|
|
胰岛β细胞去分化模型的研究进展
|
Abstract:
二型糖尿病是具有遗传倾向的多病因的慢性代谢性疾病，长期糖脂代谢紊乱引发的β细胞衰竭会引起多种并发症。针对二型糖尿病的以往研究主要关注于降低血糖和胰岛素增敏。但随着胰岛β细胞去分化的发现，实现胰岛β细胞的内源性更新成为二型糖尿病领域新的研究方向。促进去分化的胰岛β细胞再生，建立β细胞质量和功能的稳态对于二型糖尿病早期的治疗具有很大的前景，而对于胰岛β细胞去分化药物的筛选及评价需要建立合理有效的实验模型。本综述通过详细介绍胰岛β细胞及其去分化的可能机制、模型建立及相关研究方法，为胰岛β细胞去分化的研究提供思路方法。
Type 2 diabetes mellitus is a chronic metabolic disease with genetic predisposition and multiple etiology. The β-cell failure caused by long-term disorder of glucose and lipid metabolism can lead to many complications. Previous studies on type 2 diabetes have focused on lowering blood sugar and insulin sensitization. However, with the discovery of dedifferentiation of islet beta cells, endogenous renewal of islet beta cells has become a new research direction in type 2 diabetes. Promoting the regeneration of dedifferentiated pancreatic β cells and establishing the homeostasis of β cell mass and function have great prospects for the early treatment of type 2 diabetes. However, it is necessary to establish a reasonable and effective experimental model for the screening and evaluation of drugs for dedifferentiated pancreatic β cells. In this review, the possible mechanism, model establishment and related research methods of islet beta cells and their dedifferentiation are introduced in detail, so as to provide ideas and methods for the study of islet beta cell dedifferentiation.
| [1] | Mastrototaro, L. and Roden, M. (2021) Insulin Resistance and Insulin Sensitizing Agents. Metabolism, 125, Article ID: 154892. https://doi.org/10.1016/j.metabol.2021.154892 |
| [2] | Chang, W., Chen, L. and Hatch, G.M. (2015) Berberine as a Therapy for Type 2 Diabetes and Its Complications: From Mechanism of Action to Clinical Studies. Biochemistry and Cell Biology, 93, 479-486.
https://doi.org/10.1139/bcb-2014-0107 |
| [3] | Mastracci, T.L. and Sussel, L. (2012) The Endocrine Pancreas: Insights into Development, Differentiation and Diabetes. Wiley Interdisciplinary Reviews. Developmental Biology, 1, 609-628. https://doi.org/10.1002/wdev.44 |
| [4] | Lee, S., Zhang, J., Saravanakumar, S., Flisher, M.F. and Grimm, D.R. (2021) Virgin β-Cells at the Neogenic Niche Proliferate Normally and Mature Slowly. Diabetes, 70, 1070-1083. https://doi.org/10.2337/db20-0679 |
| [5] | (2012) A Clinical Trial to Maintain Glycemic Control in Youth with Type 2 Diabetes. The New England Journal of Medicine, 366, 2247-2256. https://doi.org/10.1056/NEJMoa1109333 |
| [6] | Butler, P.C., Meier, J.J., Butler, A.E. and Bhushan, A. (2007) The Replication of β Cells in Normal Physiology, in Disease and for Therapy. Nature Clinical Practice Endocrinology & Metabolism, 3, 758-768.
https://doi.org/10.1038/ncpendmet0647 |
| [7] | Remedi, M.S. and Emfinger, C. (2016) Pancreatic β-Cell Identity in Diabetes. Diabetes, Obesity and Metabolism, 18, 110-116. https://doi.org/10.1111/dom.12727 |
| [8] | Butler, A.E., Janson, J., Bonner-Weir, S., Ritzel, R., Rizza, R.A., et al. (2003) Beta-Cell Deficit and Increased Beta-Cell Apoptosis in Humans with Type 2 Diabetes. Diabetes, 52, 102-110. https://doi.org/10.2337/diabetes.52.1.102 |
| [9] | Deng, Z., Kuno, A., Ojima, M. and Takahashi, S. (2022) MafB Maintains β-Cell Identity under MafA-Deficient Conditions. Molecular and Cellular Biology, 42, e00541-21. https://doi.org/10.1128/mcb.00541-21 |
| [10] | Casteels, T., Zhang, Y., Frogne, T., Sturtzel, C., Lardeau, C.-H., et al. (2021) An Inhibitor-Mediated Beta-Cell Dedifferentiation Model Reveals Distinct Roles for FoxO1 in Glucagon Repression and Insulin Maturation. Molecular Metabolism, 54, Article ID: 101329. https://doi.org/10.1016/j.molmet.2021.101329 |
| [11] | Calissi, G., Lam, E.W.-F. and Link, W. (2021) Therapeutic Strategies Targeting FOXO Transcription Factors. Nature Reviews Drug Discovery, 20, 21-38. https://doi.org/10.1038/s41573-020-0088-2 |
| [12] | Jeffery, N. and Harries, L.W. (2016) β-Cell Differentiation Status in Type 2 Diabetes. Diabetes, Obesity and Metabolism, 18, 1167-1175. https://doi.org/10.1111/dom.12778 |
| [13] | Salinno, C., Büttner, M., Cota, P., Tritschler, S., Tarquis-Medina, M., et al. (2021) CD81 Marks Immature and Dedifferentiated Pancreatic β-Cells. Molecular Metabolism, 49, Article ID: 101188.
https://doi.org/10.1016/j.molmet.2021.101188 |
| [14] | Christensen, A.A. and Gannon, M. (2019) The Beta Cell in Type 2 Diabetes. Current Diabetes Reports, 19, 81.
https://doi.org/10.1007/s11892-019-1196-4 |
| [15] | Yan, Z., Fortunato, M., Shyr, Z.A., Clark, A.L., Fuess, M., et al. (2022) Genetic Reduction of Glucose Metabolism Preserves Functional β-Cell Mass in KATP-Induced Neonatal Diabetes. Diabetes, 71, 1233-1245.
https://doi.org/10.2337/db21-0992 |
| [16] | Lebreton, F., Lavallard, V., Bellofatto, K., Bonnet, R., Wassmer, C.H., et al. (2019) Insulin-Producing Organoids Engineered from Islet and Amniotic Epithelial Cells to Treat Diabetes. Nature Communications, 10, 4491.
https://doi.org/10.1038/s41467-019-12472-3 |
| [17] | Nimkulrat, S.D., Bernstein, M.N., Ni, Z., Brown, J., Kendziorski, C., et al. (2021) The Anna Karenina Model of β-Cell Maturation in Development and Their Dedifferentiation in Type 1 and Type 2 Diabetes. Diabetes, 70, 2058-2066.
https://doi.org/10.2337/db21-0211 |
| [18] | Ma, X., Lu, Y., Zhou, Z., Li, Q., Chen, X., et al. (2022) Human Expandable Pancreatic Progenitor-Derived β Cells Ameliorate Diabetes. Science Advances, 8, eabk1826. https://doi.org/10.1126/sciadv.abk1826 |
| [19] | Boland, B.B., Brown, C., Boland, M.L., Cann, J., Sulikowski, M., et al. (2019) Pancreatic β-Cell Rest Replenishes Insulin Secretory Capacity and Attenuates Diabetes in an Extreme Model of Obese Type 2 Diabetes. Diabetes, 68, 131-140. https://doi.org/10.2337/db18-0304 |
| [20] | Wang, J., Wang, D., Chen, X., Yuan, S., Bai, L., et al. (2022) Isolation of Mouse Pancreatic Islet Procr+ Progenitors and Long-Term Expansion of Islet Organoids in Vitro. Nature Protocols, 17, 1359-1384.
https://doi.org/10.1038/s41596-022-00683-w |
| [21] | J？rgensen, M.C., Ahnfelt-R？nne, J., Hald, J., Madsen, O.D., Serup, P., et al. (2007) An Illustrated Review of Early Pancreas Development in the Mouse. Endocrine Reviews, 28, 685-705. https://doi.org/10.1210/er.2007-0016 |
| [22] | Brissova, M., et al. (2005) Assessment of Human Pancreatic Islet Architecture and Composition by Laser Scanning Confocal Microscopy. Journal of Histochemistry & Cytochemistry, 53, 1087-1097. |
| [23] | Lin, C.-L.V. and Vuguin, P.M. (2012) Determinants of Pancreatic Islet Development in Mice and Men: A Focus on the Role of Transcription Factors. Hormone Research in Paediatrics, 77, 205-213. https://doi.org/10.1159/000337219 |
| [24] | Edlund, H. (2001) Section 1: NL-Cell Differentiation and Growth. 50. |
| [25] | Afelik, S. and Jensen, J. (2013) Notch Signaling in the Pancreas: Patterning and Cell Fate Specification. WIREs Developmental Biology, 2, 531-544. https://doi.org/10.1002/wdev.99 |
| [26] | Afelik, S., Qu, X., Hasrouni, E., Bukys, M.A., Deering, T., et al. (2012) Notch-Mediated Patterning and Cell Fate Allocation of Pancreatic Progenitor Cells. Development, 139, 1744-1753. https://doi.org/10.1242/dev.075804 |
| [27] | Magenheim, J., Klein, A.M., Stanger, B.Z., Ashery-Padan, R., Sosa-Pineda, B., et al. (2011) Ngn3+ Endocrine Progenitor Cells Control the Fate and Morphogenesis of Pancreatic Ductal Epithelium. Developmental Biology, 359, 26-36.
https://doi.org/10.1016/j.ydbio.2011.08.006 |
| [28] | Fernandez-Ruiz, R., García-Alamán, A., Esteban, Y., Mir-Coll, J., Serra-Navarro, B., et al. (2020) Tra. Nature Communications, 11, 5982. https://doi.org/10.1038/s41467-020-19657-1 |
| [29] | Moin, A.S.M. and Butler, A.E. (2019) Alterations in Beta Cell Identity in Type 1 and Type 2 Diabetes. Current Diabetes Reports, 19, 83. https://doi.org/10.1007/s11892-019-1194-6 |
| [30] | Oberhauser, L., Jiménez-Sánchez, C., Madsen, J.G.S., Duhamel, D., Mandrup, S., et al. (2022) Glucolipotoxicity Promotes the Capacity of the Glycerolipid/NEFA Cycle Supporting the Secretory Response of Pancreatic Beta Cells. Diabetologia, 65, 705-720. https://doi.org/10.1007/s00125-021-05633-x |
| [31] | Oberhauser, L. and Maechler, P. (2021) Lipid-Induced Adaptations of the Pancreatic Beta-Cell to Glucotoxic Conditions Sustain Insulin Secretion. International Journal of Molecular Sciences, 23, 324.
https://doi.org/10.3390/ijms23010324 |
| [32] | Zhang, I.X., Raghavan, M. and Satin, L.S. (2020) The Endoplasmic Reticulum and Calcium Homeostasis in Pancreatic Beta Cells. Endocrinology, 161, bqz028. https://doi.org/10.1210/endocr/bqz028 |
| [33] | Cunha, D.A., Hekerman, P., Ladrière, L., Bazarra-Castro, A., Ortis, F., et al. (2008) Initiation and Execution of Lipotoxic ER Stress in Pancreatic β-Cells. Journal of Cell Science, 121, 2308-2318. https://doi.org/10.1242/jcs.026062 |
| [34] | Cnop, M., Ladrière, L., Igoillo-Esteve, M., Moura, R.F. and Cunha, D.A. (2010) Causes and Cures for Endoplasmic Reticulum Stress in Lipotoxic β-Cell Dysfunction. Diabetes, Obesity and Metabolism, 12, 76-82.
https://doi.org/10.1111/j.1463-1326.2010.01279.x |
| [35] | Li, N., Frigerio, F. and Maechler, P. (2008) The Sensitivity of Pancreatic β-Cells to Mitochondrial Injuries Triggered by Lipotoxicity and Oxidative Stress. Biochemical Society Transactions, 36, 930-934.
https://doi.org/10.1042/BST0360930 |
| [36] | Wysham, C. and Shubrook, J. (2020) Beta-Cell Failure in Type 2 Diabetes: Mechanisms, Markers, and Clinical Implications. Postgraduate Medicine, 132, 676-686. https://doi.org/10.1080/00325481.2020.1771047 |
| [37] | Escribano-López, I., de Mara？on, A.M., Iannantuoni, F., López-Domènech, S., Abad-Jiménez, Z., et al. (2019) The Mitochondrial Antioxidant SS-31 Modulates Oxidative Stress, Endoplasmic Reticulum Stress, and Autophagy in Type 2 Diabetes. Journal of Clinical Medicine, 8, 1322. https://doi.org/10.3390/jcm8091322 |
| [38] | Yuan, Y., Zhou, J., Hu, R., Zou, L., Ji, L., et al. (2021) Piperine Protects against Pancreatic β-Cell Dysfunction by Alleviating Macrophage Inflammation in Obese Mice. Life Sciences, 274, Article ID: 119312.
https://doi.org/10.1016/j.lfs.2021.119312 |
| [39] | Inaishi, J. and Saisho, Y. (2020) Beta-Cell Mass in Obesity and Type 2 Diabetes, and Its Relation to Pancreas Fat: A Mini-Review. Nutrients, 12, 3846. https://doi.org/10.3390/nu12123846 |
| [40] | Saisho, Y. (2019) Changing the Concept of Type 2 Diabetes: Beta Cell Workload Hypothesis Revisited. Endocrine, Metabolic & Immune Disorders Drug Targets, 19, 121-127. https://doi.org/10.2174/1871530318666180821161825 |
| [41] | Poitout, V. and Robertson, R.P. (2008) Glucolipotoxicity: Fuel Excess and β-Cell Dysfunction. Endocrine Reviews, 29, 351-366. https://doi.org/10.1210/er.2007-0023 |
| [42] | Marasco, M.R. and Linnemann, A.K. (2018) β-Cell Autophagy in Diabetes Pathogenesis. Endocrinology, 159, 2127- 2141. https://doi.org/10.1210/en.2017-03273 |
| [43] | Muralidharan, C. and Linnemann, A.K. (2021) β-Cell Autophagy in the Pathogenesis of Type 1 Diabetes. American Journal of Physiology-Endocrinology and Metabolism, 321, E410-E416. https://doi.org/10.1152/ajpendo.00151.2021 |
| [44] | Masjkur, J., Arps-Forker, C., Poser, S.W., Nikolakopoulou, P., Toutouna, L., et al. (2014) Hes3 Is Expressed in the Adult Pancreatic Islet and Regulates Gene Expression, Cell Growth, and Insulin Release. The Journal of Biological Chemistry, 289, 35503-35516. https://doi.org/10.1074/jbc.M114.590687 |
| [45] | Masjkur, J., Poser, S.W., Nikolakopoulou, P., Chrousos, G., McKay, R.D., et al. (2016) Endocrine Pancreas Development and Regeneration: Noncanonical Ideas from Neural Stem Cell Biology. Diabetes, 65, 314-330.
https://doi.org/10.2337/db15-1099 |
| [46] | Seymour, P.A., Collin, C.A., Egeskov-Madsen, A.R., J？rgensen, M.C., Shimojo, H., et al. (2020) Jag1 Modulates an Oscillatory Dll1-Notch-Hes1 Signaling Module to Coordinate Growth and Fate of Pancreatic Progenitors. Developmental Cell, 52, 731-747.e8. https://doi.org/10.1016/j.devcel.2020.01.015 |
| [47] | Zheng, L. and Conner, S.D. (2018) Glycogen Synthase Kinase 3β Inhibition Enhances Notch1 Recycling. Molecular Biology of the Cell, 29, 389-395. https://doi.org/10.1091/mbc.E17-07-0474 |
| [48] | Liu, C., Xu, X., Gao, J., Zhang, T. and Yang, Z. (2016) Hydrogen Sulfide Prevents Synaptic Plasticity from VD-In- duced Damage via Akt/GSK-3β Pathway and Notch Signaling Pathway in Rats. Molecular Neurobiology, 53, 4159- 4172. https://doi.org/10.1007/s12035-015-9324-x |
| [49] | Espinosa, L., Inglés-Esteve, J., Aguilera, C. and Bigas, A. (2003) Phosphorylation by Glycogen Synthase Kinase-3β Down-Regulates Notch Activity, a Link for Notch and Wnt Pathways. Journal of Biological Chemistry, 278, 32227- 32235. https://doi.org/10.1074/jbc.M304001200 |
| [50] | Zhu, Z., Chen, X., Xiao, Y., Wen, J., Chen, J., et al. (2019) Gestational Diabetes Mellitus Alters DNA Methylation Profiles in Pancreas of the Offspring Mice. Journal of Diabetes and Its Complications, 33, 15-22.
https://doi.org/10.1016/j.jdiacomp.2018.11.002 |
| [51] | Blum, B., Roose, A.N., Barrandon, O., Maehr, R., Arvanites, A.C., et al. (2014) Reversal of β Cell De-Differentiation by a Small Molecule Inhibitor of the TGFβ Pathway. eLife, 3, e02809. https://doi.org/10.7554/eLife.02809 |
| [52] | Wang, H.-L., Wang, L., Zhao, C.-Y. and Lan, H.-Y. (2022) Role of TGF-Beta Signaling in Beta Cell Proliferation and Function in Diabetes. Biomolecules, 12, 373. https://doi.org/10.3390/biom12030373 |
| [53] | Toren-Haritan, G. and Efrat, S. (2015) TGFβ Pathway Inhibition Redifferentiates Human Pancreatic Islet β Cells Expanded in Vitro. PLOS ONE, 10, e0139168. https://doi.org/10.1371/journal.pone.0139168 |
| [54] | Ji, J., Qian, L., Zhu, Y., Wu, Y., Guo, J., et al. (2020) Serpina3c Protects against High-Fat Diet-Induced Pancreatic Dysfunction through the JNK-Related Pathway. Cellular Signalling, 75, Article ID: 109745.
https://doi.org/10.1016/j.cellsig.2020.109745 |
| [55] | Kim-Muller, J.Y., Kim, Y.J.R., Fan, J., Zhao, S., Banks, A.S., et al. (2016) FoxO1 Deacetylation Decreases Fatty Acid Oxidation in β-Cells and Sustains Insulin Secretion in Diabetes. Journal of Biological Chemistry, 291, 10162-10172.
https://doi.org/10.1074/jbc.M115.705608 |
| [56] | Xu, Y., Tang, Z., Dai, H., Hou, J., Li, F., et al. (2022) MiR-195 Promotes Pancreatic β-Cell Dedifferentiation by Targeting Mfn2 and Impairing Pi3k/Akt Signaling in Type 2 Diabetes. Obesity, 30, 447-459.
https://doi.org/10.1002/oby.23360 |
| [57] | Skelin, M., Rupnik, M. and Cenci？, A. (2010) Pancreatic Beta Cell Lines and Their Applications in Diabetes Mellitus Research. ALTEX Alternatives to Animal Experimentation, 27, 105-113. https://doi.org/10.14573/altex.2010.2.105 |
| [58] | Moreno-Amador, J.L., Téllez, N., Marin, S., Aloy-Reverté, C., Semino, C., et al. (2018) Epithelial to Mesenchymal Transition in Human Endocrine Islet Cells. PLOS ONE, 13, e0191104. https://doi.org/10.1371/journal.pone.0191104 |
| [59] | Al-Masri, M., Krishnamurthy, M., Li, J., Fellows, G.F., Dong, H.H., et al. (2010) Effect of Forkhead Box O1 (FOXO1) on Beta Cell Development in the Human Fetal Pancreas. Diabetologia, 53, 699-711.
https://doi.org/10.1007/s00125-009-1632-0 |
| [60] | Russ, H.A., Ravassard, P., Kerr-Conte, J., Pattou, F. and Efrat, S. (2009) Epithelial-Mesenchymal Transition in Cells Expanded in Vitro from Lineage-Traced Adult Human Pancreatic Beta Cells. PLOS ONE, 4, e6417.
https://doi.org/10.1371/journal.pone.0006417 |
| [61] | Neelankal, J.A., Morahan, G. and Jiang, F.-X. (2017) Incomplete Re-Expression of Neuroendocrine Progenitor/Stem Cell Markers Is a Key Feature of β-Cell Dedifferentiation. Journal of Neuroendocrinology, 29.
https://doi.org/10.1111/jne.12450 |
| [62] | Ma, X., Gao, F., Chen, Q., Xuan, X., Wang, Y., et al. (2020) ACE2 Modulates Glucose Homeostasis through GABA Signaling during Metabolic Stress. Journal of Endocrinology, 246, 223-236. https://doi.org/10.1530/JOE-19-0471 |
| [63] | Li, F., Nitteranon, V., Tang, X., Liang, J., Zhang, G., et al. (2012) In Vitro Antioxidant and Anti-Inflammatory Activities of 1-dehydro-[6]-gingerdione, 6-shogaol, 6-dehydroshogaol and Hexahydrocurcumin. Food Chemistry, 135, 332-337. https://doi.org/10.1016/j.foodchem.2012.04.145 |
| [64] | 程瑞婷, 王晨斌, 田春雨, 高秀娟, 吴晨曦, 等. MIN6细胞损伤模型不同造模方法对比研究[J]. 华北理工大学学报(医学版), 2017, 19(4): 258-262. |
| [65] | 刘玉溥, 吕庆国, 和童南伟, 等. 大鼠胰岛β细胞分离与原代培养方法探讨[J]. 四川大学学报(医学版), 2009, 40(1): 153-156. |
| [66] | Cinti, F., Bouchi, R., Kim-Muller, J.Y., Ohmura, Y., Sandoval, P.R., et al. (2016) Evidence of β-Cell Dedifferentiation in Human Type 2 Diabetes. The Journal of Clinical Endocrinology & Metabolism, 101, 1044-1054.
https://doi.org/10.1210/jc.2015-2860 |
| [67] | Diedisheim, M., Oshima, M., Albagli, O., Huldt, C.W., Ahlstedt, I., et al. (2018) Modeling Human Pancreatic Beta Cell Dedifferentiation. Molecular Metabolism, 10, 74-86. https://doi.org/10.1016/j.molmet.2018.02.002 |
| [68] | Pastore, D., Della-Morte, D., Capuani, B., Lombardo, M.F., et al. (2017) FGF-2b and h-PL Transform Duct and Non- Endocrine Human Pancreatic Cells into Endocrine Insulin Secreting Cells by Modulating Differentiating Genes. International Journal of Molecular Sciences, 18, 2234. https://doi.org/10.3390/ijms18112234 |
| [69] | de Jesus, D.S., Mak, T.C.S., Wang, Y.-F., von Ohlen, Y., Bai, Y., et al. (2021) Dysregulation of the Pdx1/Ovol2/Zeb2 Axis in Dedifferentiated β-Cells Triggers the Induction of Genes Associated with Epithelial-Mesenchymal Transition in Diabetes. Molecular Metabolism, 53, Article ID: 101248. https://doi.org/10.1016/j.molmet.2021.101248 |
| [70] | Chen, H., Zhou, W., Ruan, Y., Yang, L., Xu, N., et al. (2018) Reversal of Angiotensin ll-Induced β-Cell Dedifferentiation via Inhibition of NF-κb Signaling. Molecular Medicine, 24, 43. https://doi.org/10.1186/s10020-018-0044-3 |
| [71] | Hu, X., Liu, Z., Lu, Y., Chi, X., Han, K., et al. (2022) Glucose Metabolism Enhancement by 10-Hydroxy-2-Decenoic Acid via the PI3K/AKT Signaling Pathway in High-Fat-Diet/Streptozotocin Induced Type 2 Diabetic Mice. Food & Function, 13, 9931-9946. https://doi.org/10.1039/D1FO03818D |
| [72] | Ilegems, E., Bryzgalova, G., Correia, J., Yesildag, B., Berra, E., et al. (2022) HIF-1α Inhibitor PX-478 Preserves Pancreatic β Cell Function in Diabetes. Science Translational Medicine, 14, eaba9112.
https://doi.org/10.1126/scitranslmed.aba9112 |
| [73] | Zhang, C., Deng, J., Liu, D., Tuo, X., Xiao, L., et al. (2018) Nuciferine Ameliorates Hepatic Steatosis in High-Fat Diet/Streptozocin-Induced Diabetic Mice through a PPARα/PPARγ Coactivator-1α Pathway. British Journal of Pharmacology, 175, 4218-4228. https://doi.org/10.1111/bph.14482 |
| [74] | Lee, K., Chan, J.Y., Liang, C., Ip, C.K., Shi, Y.-C., et al. (2022) XBP1 Maintains Beta Cell Identity, Represses Beta-to-Alpha Cell Transdifferentiation and Protects against Diabetic Beta Cell Failure during Metabolic Stress in Mice. Diabetologia, 65, 984-996. https://doi.org/10.1007/s00125-022-05669-7 |
| [75] | Kahn, S.E., Cooper, M.E. and Del Prato, S. (2014) Pathophysiology and Treatment of Type 2 Diabetes: Perspectives on the Past, Present, and Future. The Lancet, 383, 1068-1083. https://doi.org/10.1016/S0140-6736(13)62154-6 |
| [76] | 何风英, 孙琳楠, 王玉洁, 杨孟迪, 丁雨露, 等. T2DM胰岛β细胞去分化相关转录因子的研究进展[J]. 医学研究杂志, 2022, 51(8): 173-176. |
| [77] | Zalokar, M. and Sardet, C. (1984) Tracing of Cell Lineage in Embryonic Development of Phallusia mammillata (Ascidia) by Vital Staining of Mitochondria. Developmental Biology, 102, 195-205.
https://doi.org/10.1016/0012-1606(84)90184-2 |
| [78] | Schulz, T.J., Glaubitz, M., Kuhlow, D., Thierbach, R., Birringer, M., et al. (2007) Variable Expression of Cre Recombinase Transgenes Precludes Reliable Prediction of Tissue-Specific Gene Disruption by Tail-Biopsy Genotyping. PLOS ONE, 2, e1013. https://doi.org/10.1371/journal.pone.0001013 |
| [79] | He, L., Pu, W., Liu, X., Zhang, Z., Han, M., et al. (2021) Proliferation Tracing Reveals Regional Hepatocyte Generation in Liver Homeostasis and Repair. Science, 371, eabc4346. https://doi.org/10.1126/science.abc4346 |
