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中华细胞与干细胞杂志(电子版)

中华细胞与干细胞杂志(电子版) ›› 2023, Vol. 13 ›› Issue (06) : 355 -362. doi: 10.3877/cma.j.issn.2095-1221.2023.06.005

综述

干细胞衍生的胰岛素分泌细胞治疗糖尿病的研究进展
晏婷1, 梁瑶瑶1, 陈津1,†()   
  1. 1. 570311　海口，海南医学院第二附属医院临床医学研究所
  • 收稿日期:2023-05-17 出版日期:2023-12-01
  • 通信作者: 陈津
  • 基金资助:
    国家自然科学基金(82260161); 福建省自然科学基金(2021J011266); 海南省自然科学基金(822MS179)

Current advances in stem cells derived insulin-producing cells for diabetes mellitus therapy

Ting Yan1, Yaoyao Liang1, Jin Chen1,†()   

  1. 1. Institute of Clinical Medicine, the Second Affiliated Hospital of Hainan Medical University, Haikou 570311, China
  • Received:2023-05-17 Published:2023-12-01
  • Corresponding author: Jin Chen
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晏婷, 梁瑶瑶, 陈津. 干细胞衍生的胰岛素分泌细胞治疗糖尿病的研究进展[J]. 中华细胞与干细胞杂志(电子版), 2023, 13(06): 355-362.

Ting Yan, Yaoyao Liang, Jin Chen. Current advances in stem cells derived insulin-producing cells for diabetes mellitus therapy[J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2023, 13(06): 355-362.

糖尿病是一种因胰岛素绝对或相对分泌不足引起高血糖的代谢性疾病，胰岛β细胞是体内唯一分泌胰岛素的细胞，β细胞替代或补充疗法是治疗糖尿病的根本途径。生物工程方法诱导干细胞分化成胰岛素分泌细胞（IPC）产生胰岛素可用于β细胞替代疗法，这种疗法可能为糖尿病治疗带来希望。但是现阶段干细胞分化为IPC治疗糖尿病的过程中，仍然存在干细胞来源的β细胞功能不成熟、治疗的生物安全性及可靠性问题和移植免疫排斥等问题。本文综述了不同来源干细胞诱导分化成IPC、不同的诱导方案、当前临床研究进展及存在的问题和解决方法，期望为研究者研究IPC治疗糖尿病的方法提供参考。

关键词: 糖尿病, 干细胞, 胰岛素分泌细胞, 诱导方案

Diabetes mellitus is a metabolic disease caused by an absolute or relative deficiency in insulin secretion, resulting in high hyperglycemia. Pancreatic β cells are the only cells in the body that secrete insulin, and β cell replacement or supplementation therapy is the fundamental approach for treating diabetes. Inducing stem cell differentiation into insulin-secreting cells (IPCs) through biotechnology can produce insulin for β cell replacement therapy and bring hope for diabetes treatment. However, in stem cell differentiation into IPCs for diabetes treatment, there are still issues such as immature functionality of β cells derived from stem cells, biologic safety and reliability of treatment, and transplant rejection. This article summarizes different sources of stem- induced differentiation into IPCs, other induction protocols, current progress in clinical research, and the existing problems and solutions, with the hope of providing reference for researchers studying methods of IPCs therapy for diabetes.

Key words: Diabetes mellitus, Stem cells, Insulin producing cells, Induction protocols
图1 IPC的来源注：ESCs为胚胎干细胞；MSCs为间充质干细胞；IPC为胰岛素分泌细胞；iPSCs为诱导多能干细胞
图2 利用不同细胞因子和小分子化合物组合诱导干细胞分化成IPC的方案注：a图为胚胎干细胞和iPSC诱导成IPC方案；b图为成体干细胞诱导分化IPC方案。SC为干细胞；DE为内胚层；PGT为原肠管；PP为胰腺祖细胞；EP为胰腺前体细胞；PE为胰腺内胚层；MSC为间充质干细胞；DPSCs为牙髓干细胞；GSK3βi为GSK3β抑制剂；TGFβi为TGFβ抑制剂；ALK5i为间变性淋巴瘤激酶5抑制剂
表1 不同来源干细胞作为胰岛素分泌细胞来源的优缺点
细胞种类 优点 缺点 参考文献
ESCs 具有无限增殖能力的全能干细胞 存在伦理争议，明显的宿主免疫排斥，诱导分化程序复杂、成本高，畸胎瘤形成的风险最高 [4]
iPSCs 可持续的细胞来源，没有伦理争议 重编程效率低，畸胎瘤风险，存活率和植入率低，移植后细胞表型丧失，遗传不稳定，固有免疫原性以及成本高，除杂细胞和规模化生产难 [17,40,41,42]
ASCs 不受伦理问题的限制，致瘤风险较低，数量众多，不存在匹配或免疫排斥问题，具有很强的免疫调节能力 扩增潜力与年龄相关性下降，标准化治疗和大规模培养方面的难题，基因编辑过程中的安全性问题 [1,43,44,45]
表2 胰岛素分泌细胞临床试验研究情况
临床研究注册号 研究名称 研究类型 研究阶段 纳入标准 发起人
NCT04786262 VX-880在1型糖尿病参与者中的安全性、耐受性和有效性研究 是一种研究性同种异体干细胞衍生的、完全分化的、产生胰岛素的胰岛细胞疗法 1，2 持续时间> 5年的1型糖尿病临床病史；在入组前12个月内至少有两次记录的严重低血糖发作；稳定的糖尿病治疗；在筛查前至少3个月持续使用连续血糖监测仪（CGM），并愿意在研究期间使用CGM Vertex
NCT05791201 VX-264在1型糖尿病参与者中的安全性、耐受性和有效性研究 VX-264同种异体人类干细胞来源的胰岛 1，2 持续时间大于（>） 5年的1型糖尿病临床病史；参与者正在接受稳定的糖尿病治疗；在筛查前至少4周持续使用连续血糖监测（CGM），并愿意在研究期间使用CGM Vertex
NCT02239354 VC-01™联合产品在1型糖尿病患者中的安全性、耐受性和有效性研究 VC-01™组合产品生物制剂和设备 1，2 男性和女性（非怀孕和非生育能力）；1型糖尿病诊断至少3年；稳定的糖尿病治疗；愿意使用连续血糖仪；可接受的植入候选者 ViaCyte
NCT03162926 VC-02™联合产品在1型糖尿病患者中的安全性和耐受性研究 VC-02组合产品：将PEC-01细胞加载到输送装置中 1 有无生育能力的男性和非孕妇；1型糖尿病诊断至少五（5）年；稳定的糖尿病治疗；愿意使用连续血糖仪；可接受的植入候选者 ViaCyte
NCT02939118 对先前植入VC-01™的受试者进行为期一年的随访安全性研究 观测 1 先前植入VC-01组合产物，随后所有VC-01™单元的植入 ViaCyte
NCT04678557 一项评估VC-01在1型糖尿病患者中的安全性、植入和有效性的研究 VC-01组合产品：PEC-01细胞加载到Encaptra药物递送系统中 1，2 男性和非孕妇；1型糖尿病诊断至少3年；稳定、优化的糖尿病治疗方案；植入和外植体手术的可接受候选者；愿意并能够遵守协议要求；满足每个实验方案的胰岛素剂量要求 ViaCyte
NCT03162926 VC-02™联合产品在1型糖尿病患者中的安全性和耐受性研究 组合产品：VC-02组合产品：将PEC-01细胞加载到输送装置中 1 有无生育能力的男性和非孕妇；1型糖尿病诊断至少五（5）年；稳定的糖尿病治疗；愿意使用连续血糖仪；可接受的植入候选者 ViaCyte
NCT03163511 VC-02™联合产品在1型糖尿病和低血糖无意识受试者中的安全性、耐受性和有效性研究 VC-02组合产品：将PEC-01细胞加载到输送装置中 1，2 男性和非孕妇；1型糖尿病诊断至少五（5）年；低血糖意识不清或显著血糖不稳定；稳定的糖尿病治疗；愿意使用连续血糖仪；可接受的植入候选者 ViaCyte
NCT05210530 一项开放标签的FIH研究，评估VCTX210A组合产品在1型糖尿病受试者中的安全性和耐受性 组合产品：VCTX210A单位CRISPR-Cas9转基因PEC210A细胞加载到递送装置中 1 1型糖尿病诊断至少5年；入组前至少3个月的稳定、优化的糖尿病治疗方案 ViaCyte
NCT05565248 一项开放标签的FIH研究，评估VCTX211联合产品在1型糖尿病受试者中的安全性、耐受性和有效性 组合产品：VCTX211将CRISPR-Cas9转基因PEC211细胞加载到递送装置中 1，2 1型糖尿病诊断至少5年；入组前至少3个月的稳定糖尿病治疗方案 ViaCyte
MR-12-23-017130 自体多能干细胞来源的胰岛样细胞移植治疗1型糖尿病的探索性临床研究 干预性研究 1，2 1型糖尿病（包括已接受肝、肾等器官移植）患者；激发C肽< 0.3ng/mL；近3个月，糖化血红蛋白（HbA1c）7%~ 10%；患者在纳入此项目前12个月内，至少发生过1次严重的低血糖症；能够参与强化血糖管理，依从性较好 天津市第一中心医院
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