空间分辨代谢组学在疾病诊断研究中的应用进展

doi:10.13560/j.cnki.biotech.bull.1985.2023-0351

摘要/Abstract

摘要：

基于质谱成像技术发展而来的空间分辨代谢组学，能够直接对动植物组织或细胞中的代谢产物进行原位定性、定量，以及借力图像整体或局部特征对代谢物进行结构、含量、时空动态变化及其空间分布定位分析，识别潜在可靠的生物标志物。该技术具有高灵敏度、高分辨率、高可视化性以及无需标记等优点，已被越来越广泛地运用在临床疾病诊断与研究中。本文主要总结了近年来空间分辨代谢组学的技术发展，阐述其在肿瘤、神经精神疾病、糖尿病等疾病中的应用进展，旨在为空间分辨代谢组学在疾病诊断中的应用提供借鉴和参考。

关键词: 空间分辨代谢组学, 质谱成像, 疾病诊断, 代谢物, 生物标志物

Abstract:

Mass spectrometry imaging（MSI）based on spatially resolved metabolomics（SRM）has been recently developed to be a powerful technology. SRM can not only directly identify and quantify the metabolites in animal and plant tissues or cells in situ, but also use overall or local features of the image to determine the structure, content, spatiotemporal dynamic change, and spatial distribution of metabolites. It also may identify potential metabolic biomarkers. This technology has the advantages of high sensitivity, high resolution, judicious visualization and label-free, and therefore has been more and more widely applied in clinical disease diagnosis and research. This review summarizes some of the technological advances of SRM in recent years, and its emerging application in the fields of tumor, neuropsychiatric disorder, diabetes mellitus, among others, in an attempt to guide future application of SRM in disease diagnosis.

Key words: spatially resolved metabolomics（SRM）, mass spectrometry imaging（MSI）, disease diagnosis, metabolite, biomarker

何诗瑜, 曾仲大, 李博岩. 空间分辨代谢组学在疾病诊断研究中的应用进展[J]. 生物技术通报, 2024, 40(1): 145-159.

HE Shi-yu, ZENG Zhong-da, LI Bo-yan. Application Progress of Spatially Resolved Metabolomics in Disease Diagnosis Research[J]. Biotechnology Bulletin, 2024, 40(1): 145-159.

图/表 6

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检测方法 Detection method	NMR	GC-MS	LC-MS	MSI
灵敏度	一般	较高	高	高
分辨率	较高	较高	高	高，可达μm级
重现性	好	较好	较好	好
样品前处理方式	较简单，无需衍生化	繁琐，样品需做衍生化处理	简单	简单，样品无需衍生化且无需标记
适用范围	分子物质，可检测糖类、氨基酸类等含氢水溶性小分子	分子物质，可检测极性小的易挥发、可衍生化且不易降解的含活性氢基团物质	分子物质，可检测极性大的化合物，或不稳定、难挥发、难衍生化的物质	组织、单细胞均可

检测方法 Detection method	NMR	GC-MS	LC-MS	MSI
灵敏度	一般	较高	高	高
分辨率	较高	较高	高	高，可达μm级
重现性	好	较好	较好	好
样品前处理方式	较简单，无需衍生化	繁琐，样品需做衍生化处理	简单	简单，样品无需衍生化且无需标记
适用范围	分子物质，可检测糖类、氨基酸类等含氢水溶性小分子	分子物质，可检测极性小的易挥发、可衍生化且不易降解的含活性氢基团物质	分子物质，可检测极性大的化合物，或不稳定、难挥发、难衍生化的物质	组织、单细胞均可

类别 Item	MALDI-MSI	SIMS imaging	LAESI-MSI	DESI-MSI
离子源	MALDI	SIMS	LAESI	DESI
电离类型	软	静态：软动态：硬	软	软
空间分辨率	最低可至1.4，多数 5-100	静态：0.1-10 动态：0.01-1	2.4-200	最低可至10-20，多数50-200
样品制备	需要	需要	无需	几乎无需
质量范围/Da	300-100 000	静态：1-3 000 动态：1-250	1-5 000	100-10 000
扫描深度/μm	0.1-20	0.5-10	0.1-50	1-500
检测限	amol-fmol	fmol-pmol	fmol-pmol	fmol-pmol
适用范围	代谢物、脂类、多聚糖、多肽、蛋白质、核酸	元素、代谢物、脂类	代谢物、脂类、多肽、含水量大的样本	代谢物、脂类、多肽
定量能力	可行	静态：困难动态：可行	可行	可行
工作环境	常压/真空	真空	常压	常压

类别 Item	MALDI-MSI	SIMS imaging	LAESI-MSI	DESI-MSI
离子源	MALDI	SIMS	LAESI	DESI
电离类型	软	静态：软动态：硬	软	软
空间分辨率	最低可至1.4，多数 5-100	静态：0.1-10 动态：0.01-1	2.4-200	最低可至10-20，多数50-200
样品制备	需要	需要	无需	几乎无需
质量范围/Da	300-100 000	静态：1-3 000 动态：1-250	1-5 000	100-10 000
扫描深度/μm	0.1-20	0.5-10	0.1-50	1-500
检测限	amol-fmol	fmol-pmol	fmol-pmol	fmol-pmol
适用范围	代谢物、脂类、多聚糖、多肽、蛋白质、核酸	元素、代谢物、脂类	代谢物、脂类、多肽、含水量大的样本	代谢物、脂类、多肽
定量能力	可行	静态：困难动态：可行	可行	可行
工作环境	常压/真空	真空	常压	常压

疾病类型 Disease type	研究对象 Research object	研究技术与方法 Research techniques and methods	关键代谢物 Key metabolite	参与途径 Ways of participation	文献 Reference
肿瘤	前列腺癌	MALDI-MSI、DESI-MSI	丝裂原活化蛋白激酶/细胞外信号调节激酶、硫酸胆固醇、磷脂酰肌醇和胆绿素还原酶B，多种磷脂类丰度增加，柠檬酸盐水平显著下降	Mitogen-activated protein kinase（MAPK）, Phosphatidylinositol 3-kinase（PI3K）代谢通路	[16,66 -67]
	乳腺癌	MALDI-MSI、DESI-MSI	L-肉碱和短链酰基肉碱，肉碱棕榈酰转移酶1A、肉碱/酰基肉碱转移酶和肉碱棕榈酰转移酶2，脂肪酸和磷脂组成明显变化	脂肪酸β-氧化途径	[42,68 -69]
	膀胱癌	红外基质辅助激光解吸电喷雾电离质谱成像IR-MALDESI MSI	游离脂肪酸显著增加，肌醇磷脂、磷脂酸聚集	脂质代谢	[70]
	结直肠癌	AFADESI-MSI、MALDI-MSI、DESI-MSI	N,O-双-（三甲基甲硅烷基）苯丙氨酸丰度上调，长链脂肪酸、极长链脂肪酸和多种氧化磷脂增加	脂质代谢	[14,71]
	胃癌	液体提取-电声喷雾电离-傅里叶变换离子回旋共振质谱成像LE-ESSI MSI FTICR-MSI、MALDI-MSI、DESI-MSI	血清磷脂酰胆碱（32:0）、磷脂酰胆碱（34:3）	胆碱代谢	[72-73]
	肝细胞癌	AFADESI-MSI	有机酸及其衍生物丰度上调，不同微区存在差异代谢物	氨基酸代谢（β-丙氨酸代谢、精氨酸和脯氨酸代谢），胆碱代谢，甘油磷脂代谢	[74-75]
	非小细胞肺癌	2D-imaging MSI	鞘磷脂和多种磷脂酰丝氨酸减少，以及磷脂酰乙醇胺和磷脂酰胆碱种类增加	磷脂谱代谢差异	[76]
	甲状腺癌	2D DESI-MSI	神经酰胺和甘油磷酸肌醇相对丰度上调	脂质代谢	[77]
	口腔鳞状细胞癌	DESI-MSI	14种特征脂质代谢物	脂质代谢	[78]
神经精神疾病	阿尔茨海默病	TOF-SIMS imaging、MALDI-MSI	硫苷脂丰度下调，腺嘌呤和腺嘌呤核糖核酸浓度显著下降，溶血磷脂酰肌醇以及花生四烯酸缀合的磷脂酰肌醇显示出在Aβ斑块特异性定位	嘌呤代谢途径，脂质与β淀粉样蛋白（Aβ）肽异常沉积驱动阿尔茨海默病发生发展的机制	[79]
	癫痫	DESI-MSI	磷脂酰胆碱和磷脂酰乙醇胺表达减少	Kennedy代谢途径	[53]
	中风	MALDI-MSI	谷氨酸、N-乙酰天冬氨酸呈差异性变化	氨基酸代谢	[80]
	精神分裂症	DESI-MSI	磷脂酰胆碱水平降低	胆碱代谢	[55]
	创伤性脑损伤	MALDI-MSI	酰基肉碱代谢差异	脂肪酸代谢	[81]
糖尿病及其并发症	糖尿病	MALDI-MSI、 Nano-DESI-MSI	肾小球三磷酸腺苷与单磷酸腺苷（ATP/AMP）的比例增加，且鞘磷脂（d18:1/16:0）在糖尿病大鼠中累积、酰基肉碱在肾组织中明显增加	鞘脂代谢	[59]
	糖尿病肾病	液体萃取表面分析质谱成像LESA-MSI、AFADESI-MSI、MALDI-MSI	多种脂肪酸、磷脂类代谢物有明显差异性改变且改变具有区域特异性，肉碱类和胆碱类代谢物也发生表达差异	亚油酸代谢、花生四烯酸代谢、α-亚麻酸代谢、甘油磷脂代谢和三羧酸循环（TCA）	[18,60,82]
	糖尿病脑病	AFADESI-MSI	脂肪醛（Fals）在DE大鼠脑中区域性特异性分布并且在大脑皮层、海马体和杏仁核中富集，脑区域特异性发生脂代谢紊乱，线粒体代谢功能障碍	糖酵解和戊糖磷酸途径（PPP）	[62]
其他	乙肝	MALDI-MSI	磷脂酰胆碱显著减少	胆碱代谢	[64-65]
	传染病	MALDI-MSI	脂质A、肉毒素（SAP1）、前列腺素E2（PGE2）代谢异常	脂肪酸代谢	[63]
	动脉粥样硬化	DESI-MSI、MALDI-MSI	鞘磷脂和氧化胆固醇酯丰度上调	坏死性凋亡、鞘脂信号通路和甘油磷脂代谢	[83]
	视网膜病变	MALDI-MSI	磷脂酰乙醇胺在病变部位丰度下调，鞘氨醇髓鞘则更丰富	氨基酸代谢	[84]
	心力衰竭	TOF-SIMS imaging	存在差异代谢谱，细胞中代谢差异体现在溶血磷脂酸、PI、PE	脂质代谢	[85]