牙髓干细胞治疗糖尿病的研究进展

doi:10.13591/j.cnki.kqyx.2024.06.010

摘要/Abstract

摘要：

糖尿病(diabetes mellitus,DM)是一种以高血糖为主要特征的慢性代谢性疾病,由胰岛素抵抗或胰岛素分泌异常引起,因胰岛β细胞的破坏导致患者持续高血糖,可诱导多发性神经病变等并发症,患病率与死亡率均较高。牙髓干细胞(dental pulp stem cells,DPSCs)获取容易,具有自我更新、多向分化及高度增殖的能力,可被诱导分化为胰岛β细胞参与胰岛素分泌和免疫调节,在慢性疾病的治疗中取得了一定成果。此外,DPSCs还可通过抑制自身免疫、调节炎症及抗氧化应激等途径改善1型糖尿病患者症状。本文综述了DPSCs的生物学特性并探究其通过对DM及其并发症治疗不同机制,以期完善DM管理。

关键词: 牙髓干细胞, 糖尿病, 胰岛素, 并发症, 免疫调节

Abstract:

Diabetes mellitus (DM) stands as a chronic metabolic ailment predominantly characterized by elevated blood glucose levels, stemming from either a resistance to insulin or aberrations in insulin secretion. The ensuing persistent hyperglycemia, a direct consequence of pancreatic β-cell devastation, acts as a catalyst for a myriad of complications, inclusive of extensive neuropathies. The disease has substantial prevalence and mortality rates, underscoring the gravity of its impact on public health. Dental pulp stem cells (DPSCs) are readily obtainable, and they exhibit a profound capacity for self-renewal, multi-lineage differentiation, and vigorous proliferation. Remarkably, DPSCs can differentiate into pancreatic β-cells, subsequently participate in insulin secretion and play a pivotal role in immune modulation. This has achieved notable advancements in the therapeutic domain, particularly in the treatment of chronic diseases. Furthermore, DPSCs harbor the potential to mitigate symptoms in patients afflicted with type 1 diabetes. They navigate this therapeutic pathway through mechanisms that involve suppressing autoimmunity, modulating inflammatory responses, and counteracting oxidative stress. This article meticulously reviews the biological characteristics inherent to DPSCs and explores their multifaceted therapeutic potential in addressing DM and its associated complications. Through this endeavor, the article aims to contribute to the refinement and enhancement of DM management strategies.

Key words: dental pulp stem cells, diabetes mellitus, insulin, complication, immunoregulation

中图分类号:

黄蔼岚, 郭培培, 陆晓庆, 吴锦涛, 李泽汉, 徐秀清, 王娟, 周莉丽. 牙髓干细胞治疗糖尿病的研究进展[J]. 口腔医学, 2024, 44(6): 452-457.

HUANG Ailan, GUO Peipei, LU Xiaoqing, WU Jintao, LI Zehan, XU Xiuqing, WANG Juan, ZHOU Lili. Progress and prospects of dental pulp stem cells in diabetes treatment[J]. Stomatology, 2024, 44(6): 452-457.

图/表 1

参考文献 55

[1]	Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications[J]. Nat Rev Endocrinol, 2018, 14(2):88-98. doi: 10.1038/nrendo.2017.151 pmid: 29219149
[2]	Canto ED, Ceriello A, Rydén L, et al. Diabetes as a cardiovascular risk factor: An overview of global trends of macro and micro vascular complications[J]. Eur J Prev Cardiol, 2019, 26(2_suppl):25-32. doi: 10.1177/2047487319878371 pmid: 31722562
[3]	Park JJ. Epidemiology, pathophysiology, diagnosis and treatment of heart failure in diabetes[J]. Diabetes Metab J, 2021, 45(2):146-157. doi: 10.4093/dmj.2020.0282 pmid: 33813813
[4]	Cole JB, Florez JC. Genetics of diabetes mellitus and diabetes complications[J]. Nat Rev Nephrol, 2020, 16(7):377-390. doi: 10.1038/s41581-020-0278-5 pmid: 32398868
[5]	Uribe-Etxebarria V, Agliano A, Unda F, et al. Wnt signaling reprograms metabolism in dental pulp stem cells[J]. J Cell Physiol, 2019, 234(8):13068-13082. doi: 10.1002/jcp.27977 pmid: 30549037
[6]	Tsutsui TW. Dental pulp stem cells: Advances to applications[J]. Stem Cells Cloning, 2020, 13: 33-42.
[7]	Liu Y, Gan L, Cui DX, et al. Epigenetic regulation of dental pulp stem cells and its potential in regenerative endodontics[J]. World J Stem Cells, 2021, 13(11):1647-1666. doi: 10.4252/wjsc.v13.i11.1647 pmid: 34909116
[8]	Cui Y, Ji W, Gao YY, et al. Single-cell characterization of monolayer cultured human dental pulp stem cells with enhanced differentiation capacity[J]. Int J Oral Sci, 2021, 13(1):44. doi: 10.1038/s41368-021-00140-6 pmid: 34911932
[9]	Li XS, Yang KY, Chan VW, et al. Single-cell RNA-seq reveals that CD9 is a negative marker of glucose-responsive pancreatic β-like cells derived from human pluripotent stem cells[J]. Stem Cell Reports, 2020, 15(5):1111-1126. doi: 10.1016/j.stemcr.2020.09.009 pmid: 33096048
[10]	Shi X, Mao J, Liu Y. Pulp stem cells derived from human permanent and deciduous teeth: Biological characteristics and therapeutic applications[J]. Stem Cells Transl Med, 2020, 9(4):445-464.
[11]	Aly RM, Aglan HA, Eldeen GN, et al. Efficient generation of functional pancreatic β cells from dental-derived stem cells via laminin-induced differentiation[J]. J Genet Eng Biotechnol, 2022, 20(1):85.
[12]	Aly RM, Aglan HA, Eldeen GN, et al. Optimization of differentiation protocols of dental tissues stem cells to pancreatic β-cells[J]. BMC Mol Cell Biol, 2022, 23(1):41. doi: 10.1186/s12860-022-00441-6 pmid: 36123594
[13]	Bar JK, Lis-Nawara A, Grelewski PG. Dental pulp stem cell-derived secretome and its regenerative potential[J]. Int J Mol Sci, 2021, 22(21):12018.
[14]	Honda M, Ohshima H. Biological characteristics of dental pulp stem cells and their potential use in regenerative medicine[J]. J Oral Biosci, 2022, 64(1):26-36. doi: 10.1016/j.job.2022.01.002 pmid: 35031479
[15]	Fawzy El-Sayed KM, Elsalawy R, Ibrahim N, et al. The dental pulp stem/progenitor cells-mediated inflammatory-regenerative axis[J]. Tissue Eng Part B Rev, 2019, 25(5):445-460.
[16]	Govindasamy V, Ronald VS, Abdullah AN, et al. Differentiation of dental pulp stem cells into islet-like aggregates[J]. J Dent Res, 2011, 90(5):646-652. doi: 10.1177/0022034510396879 pmid: 21335539
[17]	Bhonde RR, Sheshadri P, Sharma S, et al. Making surrogate β-cells from mesenchymal stromal cells: Perspectives and future endeavors[J]. Int J Biochem Cell Biol, 2014, 46: 90-102. doi: 10.1016/j.biocel.2013.11.006 pmid: 24275096
[18]	Ishkitiev N, Yaegaki K, Kozhuharova A, et al. Pancreatic differentiation of human dental pulp CD117⁺ stem cells[J]. Regen Med, 2013, 8(5):597-612. doi: 10.2217/rme.13.42 pmid: 23998753
[19]	El-Kersh AOFO, El-Akabawy G, Al-Serwi RH. Transplantation of human dental pulp stem cells in streptozotocin-induced diabetic rats[J]. Anat Sci Int, 2020, 95(4):523-539. doi: 10.1007/s12565-020-00550-2 pmid: 32476103
[20]	Jin WW, Jiang W. Stepwise differentiation of functional pancreatic β cells from human pluripotent stem cells[J]. Cell Regen, 2022, 11(1):24.
[21]	Memon B, Younis I, Abubaker F, et al. PDX1^-/NKX6.1⁺ progenitors derived from human pluripotent stem cells as a novel source of insulin-secreting cells[J]. Diabetes Metab Res Rev, 2021, 37(5):e3400.
[22]	Xu BB, Fan DY, Zhao YS, et al. Three-dimensional culture promotes the differentiation of human dental pulp mesenchymal stem cells into insulin-producing cells for improving the diabetes therapy[J]. Front Pharmacol, 2020, 10: 1576.
[23]	Yagi Mendoza H, Yokoyama T, Tanaka T, et al. Regeneration of insulin-producing islets from dental pulp stem cells using a 3D culture system[J]. Regen Med, 2018, 13(6):673-687. doi: 10.2217/rme-2018-0074 pmid: 30028236
[24]	Son YB, Bharti D, Kim SB, et al. Comparison of pluripotency, differentiation, and mitochondrial metabolism capacity in three-dimensional spheroid formation of dental pulp-derived mesenchymal stem cells[J]. Biomed Res Int, 2021, 2021: 5540877.
[25]	Kuncorojakti S, Rodprasert W, Le QD, et al. In vitro induction of human dental pulp stem cells toward pancreatic lineages[J]. J Vis Exp, 2021, 2021(175):e62497.
[26]	Kuncorojakti S, Rodprasert W, Yodmuang S, et al. Alginate/Pluronic F127-based encapsulation supports viability and functionality of human dental pulp stem cell-derived insulin-producing cells[J]. J Biol Eng, 2020, 14: 23. doi: 10.1186/s13036-020-00246-1 pmid: 32855655
[27]	Fasolino M, Schwartz GW, Patil AR, et al. Single-cell multi-omics analysis of human pancreatic islets reveals novel cellular states in type 1 diabetes[J]. Nat Metab, 2022, 4(2):284-299. doi: 10.1038/s42255-022-00531-x pmid: 35228745
[28]	Wan XX, Unanue ER. Antigen recognition in autoimmune diabetes: A novel pathway underlying disease initiation[J]. Precis Clin Med, 2018, 1(3):102-110.
[29]	Ashour L, Al Habashneh RA, Al-Mrahelh MM, et al. The modulation of mature dendritic cells from patients with type 1 diabetes using human periodontal ligament stem cells. An in-vitro study[J]. J Diabetes Metab Disord, 2020, 19(2):1037-1044.
[30]	Xu YF, Chen J, Zhou H, et al. Effects and mechanism of stem cells from human exfoliated deciduous teeth combined with hyperbaric oxygen therapy in type 2 diabetic rats[J]. Clinics, 2020, 75: e1656.
[31]	许忆峰. 人乳牙牙髓干细胞联合高压氧治疗2型糖尿病大鼠疗效观察与机制探讨[D]. 上海: 中国人民解放军海军军医大学, 2019.
[32]	Ma YZ, Wang LS, Yang SL, et al. The tissue origin of human mesenchymal stem cells dictates their therapeutic efficacy on glucose and lipid metabolic disorders in type Ⅱ diabetic mice[J]. Stem Cell Res Ther, 2021, 12(1):385.
[33]	Ahmed HH, Aglan HA, Mahmoud NS, et al. Preconditioned human dental pulp stem cells with cerium and yttrium oxide nanoparticles effectively ameliorate diabetic hyperglycemia while combatting hypoxia[J]. Tissue Cell, 2021, 73: 101661.
[34]	Jing YL, Sun QM, Xiong XL, et al. Hepatocyte growth factor alleviates hepatic insulin resistance and lipid accumulation in high-fat diet-fed mice[J]. J Diabetes Investig, 2019, 10(2):251-260.
[35]	Oliveira AG, Araújo TG, Carvalho BM, et al. The role of hepatocyte growth factor (HGF) in insulin resistance and diabetes[J]. Front Endocrinol, 2018, 9: 503. doi: 10.3389/fendo.2018.00503 pmid: 30214428
[36]	谢俊豪. 人乳牙牙髓干细胞治疗STZ诱导糖尿病大鼠的疗效观察及机制研究[D]. 上海: 中国人民解放军海军军医大学, 2021.
[37]	Ziegler D. Diabetische polyneuropathie[J]. Internist, 2020, 61(3):243-253.
[38]	Ziegler D, Papanas N, Schnell O, et al. Current concepts in the management of diabetic polyneuropathy[J]. J Diabetes Investig, 2021, 12(4):464-475.
[39]	Luo LH, He Y, Wang XY, et al. Potential roles of dental pulp stem cells in neural regeneration and repair[J]. Stem Cells Int, 2018, 2018: 1731289.
[40]	Naruse K. Schwann cells as crucial players in diabetic neuropathy[J]. Adv Exp Med Biol, 2019, 1190: 345-356. doi: 10.1007/978-981-32-9636-7_22 pmid: 31760655
[41]	Pisciotta A, Bertoni L, Vallarola A, et al. Neural crest derived stem cells from dental pulp and tooth-associated stem cells for peripheral nerve regeneration[J]. Neural Regen Res, 2020, 15(3):373-381. doi: 10.4103/1673-5374.266043 pmid: 31571644
[42]	Omi M, Hata M, Nakamura N, et al. Transplantation of dental pulp stem cells improves long-term diabetic polyneuropathy together with improvement of nerve morphometrical evaluation[J]. Stem Cell Res Ther, 2017, 8(1):279. doi: 10.1186/s13287-017-0729-5 pmid: 29237486
[43]	Hata M, Omi M, Kobayashi Y, et al. Transplantation of human dental pulp stem cells ameliorates diabetic polyneuropathy in streptozotocin-induced diabetic nude mice: The role of angiogenic and neurotrophic factors[J]. Stem Cell Res Ther, 2020, 11(1):236. doi: 10.1186/s13287-020-01758-9 pmid: 32546222
[44]	Makino E, Nakamura N, Miyabe M, et al. Conditioned media from dental pulp stem cells improved diabetic polyneuropathy through anti-inflammatory, neuroprotective and angiogenic actions: Cell-free regenerative medicine for diabetic polyneuropathy[J]. J Diabetes Investig, 2019, 10(5):1199-1208.
[45]	Hata M, Omi M, Kobayashi Y, et al. Transplantation of cultured dental pulp stem cells into the skeletal muscles ameliorated diabetic polyneuropathy: Therapeutic plausibility of freshly isolated and cryopreserved dental pulp stem cells[J]. Stem Cell Res Ther, 2015, 6(1):162.
[46]	Velasco-Ortega E, Delgado-Ruiz RA, López-López J. Dentistry and diabetes: The influence of diabetes in oral diseases and dental treatments[J]. J Diabetes Res, 2016, 2016: 6073190.
[47]	Lyu JZ, Hashimoto Y, Honda Y, et al. Comparison of osteogenic potentials of dental pulp and bone marrow mesenchymal stem cells using the new cell transplantation platform, Cell Saic, in a rat congenital cleft-jaw model[J]. Int J Mol Sci, 2021, 22(17):9478.
[48]	Hu SL, Chen B, Zhou JN, et al. Dental pulp stem cell-derived exosomes revitalize salivary gland epithelial cell function in NOD mice via the GPER-mediated cAMP/PKA/CREB signaling pathway[J]. J Transl Med, 2023, 21(1):361.
[49]	姚敏慧, 吴锦涛, 周愉, 等. 牙髓再生相关细胞因子研究进展[J]. 口腔医学, 2023, 43(3):282-288.
[50]	Chen H, Fu HC, Wu X, et al. Regeneration of pulpo-dentinal-like complex by a group of unique multipotent CD24a⁺ stem cells[J]. Sci Adv, 2020, 6(15):eaay1514.
[51]	Santamaria-Jr M, do Nascimento ERA, Bagne L, et al. Pulpal outcomes in orthodontic tooth movement in diabetes mellitus[J]. Odontology, 2021, 109(4):921-929.
[52]	Gao XL, Qin W, Chen LL, et al. Effects of targeted delivery of metformin and dental pulp stem cells on osteogenesis via demineralized dentin matrix under high glucose conditions[J]. ACS Biomater Sci Eng, 2020, 6(4):2346-2356. doi: 10.1021/acsbiomaterials.0c00124 pmid: 33455311
[53]	Guimarães ET, Cruz GD, Almeida TF, et al. Transplantation of stem cells obtained from murine dental pulp improves pancreatic damage, renal function, and painful diabetic neuropathy in diabetic type 1 mouse model[J]. Cell Transplant, 2013, 22(12):2345-2354. doi: 10.3727/096368912X657972 pmid: 23068779
[54]	Al-Serwi RH, El-Kersh AOFO, El-Akabawy G. Human dental pulp stem cells attenuate streptozotocin-induced parotid gland injury in rats[J]. Stem Cell Res Ther, 2021, 12(1):577. doi: 10.1186/s13287-021-02646-6 pmid: 34775989
[55]	The Lancet. Diabetes: A defining disease of the 21st century[J]. Lancet, 2023, 401(10394):2087. doi: 10.1016/S0140-6736(23)01296-5 pmid: 37355279