, which provide important insights into the pathogenesis of gastric cancer.

show abstract

“…S3C, S3D), which can guide follow‐up experiments aimed at their isolation and characterization or validate previously reported associations. For example, it has been recently suggested that the TF STMN1 may act as a marker for progenitor‐like acinar cells . Our data supports this association given that its expression is highly correlated with acinar SSPCs in both pancreas datasets (Supporting Information Table S2; Fig.…”

Section: Resultsmentioning

confidence: 99%

Cross-Tissue Identification of Somatic Stem and Progenitor Cells Using a Single-Cell RNA-Sequencing Derived Gene Signature

et al. 2017

View full text Add to dashboard Cite

A long-standing question in biology is whether multipotent somatic stem and progenitor cells (SSPCs) feature molecular properties that could guide their system-independent identification. Population-based transcriptomic studies have so far not been able to provide a definite answer, given the rarity and heterogeneous nature of these cells. Here, we exploited the resolving power of single-cell RNA-sequencing to develop a computational model that is able to accurately distinguish SSPCs from differentiated cells across tissues. The resulting classifier is based on the combined expression of 23 genes including known players in multipotency, proliferation, and tumorigenesis, as well as novel ones, such as Lcp1 and Vgll4 that we functionally validate in intestinal organoids. We show how this approach enables the identification of stem-like cells in still ambiguous systems such as the pancreas and the epidermis as well as the exploration of lineage commitment hierarchies, thus facilitating the study of biological processes such as cellular differentiation, tissue regeneration, and cancer. Stem Cells 2017;35:2390-2402.

show abstract

Single-Cell Analysis Uncovers Clonal Acinar Cell Heterogeneity in the Adult Pancreas

Cited by 91 publications

References 55 publications

Aldh1b1 expression defines progenitor cells in the adult pancreas and is required for Kras-induced pancreatic cancer

Aldh1b1 expression defines progenitor cells in the adult pancreas and is required for Kras-induced pancreatic cancer

The Origins of Gastric Cancer From Gastric Stem Cells: Lessons From Mouse Models

Cross-Tissue Identification of Somatic Stem and Progenitor Cells Using a Single-Cell RNA-Sequencing Derived Gene Signature

Contact Info

Product

Resources

About