人脐带来源的间充质干细胞对慢性间歇低氧小鼠的影响

doi:10.11958/20250965

天津医药 ›› 2025, Vol. 53 ›› Issue (8): 814-819.doi: 10.11958/20250965

人脐带来源的间充质干细胞对慢性间歇低氧小鼠的影响

于晓猛¹(), 索睿²^,³, 杜昕桃²^,³, 索莹²^,³, 阿亚拉·阿斯哈尔²^,³, 郝天旭²^,³, 赵晓赟²^,³^,⁴^,^△()

1 天津市医药科学研究所（邮编300020）
2 天津市胸科医院呼吸与危重症医学科
3 天津医科大学胸科临床学院
4 细胞生态海河实验室

收稿日期:2025-03-11 修回日期:2025-06-16 出版日期:2025-08-15 发布日期:2025-08-12
通讯作者: ^△E-mail：zxydoctor@163.com
作者简介:于晓猛（1988），男，助理研究员，主要从事动物实验和造模方面研究。E-mail：yxm8988@163.com
基金资助:
细胞生态海河实验室揭榜挂帅项目(HH24KYZX0009);天津市卫生健康科技项目临床重点专科专项(TJWJ2024ZK003)

Effects of human umbilical cord-derived mesenchymal stem cells on chronic intermittent hypoxia in mice

YU Xiaomeng¹(), SUO Rui²^,³, DU Xintao²^,³, SUO Ying²^,³, ASIHAER Ayala²^,³, HAO Tianxu²^,³, ZHAO Xiaoyun²^,³^,⁴^,^△()

1 Tianjin Institute of Pharmaceutical Science, Tianjin 300020, China
2 Department of Respiratory and Critical Care Medicine, Tianjin Chest Hospital
3 Tianjin Medical University Chest Clinical College
4 Haihe Laboratory of Cell Ecosystem

Received:2025-03-11 Revised:2025-06-16 Published:2025-08-15 Online:2025-08-12
Contact: ^△E-mail：zxydoctor@163.com

于晓猛, 索睿, 杜昕桃, 索莹, 阿亚拉·阿斯哈尔, 郝天旭, 赵晓赟. 人脐带来源的间充质干细胞对慢性间歇低氧小鼠的影响[J]. 天津医药, 2025, 53(8): 814-819.

YU Xiaomeng, SUO Rui, DU Xintao, SUO Ying, ASIHAER Ayala, HAO Tianxu, ZHAO Xiaoyun. Effects of human umbilical cord-derived mesenchymal stem cells on chronic intermittent hypoxia in mice[J]. Tianjin Medical Journal, 2025, 53(8): 814-819.

摘要/Abstract

摘要：

目的探究人脐带来源的间充质干细胞（hUCMSCs）调节GMP-AMP合酶-干扰素基因刺激物-核转录因子-κB（cGAS-STING-NF-κB）信号通路对慢性间歇缺氧（CIH）小鼠的干预价值。方法 24只C57BL/6小鼠分为对照组、模型组、hUCMSCs组和hUCMSCs+STING激活剂（DMXAA）组，每组6只。除对照组外，其余各组置于低氧舱中每日8 h共8周制备CIH小鼠模型。8周后，将小鼠麻醉后取心尖血，随后处死各组小鼠，收集肺组织。酶联免疫吸附试验检测血清白细胞介素（IL）-6、IL-1β、肿瘤坏死因子-α（TNF-α）、IL-17A水平，根据苏木素-伊红（HE）染色和马松（Masson）染色结果进行炎症评分和纤维化评分，免疫组化染色检测E钙黏蛋白（E-Cadherin）、α平滑肌肌动蛋白（α-SMA）表达情况，RT-qPCR检测cGAS、STING、NF-κB mRNA表达水平，免疫印迹实验检测E-Cadherin、N钙黏蛋白（N-Cadherin）、波形蛋白（Vimentin）、cGAS、NF-κB、α-SMA、STING蛋白表达水平。结果与对照组相比，模型组IL-6、IL-1β、TNF-α、IL-17A水平升高，炎症评分和纤维化评分升高，cGAS、STING、NF-κB mRNA表达水平升高， N-Cadherin、α-SMA、Vimentin、cGAS、STING、NF-κB蛋白表达水平升高；E-Cadherin蛋白表达水平降低（P<0.05）。与模型组相比，hUCMSCs组IL-6、IL-1β、TNF-α、IL-17A水平降低，cGAS、STING、NF-κB mRNA表达水平降低， N-Cadherin、α-SMA、Vimentin、cGAS、STING、NF-κB蛋白表达水平降低；E-Cadherin蛋白表达水平升高（P<0.05）。STING激活剂DMXAA逆转了hUCMSCs对CIH小鼠的保护作用（P<0.05）。结论经尾静脉注射hUCMSCs可减轻间歇低氧小鼠的肺组织炎症浸润及上皮间充质转化，可能与cGAS-STING-NF-κB信号通路下调有关。

关键词: 间质干细胞, 低氧, 炎症, 上皮-间质转化, 信号传导, 慢性间歇性低氧

Abstract:

Objective To investigate the therapeutic potential of human umbilical cord-derived mesenchymal stem cells (hUCMSCs) in modulating the cGAS-STING-NF-κB signaling pathway in chronic intermittent hypoxia (CIH) mice. Methods Twenty-four C57BL/6 mice were divided into the control group, the model group, the hUCMSCs group and the hUCMSCs+STING agonist (DMXAA) group, with 6 mice in each group. Except for the control group, the other groups were exposed to hypoxic conditions for 8 hours daily for a total of 8 weeks to establish the CIH mouse model. After 8 weeks, mice were anesthetized for cardiac blood collection followed by euthanasia and lung tissue collection. Serum levels of IL-6, TNF-α, IL-1β and IL-17A were measured by ELISA. Pulmonary inflammatory infiltration and collagen deposition were assessed by HE and Masson staining. E-Cadherin and α-SMA expression levels were evaluated by immunohistochemistry. Expression levels of cGAS, STING and NF-κB mRNA were detected by RT-qPCR, while protein expression levels of E-Cadherin, N-Cadherin, α-SMA, Vimentin, cGAS, STING and NF-κB were analyzed by Western blot assay. Results Compared with the control group, levels of IL-6, IL-1β, TNF-α and IL-17A increased in the model group, inflammation and fibrosis scores increased, mRNA expression levels of cGAS, STING and NF-κB increased, and protein expression levels of N-Cadherin, α-SMA, Vimentin, cGAS, STING and NF-κB increased. In contrast, E-Cadherin protein expression was significantly decreased (P<0.05). Compared with the model group, IL-6, IL-1β, TNF-α and IL-17A decreased in the hUCMSCs group, mRNA expression levels of cGAS, STING and NF-κB were decreased, protein expression levels of N-Cadherin, α-SMA, Vimentin, cGAS, STING and NF-κB were also decreased. Meanwhile, E-Cadherin protein expression was significantly increased (P<0.05). STING activator DMXAA reversed the protective effects of hUCMSCs in CIH mice (P<0.05). Conclusion Intravenous administration of hUCMSCs alleviates pulmonary inflammatory infiltration and epithelial-mesenchymal transition in mouse model of intermittent hypoxia, which may be related to the down-regulation of the cGAS-STING-NF-κBsignaling pathway.

Key words: mesenchymal stem cells, hypoxia, inflammation, epithelial-mesenchymal transition, signal transduction, chronic intermittent hypoxia

中图分类号:

R329.2

图/表 9

参考文献 21

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基因名称	引物序列（5′→3′）		产物大小/bp
cGAS	上游：	GAGGCGCGGAAAGTCGTAA	98
	下游：	TTGTCCGGTTCCTTCCTGGA	98
STING	上游：	GGTCACCGCTCCAAATATGTAG	135
	下游：	CAGTAGTCCAAGTTCGTGCGA	135
NF-κB	上游：	AGGCTTCTGGGCCTTATGTG	111
	下游：	TGCTTCTCTCGCCAGGAATAC	111
GAPDH	上游：	AGGTCGGTGTGAACGGATTTG	123
	下游：	TGTAGACCATGTAGTTGAGGTCA	123

基因名称	引物序列（5′→3′）		产物大小/bp
cGAS	上游：	GAGGCGCGGAAAGTCGTAA	98
	下游：	TTGTCCGGTTCCTTCCTGGA	98
STING	上游：	GGTCACCGCTCCAAATATGTAG	135
	下游：	CAGTAGTCCAAGTTCGTGCGA	135
NF-κB	上游：	AGGCTTCTGGGCCTTATGTG	111
	下游：	TGCTTCTCTCGCCAGGAATAC	111
GAPDH	上游：	AGGTCGGTGTGAACGGATTTG	123
	下游：	TGTAGACCATGTAGTTGAGGTCA	123

组别	IL-6	IL-1β
对照组	28.702±6.745	6.974±2.048
模型组	119.202±31.029^a	39.970±5.659^a
hUCMSCs组	41.570±11.875^b	20.756±6.226^b
hUCMSCs+DMXAA组	167.679±25.910^c	33.981±4.150^c
F	57.070^＊	56.140^＊
组别	TNF-α	IL-17A
对照组	6.542±1.511	7.042±0.793
模型组	23.165±4.200^a	23.900±8.091^a
hUCMSCs组	12.028±1.495^b	10.428±2.030^b
hUCMSCs+DMXAA组	24.743±3.744^c	27.427±2.267^c
F	51.183^＊	31.695^＊

组别	IL-6	IL-1β
对照组	28.702±6.745	6.974±2.048
模型组	119.202±31.029^a	39.970±5.659^a
hUCMSCs组	41.570±11.875^b	20.756±6.226^b
hUCMSCs+DMXAA组	167.679±25.910^c	33.981±4.150^c
F	57.070^＊	56.140^＊
组别	TNF-α	IL-17A
对照组	6.542±1.511	7.042±0.793
模型组	23.165±4.200^a	23.900±8.091^a
hUCMSCs组	12.028±1.495^b	10.428±2.030^b
hUCMSCs+DMXAA组	24.743±3.744^c	27.427±2.267^c
F	51.183^＊	31.695^＊

组别	炎症评分	纤维化评分
对照组	0.958±0.246	0.833±0.204
模型组	3.188±0.360^a	1.729±0.399^a
hUCMSCs组	1.117±0.229^b	1.167±0.303^b
hUCMSCs+DMXAA组	2.729±0.544^c	1.708±0.332^c
F	44.153^＊	11.373^＊

人脐带来源的间充质干细胞对慢性间歇低氧小鼠的影响

Effects of human umbilical cord-derived mesenchymal stem cells on chronic intermittent hypoxia in mice

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参考文献 21

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组别	E-Cadherin	α-SMA
对照组	1.708±0.376	0.938±0.234
模型组	0.813±0.234^a	1.813±0.342^a
hUCMSCs组	1.646±0.320^b	1.208±0.323^b
hUCMSCs+DMXAA组	1.083±0.313^c	1.708±0.313^c
F	11.496^＊	11.012^＊

组别	cGAS	STING	NF-κB
对照组	1.066±0.221	1.074±0.603	1.061±0.161
模型组	2.416±0.605^a	3.373±0.948^a	4.489±1.584^a
hUCMSCs组	1.279±0.698^b	1.405±0.426^b	2.152±1.094^b
hUCMSCs+DMXAA组	2.458±0.802^c	3.219±1.265^c	4.147±1.402^c
F	8.405^＊	11.288^＊	11.238^＊

组别		E-Cadherin		N-Cadherin
对照组		1.082±0.064		0.506±0.161
模型组		0.684±0.115^a		1.021±0.331^a
hUCMSCs组		0.932±0.078^b		0.606±0.171^b
hUCMSCs+DMXAA组		0.714±0.131^c		0.972±0.169^c
F		21.054^＊		8.308^＊
组别		α-SMA		Vimentin
对照组		0.813±0.085		0.562±0.051
模型组		1.164±0.196^a		1.449±0.147^a
hUCMSCs组		0.871±0.158^b		0.728±0.069^b
hUCMSCs+DMXAA组		1.172±0.210^c		1.256±0.303^c
F		7.530^＊		35.369^＊
组别	cGAS		STING		NF-κB
对照组	0.879±0.025		0.835±0.103		0.801±0.104
模型组	1.780±0.143^a		1.126±0.230^a		1.361±0.184^a
hUCMSCs组	0.961±0.039^b		0.773±0.150^b		0.925±0.048^b
hUCMSCs+DMXAA组	1.370±0.105^c		1.056±0.113^c		1.207±0.093^c
F	122.977^＊		7.057^＊		28.249^＊

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