Single-cell resolution analysis of the human pancreatic ductal progenitor cell niche
Single-cell resolution analysis of the human pancreatic ductal progenitor cell niche
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DOI：
10.1073/pnas.1918314117
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发表时间：
2020-05-19
影响因子：
11.1
通讯作者：
Dominguez-Bendala, Juan
中科院分区：
文献类型：
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作者：
Qadir, Mirza Muhammad Fahd;Alvarez-Cubela, Silvia;Dominguez-Bendala, Juan
我们已经描述了人胰腺主要胰管(MPD)内的多能祖细胞样细胞。它们表达PDX1、其替代表面标记P2RY1和骨形态发生蛋白(BMP)受体1A(BMPR1A)/激活素样激酶3(ALK3)，但不表达碳酸酐酶II(CALL)。在这里，我们报告了ALK3(Bright+-)分离的导管细胞的单细胞RNA测序(scRNA-seq)，这部分细胞含有BMP反应的祖细胞样细胞。我们的分析揭示了沿着两个主轴存在多个亚群，一个包含导管细胞分化阶段的梯度，另一个以具有向腺泡组织过渡表型的细胞为特征。在将ALK3(BREAT+)数据集与单细胞全胰腺转录组整合后，发现了第三个潜在的导管-内分泌轴。当移植到免疫缺陷小鼠体内时，P2RY1(+)/ALK3(Bright+)群体(富含PDX1(+)/ALK3(+)/CAII(-)细胞)分化为所有胰腺系，包括功能性P细胞。当宿主被系统地用ALK3激动剂处理时，这个过程被加速。我们在1型和2型糖尿病供者的MPD中发现了PDX1(+)/ALK3(+)/CALL(-)祖细胞样细胞，无论病程长短。我们的发现为药物激活原位祖细胞打开了大门。
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 (CAll). Here we report the single-cell RNA sequencing (scRNA-seq) of ALK3(bright+-)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 ALK3(bright+) dataset with a single-cell whole-pancreas transcriptome. When transplanted into immunodeficient mice, P2RY1(+)/ALK3(bright+) populations (enriched in PDX1(+)/ALK3(+)/CAII(-) cells) differentiate into all pancreatic lineages, including functional P-cells. This process is accelerated when hosts are treated systemically with an ALK3 agonist. We found PDX1(+)/ALK3(+)/CAll(-) 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.