Xie Tianqin, Huang Qiming, Huang Qiulan, Huang Yanting, Liu Shuang, Zeng Haixia, Liu Jianping
Department of Endocrinology Medicine, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Nanchang of Jiangxi, 330006, China.
The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translation Medicine, Nanchang University, Nanchang of Jiangxi, China.
Stem Cell Res Ther. 2024 Jan 25;15(1):22. doi: 10.1186/s13287-023-03572-5.
In recent years, cell therapy has emerged as a new research direction in the treatment of diabetes. However, the underlying molecular mechanisms of mesenchymal stem cell (MSC) differentiation necessary to form such treatment have not been clarified.
In this study, human umbilical cord mesenchymal stem cells (HUC-MSCs) isolated from newborns were progressively induced into insulin-producing cells (IPCs) using small molecules. HUC-MSC (S0) and four induced stage (S1-S4) samples were prepared. We then performed transcriptome sequencing experiments to obtain the dynamic expression profiles of both mRNAs and long noncoding RNAs (lncRNAs).
We found that the number of differentially expressed lncRNAs and mRNAs trended downwards during differentiation. Gene Ontology (GO) analysis showed that the target genes of differentially expressed lncRNAs were associated with translation, cell adhesion, and cell connection. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that the NF-KB signalling pathway, MAPK signalling pathway, HIPPO signalling pathway, PI3K-Akt signalling pathway, and p53 signalling pathway were enriched in these differentially expressed lncRNA-targeting genes. We also found that the coexpression of the lncRNA CTBP1-AS2 with PROX1 and the lncRNAs AC009014.3 and GS1-72M22.1 with JARID2 mRNA was related to the development of pancreatic beta cells. Moreover, the coexpression of the lncRNAs: XLOC_ 050969, LINC00883, XLOC_050981, XLOC_050925, MAP3K14- AS1, RP11-148K1.12, and CTD2020K17.3 with p53, regulated insulin secretion by pancreatic beta cells.
In this study, HUC-MSCs combined with small molecule compounds were successfully induced into IPCs. Differentially expressed lncRNAs may regulate the insulin secretion of pancreatic beta cells by regulating multiple signalling pathways. The lncRNAs AC009014.3, Gs1-72m21.1, and CTBP1-AS2 may be involved in the development of pancreatic beta cells, and the lncRNAs: XLOC_050969, LINC00883, XLOC_050981, XLOC_050925, MAP3K14-AS1, RP11-148K1.12, and CTD2020K17.3 may be involved in regulating the insulin secretion of pancreatic beta cells, thus providing a lncRNA catalogue for future research regarding the mechanism of the transdifferentiation of HUC-MSCs into IPCs. It also provides a new theoretical basis for the transplantation of insulin-producing cells into diabetic patients in the future.
近年来，细胞疗法已成为糖尿病治疗的一个新研究方向。然而，形成这种治疗方法所必需的间充质干细胞（MSC）分化的潜在分子机制尚未阐明。
在本研究中，使用小分子将从新生儿分离的人脐带间充质干细胞（HUC-MSCs）逐步诱导为胰岛素分泌细胞（IPCs）。制备了HUC-MSC（S0）和四个诱导阶段（S1-S4）的样本。然后进行转录组测序实验，以获得mRNA和长链非编码RNA（lncRNAs）的动态表达谱。
我们发现，在分化过程中差异表达的lncRNAs和mRNAs数量呈下降趋势。基因本体（GO）分析表明，差异表达的lncRNAs的靶基因与翻译、细胞粘附和细胞连接有关。京都基因与基因组百科全书（KEGG）分析显示，NF-κB信号通路、MAPK信号通路、HIPPO信号通路、PI3K-Akt信号通路和p53信号通路在这些差异表达的lncRNA靶向基因中富集。我们还发现，lncRNA CTBP1-AS2与PROX1的共表达以及lncRNAs AC009014.3和GS1-72M22.1与JARID2 mRNA的共表达与胰腺β细胞的发育有关。此外，lncRNAs：XLOC_050969、LINC00883、XLOC_050981、XLOC_050925、MAP3K14-AS1、RP11-148K1.12和CTD2020K17.3与p53的共表达调节胰腺β细胞的胰岛素分泌。
在本研究中，HUC-MSCs与小分子化合物联合成功诱导为IPCs。差异表达的lncRNAs可能通过调节多种信号通路来调节胰腺β细胞的胰岛素分泌。lncRNAs AC009014.3、Gs1-72m21.1和CTBP1-AS2可能参与胰腺β细胞的发育，而lncRNAs：XLOC_050969、LINC00883、XLOC_050981、XLOC_050925、MAP3K14-AS1、RP11-148K1.12和CTD2020K17.3可能参与调节胰腺β细胞的胰岛素分泌，从而为未来关于HUC-MSCs向IPCs转分化机制的研究提供了一个lncRNA目录。它也为未来将胰岛素分泌细胞移植到糖尿病患者体内提供了新的理论依据。
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