合成生物学在干细胞工程化改造中的研究进展

doi:10.12211/2096-8280.2023-101

摘要/Abstract

摘要：

多能干细胞具备自我更新能力和多向分化潜能，其分化衍生的细胞及类器官在再生医学中具有巨大的应用潜力。但是干细胞临床转化仍然存在许多挑战。合成生物学“自上而下”的设计理念，结合基因编辑以及合成受体在内的强大工具库，能够赋予细胞新的功能，实现干细胞工程化改造。在此，本文总结了多能干细胞的临床应用和干细胞临床转化面临的主要挑战：干细胞分化衍生物的致瘤性、异质性、免疫原性，以及合成生物学在干细胞工程化改造中的应用：精确控制细胞命运、调控细胞通讯、优化类器官结构功能、监测并清除致瘤细胞。这些合成生物学工具为干细胞工程化改造提供了新的策略和平台，有望解决干细胞临床应用现存的诸多挑战，推动再生医学的进一步发展，实现“器官再生”这一核心目标。

关键词: 多能干细胞, 合成生物学, 细胞治疗, 类器官, 干细胞工程化改造

Abstract:

Pluripotent stem cells are characterized by self-renewal and multi-differentiation potential, which can be used to reverse structurally dysfunctional tissues and organs back to a structurally and functionally intact state of health through repair, replacement, or in-situ regeneration of new cells, tissues, and even organs. Cells or multicellular systems derived from pluripotent stem cell differentiation, especially organoids, have great potential for application in regenerative medicine. However, the clinical application of stem cell-related therapies is still in its infancy, and the current challenges to the clinical translation of stem cells include the tumorigenicity, heterogeneity, and immunogenicity of stem cell derivatives. Synthetic biology, with its "top-down" design concept and powerful toolkit including synthetic receptors and gene circuits, allows for the rational assembly of standardized modules. With the rapid development of gene editing technology and the deepening of cell biology research, the engineering object of synthetic biology has shifted from lower model organisms such as Escherichia coli or Saccharomyces cerevisiae to mammalian cells. On the one hand, "top-down" design strategies can engineer stem cells by giving them new functions, and on the other hand, the acquisition of new phenotypes by stem cells can test known gene functions and improve understanding of cell biology. Therefore, the application of these synthetic biology tools to stem cell engineering provides new strategies and platforms for relevant cell therapies or organ transplantation. It offers potential advantages in precise control of cell fate, regulation of cell communication, optimization of organoid structure and function, and monitoring and elimination of tumorigenic cells. These synthetic biology tools have provided new strategies and platforms for the engineering and reprogramming of stem cells, offering the potential to address current challenges in the clinical application of stem cells. They are expected to drive further advancements in regenerative medicine and ultimately achieve the core goal of regenerative medicine, which is organ regeneration.

Key words: pluripotent stem cell, synthetic biology, cell therapy, organoid, stem cell engineering

中图分类号:

蔡冰玉, 谭象天, 李伟. 合成生物学在干细胞工程化改造中的研究进展[J]. 合成生物学, DOI: 10.12211/2096-8280.2023-101.

Bingyu CAI, Xiangtian TAN, Wei LI. Advances in synthetic biology for engineering stem cell[J]. Synthetic Biology Journal, DOI: 10.12211/2096-8280.2023-101.

图/表 3

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工程化干细胞改造技术
基因编辑技术					合成受体
条件性基因敲除系统	ZFN系统	TALEN系统	CRISPR/Cas系统		合成传感器 + 天然致动器		天然传感器 + 合成致动器	合成传感器 + 合成致动器
条件性基因敲除系统	ZFN系统	TALEN系统	CRISPR/Cas系统		CARs、SyCyR		Tango、ChaCha	synNotch、SNIPR、MESA
工程化干细胞改造策略
细胞命运决定		细胞通讯		类器官结构功能优化		强化细胞治疗功能		监测并消除致瘤细胞

工程化干细胞改造技术
基因编辑技术					合成受体
条件性基因敲除系统	ZFN系统	TALEN系统	CRISPR/Cas系统		合成传感器 + 天然致动器		天然传感器 + 合成致动器	合成传感器 + 合成致动器
条件性基因敲除系统	ZFN系统	TALEN系统	CRISPR/Cas系统		CARs、SyCyR		Tango、ChaCha	synNotch、SNIPR、MESA
工程化干细胞改造策略
细胞命运决定		细胞通讯		类器官结构功能优化		强化细胞治疗功能		监测并消除致瘤细胞

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