McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
Cell Stem Cell. 2024 Nov 7;31(11):1591-1611.e8. doi: 10.1016/j.stem.2024.09.011. Epub 2024 Oct 14.
Organogenesis is a complex process that relies on a dynamic interplay between extrinsic factors originating from the microenvironment and tissue-specific intrinsic factors. For pancreatic endocrine cells, the local niche consists of acinar and ductal cells as well as neuronal, immune, endothelial, and stromal cells. Hematopoietic cells have been detected in human pancreas as early as 6 post-conception weeks, but whether they play a role during human endocrinogenesis remains unknown. To investigate this, we performed single-nucleus RNA sequencing (snRNA-seq) of the second-trimester human pancreas and identified a wide range of hematopoietic cells, including two distinct subsets of tissue-resident macrophages. Leveraging this discovery, we developed a co-culture system of human embryonic stem cell-derived endocrine-macrophage organoids to model their interaction in vitro. Here, we show that macrophages support the differentiation and viability of endocrine cells in vitro and enhance tissue engraftment, highlighting their potential role in tissue engineering strategies for diabetes.
器官发生是一个复杂的过程，依赖于来自微环境的外在因素与组织特异性内在因素之间的动态相互作用。对于胰腺内分泌细胞，局部小生境由腺泡和导管细胞以及神经元、免疫细胞、内皮细胞和基质细胞组成。早在受精后 6 周，造血细胞就已在人胰腺中被检测到，但它们在人内分泌发生过程中是否发挥作用尚不清楚。为了研究这一点，我们对人胰腺的第二个三个月进行了单细胞 RNA 测序 (snRNA-seq)，并鉴定出了广泛的造血细胞，包括两种不同的组织驻留巨噬细胞亚群。利用这一发现，我们开发了一种人胚胎干细胞衍生的内分泌-巨噬细胞类器官共培养系统，以在体外模拟它们的相互作用。在这里，我们表明巨噬细胞在体外支持内分泌细胞的分化和存活，并增强组织移植，突出了它们在糖尿病组织工程策略中的潜在作用。
