PDF(Pubmed)
Abstract：
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.
摘要：
NEUROGENIN3+(NEUROG3+)细胞被认为是胰腺内分泌祖细胞。我们目前对人类NEUROG3+细胞分子程序的了解很大程度上是从小鼠研究中推断出来的。我们假设单细胞RNA-seq能够直接在人类中深入探索罕见的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，总共11,174个胰腺细胞中有10个NEUROG3+上皮细胞。值得注意的是，人NEUROG3+细胞聚集有成熟的胰腺细胞，ε细胞显示出最高频率的NEUROG3阳性。我们基于胰腺组织切片的免疫染色，在蛋白质水平上证实了NEUROG3与内分泌标志物的共表达以及ε细胞中NEUROG3细胞的高百分比。我们进一步鉴定了NEUROG3+细胞的独特遗传特征。调节网络推断揭示了新的转录因子，包括Prospero同源异型盒蛋白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，从我们的研究中获得的知识将加速β细胞再生疗法的发展，以治疗糖尿病。
