| Citation: |
Dong Boqing, Wang Ying, Wang Chenge, et al. Analysis of the molecular mechanism of pancreatic islet ischemic injury and identification of core transcription factors based on single-cell transcriptomics[J]. ORGAN TRANSPLANTATION, 2024, 15(6): 920-927. DOI: 10.3969/j.issn.1674-7445.2024173
|
To explore the molecular mechanisms and cell-cell interactions in the injury process of pancreatic islet transplantation.
Single-cell transcriptome data from mouse islets treated with inflammatory factors were used, and data processing was performed using the Seurat package, with integrated data to remove batch effects. Cell subpopulations were annotated based on known markers. Cell-cell interactions in the inflammatory factor-treated group were analyzed using the CellChat package, and inferred based on the expression of cell surface receptors and ligands. Gene set enrichment analysis was used to clarify the biological processes enriched in β-cells after treatment with inflammatory factors. Finally, differentially expressed transcription factors were identified and verified using microarray datasets of donor islet ischemic injury and Western blotting.
A total of 7 different cell subpopulations were found in mouse islets, with β-cells being the most abundant. Cell-cell interaction network analysis showed that the number and strength of interactions between ductal cells and other cells were the highest. Gene set enrichment analysis showed that after treatment with inflammatory factors, the immune response was positively enriched in β-cells, while peptide hormone metabolism, bile acid metabolism, and ion homeostasis were downregulated. The common differential transcription factors identified in the mouse single-cell transcriptome and the microarray dataset of donor islet ischemic injury were early growth response 1 (EGR1), nuclear factor-κB inhibitor α (NFKBIA), and activating transcription factor 3 (ATF3). Among them, NFKBIA and ATF3 were upregulated, while EGR1 was downregulated. The expression of EGR1 protein was downregulated after 24 h, 48 h, and 72 h of cold ischemia. Conclusions EGR1 is a transcription factor closely related to islet cold ischemia, and future research should focus on the specific mechanisms of EGR1 and its downstream target genes, in order to provide more effective strategies for clinical treatment of islet transplantation.
| [1] |
SYED FZ. Type 1 diabetes mellitus[J]. Ann Intern Med, 2022, 175(3): ITC33-ITC48. DOI: 10.7326/AITC202203150.
|
| [2] |
HAJI M, ERQOU S, FONAROW GC, et al. Type 1 diabetes and risk of heart failure: a systematic review and meta-analysis[J]. Diabetes Res Clin Pract, 2023, 202: 110805. DOI: 10.1016/j.diabres.2023.110805.
|
| [3] |
PULLEN LC. Islet cell transplantation hits a milestone[J]. Am J Transplant, 2021, 21(8): 2625-2626. DOI: 10.1111/ajt.16039.
|
| [4] |
殷浩. 胰岛移植最新进展及前景展望[J]. 器官移植, 2019, 5(6): 678-683. DOI: 10.3969/j.issn.1674-7445.2019.06.008.
YIN H. The latest research progress and prospect of islet transplantation[J]. Organ Transplant, 2019, 5(6): 678-683. DOI: 10.3969/j.issn.1674-7445.2019.06.008.
|
| [5] |
GRENKO CM, TAYLOR HJ, BONNYCASTLE LL, et al. Single-cell transcriptomic profiling of human pancreatic islets reveals genes responsive to glucose exposure over 24 h[J]. Diabetologia, 2024, 67(10): 2246-2259. DOI: 10.1007/s00125-024-06214-4.
|
| [6] |
DAVIDSON RK, WU W, KANOJIA S, et al. The SWI/SNF chromatin remodelling complex regulates pancreatic endocrine cell expansion and differentiation in mice in vivo[J]. Diabetologia, 2024, 67(10): 2275-2288. DOI: 10.1007/s00125-024-06211-7.
|
| [7] |
JIN S, GUERRERO-JUAREZ CF, ZHANG L, et al. Inference and analysis of cell-cell communication using CellChat[J]. Nat Commun, 2021, 12(1): 1088. DOI: 10.1038/s41467-021-21246-9.
|
| [8] |
CHEN P, YAO F, LU Y, et al. Single-cell landscape of mouse islet allograft and syngeneic graft[J]. Front Immunol, 2022, 13: 853349. DOI: 10.3389/fimmu.2022.853349.
|
| [9] |
FU Q, JIANG H, QIAN Y, et al. Single-cell RNA sequencing combined with single-cell proteomics identifies the metabolic adaptation of islet cell subpopulations to high-fat diet in mice[J]. Diabetologia, 2023, 66(4): 724-740. DOI: 10.1007/s00125-022-05849-5.
|
| [10] |
JAMES SHAPIRO AM, POKRYWCZYNSKA M, RICORDI C. Clinical pancreatic islet transplantation[J]. Nat Rev Endocrinol, 2017, 13(5): 268-277. DOI: 10.1038/nrendo.2016.178.
|
| [11] |
HUANG X, MOORE DJ, KETCHUM RJ, et al. Resolving the conundrum of islet transplantation by linking metabolic dysregulation, inflammation, and immune regulation[J]. Endocr Rev, 2008, 29(5): 603-630. DOI: 10.1210/er.2008-0006.
|
| [12] |
WALKER S, APPARI M, FORBES S. Considerations and challenges of islet transplantation and future therapies on the horizon[J]. Am J Physiol Endocrinol Metab, 2022, 322(2): E109-E117. DOI: 10.1152/ajpendo.00310.2021.
|
| [13] |
WANG C, DU X, FU F, et al. Adiponectin gene therapy prevents islet loss after transplantation[J]. J Cell Mol Med, 2022, 26(18): 4847-4858. DOI: 10.1111/jcmm.17515.
|
| [14] |
TURAN A, TARIQUE M, ZHANG L, et al. Engineering pancreatic islets to transiently codisplay on their surface thrombomodulin and CD47 immunomodulatory proteins as a means of mitigating instant blood-mediated inflammatory reaction following intraportal transplantation[J]. J Immunol, 2024, 212(12): 1971-1980. DOI: 10.4049/jimmunol.2300743.
|
| [15] |
EIZIRIK DL, MANDRUP-POULSEN T. A choice of death—the signal-transduction of immune-mediated beta-cell apoptosis[J]. Diabetologia, 2001, 44(12): 2115-2133. DOI: 10.1007/s001250100021.
|
| [16] |
MOU L, WANG TB, WANG X, et al. Advancing diabetes treatment: the role of mesenchymal stem cells in islet transplantation[J]. Front Immunol, 2024, 15: 1389134. DOI: 10.3389/fimmu.2024.1389134.
|
| [17] |
LIN K, YANG Y, CAO Y, et al. Combining single-cell transcriptomics and CellTagging to identify differentiation trajectories of human adipose-derived mesenchymal stem cells[J]. Stem Cell Res Ther, 2023, 14(1): 14. DOI: 10.1186/s13287-023-03237-3.
|
| [18] |
LI X, ZHONG T, LI X, et al. 1483-P: distinct immune features in the partial remission phase of type 1 diabetes identified by single-cell RNA sequencing and functional analysis[J]. Diabetes, 2023, 72(Suppl 1). DOI: 10.2337/db23-1483-p.
|
| [19] |
AUGSORNWORAWAT P, HOGREBE NJ, ISHAHAK M, et al. Single-nucleus multi-omics of human stem cell-derived islets identifies deficiencies in lineage specification[J]. Nat Cell Biol, 2023, 25(6): 904-916. DOI: 10.1038/s41556-023-01150-8.
|
| [20] |
ITO Y, SUN T, TANAKA H, et al. Tissue sodium accumulation induces organ inflammation and injury in chronic kidney disease[J]. Int J Mol Sci, 2023, 24(9): 8329. DOI: 10.3390/ijms24098329.
|
| [21] |
ANDERSEN DB, HOLST JJ. Peptides in the regulation of glucagon secretion[J]. Peptides, 2022, 148: 170683. DOI: 10.1016/j.peptides.2021.170683.
|
| [22] |
LEE JH, LEE J. Endoplasmic reticulum (ER) stress and its role in pancreatic β-cell dysfunction and senescence in type 2 diabetes[J]. Int J Mol Sci, 2022, 23(9): 4843. DOI: 10.3390/ijms23094843.
|
| [23] |
LEFEBVRE P, CARIOU B, LIEN F, et al. Role of bile acids and bile acid receptors in metabolic regulation[J]. Physiol Rev, 2009, 89(1): 147-191. DOI: 10.1152/physrev.00010.2008.
|
| [24] |
CHÁVEZ-TALAVERA O, TAILLEUX A, LEFEBVRE P, et al. Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease[J]. Gastroenterology, 2017, 152(7): 1679-1694. e3. DOI: 10.1053/j.gastro.2017.01.055.
|
| [25] |
BUDD MA, MONAJEMI M, COLPITTS SJ, et al. Interactions between islets and regulatory immune cells in health and type 1 diabetes[J]. Diabetologia, 2021, 64(11): 2378-2388. DOI: 10.1007/s00125-021-05565-6.
|
| [26] |
PEIRIS H, BONDER CS, COATES PTH, et al. The β-cell/EC axis: how do islet cells talk to each other?[J]. Diabetes, 2014, 63(1): 3-11. DOI: 10.2337/db13-0617.
|
| [27] |
ALMAÇA J, CAICEDO A, LANDSMAN L. Beta cell dysfunction in diabetes: the islet microenvironment as an unusual suspect[J]. Diabetologia, 2020, 63(10): 2076-2085. DOI: 10.1007/s00125-020-05186-5.
|
| [28] |
THIEL G, MÜLLER I, RÖSSLER OG. Expression, signaling and function of EGR transcription factors in pancreatic β-cells and insulin-responsive tissues[J]. Mol Cell Endocrinol, 2014, 388(1/2): 10-19. DOI: 10.1016/j.mce.2014.03.001.
|
| [29] |
THIEL G, RÖSSLER OG. Glucose homeostasis and pancreatic islet size are regulated by the transcription factors ELK-1 and EGR-1 and the protein phosphatase calcineurin[J]. Int J Mol Sci, 2023, 24(1): 815. DOI: 10.3390/ijms24010815.
|
| [30] |
LEU SY, KUO LH, WENG WT, et al. Loss of EGR-1 uncouples compensatory responses of pancreatic β cells[J]. Theranostics, 2020, 10(9): 4233-4249. DOI: 10.7150/thno.40664.
|
| [31] |
LI L, FU G, LIU C, et al. ATF3/EGR1 regulates myocardial ischemia/reperfusion injury induced autophagy and inflammation in cardiomyocytes[J]. Cell Mol Biol (Noisy-le-grand), 2024, 70(3): 125-129. DOI: 10.14715/cmb/2024.70.3.18.
|
| [32] |
CHEN JW, HUANG MJ, CHEN XN, et al. Transient upregulation of EGR1 signaling enhances kidney repair by activating SOX9(+) renal tubular cells[J]. Theranostics, 2022, 12(12): 5434-5450. DOI: 10.7150/thno.73426.
|
| [33] |
CHANG I, KIM S, KIM JY, et al. Nuclear factor kappaB protects pancreatic beta-cells from tumor necrosis factor-alpha-mediated apoptosis[J]. Diabetes, 2003, 52(5): 1169-1175. DOI: 10.2337/diabetes.52.5.1169.
|
| [34] |
KIM EK, KWON KB, HAN MJ, et al. Coptidis rhizoma extract protects against cytokine-induced death of pancreatic beta-cells through suppression of NF-kappaB activation[J]. Exp Mol Med, 2007, 39(2): 149-159. DOI: 10.1038/emm.2007.17.
|
| [35] |
KIM EK, KWON KB, KOO BS, et al. Activation of peroxisome proliferator-activated receptor-gamma protects pancreatic beta-cells from cytokine-induced cytotoxicity via NF kappaB pathway[J]. Int J Biochem Cell Biol, 2007, 39(6): 1260-1275. DOI: 10.1016/j.biocel.2007.04.005.
|
| [36] |
WANG J, WEBB G, CAO Y, et al. Contrasting patterns of expression of transcription factors in pancreatic alpha and beta cells[J]. Proc Natl Acad Sci USA, 2003, 100(22): 12660-12665. DOI: 10.1073/pnas.1735286100.
|
| [37] |
HARTMAN MG, LU D, KIM ML, et al. Role for activating transcription factor 3 in stress-induced β-cell apoptosis[J]. Mol Cell Biol, 2004, 24(13): 5721-5732. DOI: 10.1128/mcb.24.13.5721-5732.2004.
|
| [38] |
ZMUDA EJ, QI L, ZHU MX, et al. The roles of ATF3, an adaptive-response gene, in high-fat-diet-induced diabetes and pancreatic beta-cell dysfunction[J]. Mol Endocrinol, 2010, 24(7): 1423-1433. DOI: 10.1210/me.2009-0463.
|
WeChat Subscription Account
Wechat Service Account
Supported by: Beijing Renhe Information Technology Co., Ltd. 
DownLoad: