Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL, United States.
Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, United States.
Front Endocrinol (Lausanne). 2021 Sep 8;12:736286. doi: 10.3389/fendo.2021.736286. eCollection 2021.
NEUROGENIN3+ (NEUROG3+) cells are considered to be pancreatic endocrine progenitors. Our current knowledge on the molecular program of NEUROG3+ cells in humans is largely extrapolated from studies in mice. We hypothesized that single-cell RNA-seq enables in-depth exploration of the rare NEUROG3+ cells directly in humans. We aligned four large single-cell RNA-seq datasets from postnatal human pancreas. Our integrated analysis revealed 10 NEUROG3+ epithelial cells from a total of 11,174 pancreatic cells. Noticeably, human NEUROG3+ cells clustered with mature pancreatic cells and epsilon cells displayed the highest frequency of NEUROG3 positivity. We confirmed the co-expression of NEUROG3 with endocrine markers and the high percentage of NEUROG3+ cells among epsilon cells at the protein level based on immunostaining on pancreatic tissue sections. We further identified unique genetic signatures of the NEUROG3+ cells. Regulatory network inference revealed novel transcription factors including Prospero homeobox protein 1 (PROX1) may act jointly with NEUROG3. As NEUROG3 plays a central role in endocrine differentiation, knowledge gained from our study will accelerate the development of beta cell regeneration therapies to treat diabetes.
神经元素 3+（NEUROG3+）细胞被认为是胰腺内分泌祖细胞。我们目前对人类 NEUROG3+细胞的分子程序的了解在很大程度上是从对老鼠的研究中推断出来的。我们假设单细胞 RNA 测序能够深入探索人类中罕见的 NEUROG3+细胞。我们对来自出生后人类胰腺的四个大型单细胞 RNA-seq 数据集进行了比对。我们的综合分析显示，在总共 11174 个胰腺细胞中，有 10 个 NEUROG3+上皮细胞。值得注意的是，人类 NEUROG3+细胞与成熟的胰腺细胞聚类，而 epsilon 细胞显示出最高的 NEUROG3 阳性率。我们通过对胰腺组织切片进行免疫染色，在蛋白质水平上证实了 NEUROG3 与内分泌标记物的共表达，以及 NEUROG3+细胞在 epsilon 细胞中的高比例。我们进一步确定了 NEUROG3+细胞的独特遗传特征。调控网络推断揭示了新的转录因子，包括 Prospero 同源盒蛋白 1（PROX1），可能与 NEUROG3 共同作用。由于 NEUROG3 在内分泌分化中起着核心作用，我们的研究结果将加速开发用于治疗糖尿病的β细胞再生治疗方法。
