A Single-Cell Atlas of the Murine Pancreatic Ductal Tree Identifies Novel Cell Populations With Potential Implications in Pancreas Regeneration and Exocrine Pathogenesis,Gastroenterology

当前位置： X-MOL 学术 › Gastroenterology › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

A Single-Cell Atlas of the Murine Pancreatic Ductal Tree Identifies Novel Cell Populations With Potential Implications in Pancreas Regeneration and Exocrine Pathogenesis
Gastroenterology ( IF 25.7 ) Pub Date : 2024-06-21 , DOI: 10.1053/j.gastro.2024.06.008
Ángel Fernández ₁ , Joan Casamitjana ₂ , Adrián Holguín-Horcajo ₂ , Katarina Coolens ₃ , Loris Mularoni ₄ , Li Guo ₅ , Olga Hartwig ₆ , Tim Düking ₆ , Noemi Vidal ₇ , Lincoln N Strickland ₈ , Lorenzo Pasquali ₉ , Jennifer M Bailey-Lundberg ₈ , Ilse Rooman ₃ , Yue J Wang ₅ , Meritxell Rovira ₁₀

Affiliation

Department of Physiological Science, School of Medicine, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain; Pancreas Regeneration: Pancreatic Progenitors and Their Niche Group, Regenerative Medicine Program, Instituto de Investigación Biomédica de Bellvitge - IDIBELL, L'Hospitalet de Llobregat, Spain; Program for Advancing the Clinical Translation of Regenerative Medicine of Catalonia, P-CMR[C], L'Hospitalet de Llobregat, Spain; Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
Department of Physiological Science, School of Medicine, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain; Pancreas Regeneration: Pancreatic Progenitors and Their Niche Group, Regenerative Medicine Program, Instituto de Investigación Biomédica de Bellvitge - IDIBELL, L'Hospitalet de Llobregat, Spain; Program for Advancing the Clinical Translation of Regenerative Medicine of Catalonia, P-CMR[C], L'Hospitalet de Llobregat, Spain.
Vrije Universiteit Brussel, Translational Oncology Research Center, Laboratory for Medical and Molecular Oncology, Brussels, Belgium.
Program for Advancing the Clinical Translation of Regenerative Medicine of Catalonia, P-CMR[C], L'Hospitalet de Llobregat, Spain.
Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, Florida.
Miltenyi Biotec B.V. & Co KG, Bergisch Gladbach, Germany.
Pathology Department, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain.
Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas.
Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
Department of Physiological Science, School of Medicine, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain; Pancreas Regeneration: Pancreatic Progenitors and Their Niche Group, Regenerative Medicine Program, Instituto de Investigación Biomédica de Bellvitge - IDIBELL, L'Hospitalet de Llobregat, Spain; Program for Advancing the Clinical Translation of Regenerative Medicine of Catalonia, P-CMR[C], L'Hospitalet de Llobregat, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain.

Background & Aims

Pancreatic ducts form an intricate network of tubules that secrete bicarbonate and drive acinar secretions into the duodenum. This network is formed by centroacinar cells, terminal, intercalated, intracalated ducts, and the main pancreatic duct. Ductal heterogeneity at the single-cell level has been poorly characterized; therefore, our understanding of the role of ductal cells in pancreas regeneration and exocrine pathogenesis has been hampered by the limited knowledge and unexplained diversity within the ductal network.

Methods

We used single cell RNA sequencing to comprehensively characterize mouse ductal heterogeneity at single-cell resolution of the entire ductal epithelium from centroacinar cells to the main duct. Moreover, we used organoid cultures, injury models, and pancreatic tumor samples to interrogate the role of novel ductal populations in pancreas regeneration and exocrine pathogenesis.

Results

We have identified the coexistence of 15 ductal populations within the healthy pancreas and characterized their organoid formation capacity and endocrine differentiation potential. Cluster isolation and subsequent culturing let us identify ductal cell populations with high organoid formation capacity and endocrine and exocrine differentiation potential in vitro, including a Wnt-responsive population, a ciliated population, and Flrt3⁺ cells. Moreover, we have characterized the location of these novel ductal populations in healthy pancreas, chronic pancreatitis, and tumor samples. The expression of Wnt-responsive, interferon-responsive, and epithelial-to-mesenchymal transition population markers increases in chronic pancreatitis and tumor samples.

Conclusions

In light of our discovery of previously unidentified ductal populations, we unmask potential roles of specific ductal populations in pancreas regeneration and exocrine pathogenesis. Thus, novel lineage-tracing models are needed to investigate ductal-specific populations in vivo.

中文翻译：

小鼠胰管树的单细胞图谱确定了对胰腺再生和外分泌发病机制具有潜在影响的新型细胞群

背景和目标

胰管形成一个错综复杂的小管网络，分泌碳酸氢盐并将腺泡分泌物驱赶到十二指肠。该网络由中心腺泡细胞、终末、插层、闰内导管和主胰管形成。单细胞水平的导管异质性表征不佳;因此，我们对导管细胞在胰腺再生和外分泌发病机制中的作用的理解受到知识有限和无法解释的导管网络多样性的阻碍。

方法

我们使用单细胞 RNA 测序在从中心腺泡细胞到主导管的整个导管上皮的单细胞分辨率下全面表征小鼠导管异质性。此外，我们使用类器官培养、损伤模型和胰腺肿瘤样本来询问新的导管群体在胰腺再生和外分泌发病机制中的作用。

结果

我们已经确定了健康胰腺内 15 个导管群的共存，并表征了它们的类器官形成能力和内分泌分化潜力。簇分离和随后的培养使我们能够在体外鉴定具有高类器官形成能力以及内分泌和外分泌分化潜力的导管细胞群，包括 Wnt 反应性群体、纤毛细胞群和 Flrt3 ⁺ 细胞。此外，我们还表征了这些新的导管群体在健康胰腺、慢性胰腺炎和肿瘤样本中的位置。Wnt 反应性、干扰素反应性和上皮-间充质转化群体标志物的表达在慢性胰腺炎和肿瘤样本中增加。