经血干细胞移植联合运动训练促进大鼠脊髓损伤康复的转录组学分析

doi:10.12300/j.issn.1674-5817.2024.031

实验动物与比较医学 ›› 2024, Vol. 44 ›› Issue (5): 531-542.DOI: 10.12300/j.issn.1674-5817.2024.031

经血干细胞移植联合运动训练促进大鼠脊髓损伤康复的转录组学分析

戚龙菊¹(), 陈世园¹^,³, 廖泽华¹^,³, 石袁虎¹^,³, 孙郁雨¹, 王庆华²()()

^1.南通大学附属南通第三医院, 南通市第三人民医院, 南通 226000
^2.南通大学实验动物中心, 南通 226001
^3.南通大学医学院, 南通 226001

收稿日期:2024-02-27 修回日期:2024-08-06 出版日期:2024-10-25 发布日期:2024-10-25
通讯作者: 王庆华（1978—），男，博士，讲师，研究方向为脊髓损伤后功能康复。E-mail： wangqh@ntu.edu.cn。ORCID： 0000-0003-3661-6408
作者简介:戚龙菊（1985—），女，硕士，副主任护师，研究方向为脊髓损伤后功能康复。E-mail： qilongjunt@163.com
基金资助:
南通市科技计划项目“GelMA水凝胶负载MenSCs-Exo调控miR-421 / MAGED1 /PI3K-Akt分子轴改善脊髓损伤后功能恢复的机制研究”(JC2023040);“MenSCs外泌体调控miR-421/MAGED1/PPARγ轴改善脊髓损伤后轴突再生机制及其临床诊疗技术攻关”(MS22022012);南通市卫生健康委员会科研课题面上项目“有氧运动调控GDNF减轻脊髓损伤后疼痛的机制及临床应用研究”(MS2022062)

Transcriptomic Analysis of Menstrual Blood-Derived Stem Cells Transplantation Combined with Exercise Training in Promoting Spinal Cord Injury Recovery in Rats

QI Longju¹(), CHEN Shiyuan¹^,³, LIAO Zehua¹^,³, SHI Yuanhu¹^,³, SUN Yuyu¹, WANG Qinghua²()()

^1.Affiliated Nantong Third Hospital of Nantong University, Nantong Third People's Hospital, Nantong 226000, China
^2.Laboratory Animal Center of Nantong University, Nantong 226001, China
^3.Medical School of Nantong University, Nantong 226001, China

Received:2024-02-27 Revised:2024-08-06 Published:2024-10-25 Online:2024-10-25
Correspondence to: WANG Qinghua (ORCID: 0000-0003-3661-6408), E-mail: wangqh@ntu.edu.cn

摘要/Abstract

摘要：

目的通过转录组测序分析探讨经血干细胞（menstrual blood-derived stem cells，MenSCs）移植联合运动训练治疗脊髓损伤（spinal cord injury，SCI）大鼠的潜在干预靶点和分子机制。方法选用SPF级2月龄雌性SD大鼠，采用第十胸椎（T10）处半切方式构建SCI模型后，分为SCI后MenSCs移植联合运动训练组［简称细胞与跑步机训练（cell and treadmill training，CTMT）组］和SCI组（作为对照），每组12只大鼠。其中，CTMT组大鼠在建模后1周于损伤局部显微注射MenSCs 1×10⁵个，随后进行为期2周的减重有氧运动训练。选取损伤处的脊髓组织进行转录组测序分析，获得SCI组和CTMT组大鼠的脊髓组织中mRNA表达数据，进行基因表达差异分析、GO功能富集分析、KEGG通路富集分析和蛋白质互作网络分析。同时，采用BBB评分评估两组大鼠的运动功能康复情况，苏木精-伊红（hematoxylin and eosin，HE）染色评估两组大鼠损伤局部的组织病理学改善程度，采用实时荧光定量PCR法和蛋白质印迹法对差异基因表达进行验证。结果转录组测序分析差异基因的表达数据显示，与SCI组相比，CTMT组有247个上调基因及174个下调基因，其中Bdnf、Hmox1、Sd4、Mmp3和Cd163等基因显著上调［|log2（FoldChange）|≥0.66，P<0.05］。KEGG通路富集分析与GO功能富集分析提示，这些差异基因主要参与了生长发育、代谢反应及免疫炎症过程，例如轴突生长、电子传递链等。其中，Bdnf基因富集在PI3K-Akt信号通路。BBB评分显示，MenSCs移植联合运动训练显著提高SCI大鼠的运动能力。HE染色提示治疗组大鼠的损伤局部病理变化程度显著减轻。实时荧光定量PCR法和蛋白质印迹法证明，CTMT组脊髓组织中脑源性神经营养因子（brain-derived neurotrophic factor，BDNF）mRNA和蛋白表达水平均显著高于SCI组（P<0.001）。结论 MenSCs移植联合运动训练治疗可能通过上调BDNF表达促进SCI大鼠运动功能的恢复，这为SCI的临床康复治疗提供了一个新思路。

关键词: 脊髓损伤, 转录组测序, 经血干细胞, 运动训练, 脑源性神经生长因子, 大鼠

Abstract:

Objective To explore the potential therapeutic targets and molecular mechanisms of menstrual blood-derived stem cells (MenSCs) transplantation combined with exercise training in promoting recovery in rats with spinal cord injury (SCI) through transcriptome sequencing analysis. Methods Female SD rats aged two months were selected and a SCI model was established by a hemisection at the tenth thoracic vertebra (T10). The rats were then divided into two groups: the Cell and Treadmill Training (CTMT) group, which received MenSCs transplantation and treadmill training after SCI, and the SCI group (control), with 12 rats in each group. One week after modeling, the CTMT group received a microinjection of 1×10⁵ MenSCs at the injury site, followed by two weeks of weight-supported aerobic exercise training. Spinal cord tissue from the injury site was selected for transcriptome sequencing, and mRNA expression data from both the SCI and CTMT groups were analyzed. Differential gene expression, GO (Gene Ontology) functional enrichment, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment, and protein-protein interaction (PPI) network analyses were performed. Motor function recovery was assessed using the Basso, Beattie, and Bresnahan (BBB) score, while histopathological changes at the injury site were evaluated through hematoxylin-eosin (HE) staining. Real-time fluorescent quantitative PCR and Western blotting were used to verify the expression of differentially expressed genes. Results Transcriptome sequencing analysis showed 247 upregulated genes and 174 downregulated genes in the CTMT group compared to the SCI group. Notably, genes such as Bdnf, Hmox1, Sd4, Mmp3, and Cd163 were significantly upregulated [|log2(FoldChange)|≥0.66, P<0.05]. KEGG pathway enrichment analysis and GO functional enrichment analysis indicated that these differentially expressed genes were mainly involved in growth and development, metabolic reactions, and immune-inflammatory processes, such as axon growth and the electron transport chain. The Bdnf gene was notably enriched in the PI3K-Akt signaling pathway. The BBB score showed that MenSCs transplantation combined with exercise training significantly improved the motor function of SCI rats. HE staining revealed that pathological changes at the injury site were significantly reduced in the treatment group. Furthermore, real-time quantitative PCR and Western blotting confirmed that brain-derived neurotrophic factor (BDNF) mRNA and protein expression levels in the CTMT group were significantly higher than those in the SCI group (P<0.001). Conclusion The combined exercise training with MenSCs effectively promotes the recovery of motor function in SCI rats by upregulating BDNF expression, providing a novel strategy for SCI treatment.

Key words: Spinal cord injury, Transcriptome sequencing, Menstrual blood-derived stem cells, Exercise training, Brain-derived neurotrophic factor, Rats

中图分类号:

R744

戚龙菊,陈世园,廖泽华,等. 经血干细胞移植联合运动训练促进大鼠脊髓损伤康复的转录组学分析[J]. 实验动物与比较医学, 2024, 44(5): 531-542. DOI: 10.12300/j.issn.1674-5817.2024.031.

QI Longju,CHEN Shiyuan,LIAO Zehua,et al. Transcriptomic Analysis of Menstrual Blood-Derived Stem Cells Transplantation Combined with Exercise Training in Promoting Spinal Cord Injury Recovery in Rats[J]. Laboratory Animal and Comparative Medicine, 2024, 44(5): 531-542. DOI: 10.12300/j.issn.1674-5817.2024.031.

图/表 7

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表达上调基因 Up-regulated gene	log2(差异倍数) log2 (FoldChange)	t值 t value	P值 P value	表达下调基因 Down-regulated gene	log2(差异倍数) log2 (FoldChange)	t值 t value	P值 P value
Psme3	2.542 363 895	2.672 366 157	0.040 381 267	Ptpdc1	-0.941 169 616	-2.823 151 331	0.033 418 310
Fgd2	1.870 409 798	5.277 683 881	0.002 476 179	RT1-N2	-0.961 937 408	-3.508 946 559	0.014 746 432
Sdc4	1.591 559 898	2.530 079 050	0.048 412 378	Cd79al	-1.007 349 648	-3.292 831 274	0.018 934 378
Cthrc1	1.259 963 833	3.177 793 692	0.021 693 595	Six4	-1.071 889 332	-15.482 205 520	0.000 009 930
RGD1302996	1.205 943 515	12.811 980 370	0.000 027 300	Matn2	-1.137 472 728	-3.927 529 073	0.009 277 287
Rabepk	1.201 118 420	2.962 815 910	0.028 125 989	Clec4a3	-1.273 541 156	-2.512 270 495	0.049 532 946
Bdnf	1.141 863 432	3.525 110 815	0.001 447 754	AABR07051551.2	-1.308 692 094	-2.825 531 707	0.033 319 465
Pkig	1.036 827 364	6.255 767 217	0.001 095 780	Cmtm3	-1.324 596 882	-5.371 453 966	0.002 279 345
AABR07065925.1	0.970 924 295	6.151 591 228	0.001 189 396	Dpy19l3	-1.623 739 520	-3.419 084 313	0.016 347 174
Ehmt1	0.944 670 184	6.578 534 619	0.000 855 702	Cd74	-2.034 312 055	-2.712 776 259	0.038 372 308
AABR07062152.1	0.939 321 669	6.344 499 009	0.001 022 741	Cxcl13	-2.697 259 120	-3.378 916 162	0.017 124 825
Ctbp1	0.898 198 041	5.961 511 123	0.001 385 227	RGD1563231	-3.151 695 504	-2.603 665 774	0.044 063 014
Akr1b10	0.859 136 478	3.868 507 287	0.009 887 528	Jchain	-3.390 915 739	-2.827 200 269	0.033 250 368
Ssh1	0.818 982 469	5.813 203 431	0.001 564 263	Ighm	-3.673 986 054	-3.369 414 954	0.017 314 754
Piga	0.785 438 853	3.303 450 635	0.018 700 031	AABR07060872.1	-5.052 108 514	-3.355 872 330	0.017 589 546

表达上调基因 Up-regulated gene	log2(差异倍数) log2 (FoldChange)	t值 t value	P值 P value	表达下调基因 Down-regulated gene	log2(差异倍数) log2 (FoldChange)	t值 t value	P值 P value
Psme3	2.542 363 895	2.672 366 157	0.040 381 267	Ptpdc1	-0.941 169 616	-2.823 151 331	0.033 418 310
Fgd2	1.870 409 798	5.277 683 881	0.002 476 179	RT1-N2	-0.961 937 408	-3.508 946 559	0.014 746 432
Sdc4	1.591 559 898	2.530 079 050	0.048 412 378	Cd79al	-1.007 349 648	-3.292 831 274	0.018 934 378
Cthrc1	1.259 963 833	3.177 793 692	0.021 693 595	Six4	-1.071 889 332	-15.482 205 520	0.000 009 930
RGD1302996	1.205 943 515	12.811 980 370	0.000 027 300	Matn2	-1.137 472 728	-3.927 529 073	0.009 277 287
Rabepk	1.201 118 420	2.962 815 910	0.028 125 989	Clec4a3	-1.273 541 156	-2.512 270 495	0.049 532 946
Bdnf	1.141 863 432	3.525 110 815	0.001 447 754	AABR07051551.2	-1.308 692 094	-2.825 531 707	0.033 319 465
Pkig	1.036 827 364	6.255 767 217	0.001 095 780	Cmtm3	-1.324 596 882	-5.371 453 966	0.002 279 345
AABR07065925.1	0.970 924 295	6.151 591 228	0.001 189 396	Dpy19l3	-1.623 739 520	-3.419 084 313	0.016 347 174
Ehmt1	0.944 670 184	6.578 534 619	0.000 855 702	Cd74	-2.034 312 055	-2.712 776 259	0.038 372 308
AABR07062152.1	0.939 321 669	6.344 499 009	0.001 022 741	Cxcl13	-2.697 259 120	-3.378 916 162	0.017 124 825
Ctbp1	0.898 198 041	5.961 511 123	0.001 385 227	RGD1563231	-3.151 695 504	-2.603 665 774	0.044 063 014
Akr1b10	0.859 136 478	3.868 507 287	0.009 887 528	Jchain	-3.390 915 739	-2.827 200 269	0.033 250 368
Ssh1	0.818 982 469	5.813 203 431	0.001 564 263	Ighm	-3.673 986 054	-3.369 414 954	0.017 314 754
Piga	0.785 438 853	3.303 450 635	0.018 700 031	AABR07060872.1	-5.052 108 514	-3.355 872 330	0.017 589 546

信号通路名 Term of signal pathway	计数 Count	富集系数 Gene ratio	P值 P value	基因名 Genes
Rap1 signaling pathway	10	2.506 265 664	0.010 546 665	Angpt1, Rassf5、Vegfb、Lpar1、Rapgef6、Efna4、Met、Bcar1、Rap1gap、Adcy6
Fluid shear stress and atherosclerosis	8	2.005 012 531	0.014 625 259	Prkaa1、Mef2c、Sdc4、Gsta4、Il1r2、Gstt3、Hmox1
PI3K-Akt signaling pathway	13	3.258 145 363	0.014 714 234	Prkaa1、Itga4、Angpt1、Bdnf、 Lama4、Lpar1、Vegfb、Ppp2r3b、Efna4、Gng7、Spp1、Col9a3、Met
ECM-receptor interaction	6	1.503 759 398	0.016 252 600	Sdc4、Itga4、Rgd1565355、Lama4、Spp1、Col9a3
Cytokine-cytokine receptor interaction	11	2.756 892 231	0.016 582 561	Cxcl10、Cntf、Il25、Tnfsf15、Tnfrsf9、Il1r2、Il21r、Ccr7、Ltb、Cxcl13、Ccl17
IL-17 signaling pathway	6	1.503 759 398	0.020 227 194	Cxcl10、Il25、Traf3、Mmp3、Lcn2、Ccl17
Pathways in cancer	17	4.260 651 629	0.020 758 687	Ctbp1、Lama4、Lpar1、Vegfb、Gstt3、Adcy6、Dll4、Gsta4、Peg12、Traf3、Gng7、Rassf5、Ccdc6、Hmox1、E2f3、Met
Chemical carcinogenesis- DNA adducts	5	1.253 132 832	0.040 451 734	Cyp3a9、Hpgds、Gsta4、Gstt3
Cholesterol metabolism	4	1.002 506 266	0.053 168 933	Rgd1565355、Apoh、Apoc1、Apoc3
Focal adhesion	8	2.005 012 531	0.054 767 437	Itga4、Lama4、Vegfb、Spp1、Col9a3、 Pip5k1c、Met、Bcar1
Metabolic pathway	36	9.022 556 391	0.068 256 357	Mtmr2、Gldc、Mtmr14、Pde3b、Gstt3、Hexd、Ehmt1、Adcy6、Abo、Selenbp1、Cyp3a9、Hpgds、Neu4、Spp1、Hmox1、St3gal6、Ca8、Pip5k1c、Csgalnact1、Car1、Uros、Qrsl1、 Coq7、Sirt3、Nt5c3b、Akr1b10、 Cyp2u1、Gsta4、Akr1c15、P4ha3、Piga、Cat、Acot1、Idnk
Mineral absorption	4	1.002 506 266	0.072 932 376	Atp7b、Slc40a1、Hmox1、Slc39a4
Toll-like receptor signaling pathway	5	1.253 132 832	0.074 076 217	Cxcl10、Irf3、Traf3、Spp1、Tlr3
Human papillomavirus infection	11	2.756 892 231	0.079 092 324	Irf3、Itga4、Traf3、Rt1-N2、Lama4、Spp1、Col9a3、Ppp2r3b、Rt1-T24-1、Tlr3、Llgl1
Glycosphingolipid biosynthesis	3	0.751 879 699	0.081 761 102	St3gal6、Abo

信号通路名 Term of signal pathway	计数 Count	富集系数 Gene ratio	P值 P value	基因名 Genes
Rap1 signaling pathway	10	2.506 265 664	0.010 546 665	Angpt1, Rassf5、Vegfb、Lpar1、Rapgef6、Efna4、Met、Bcar1、Rap1gap、Adcy6
Fluid shear stress and atherosclerosis	8	2.005 012 531	0.014 625 259	Prkaa1、Mef2c、Sdc4、Gsta4、Il1r2、Gstt3、Hmox1
PI3K-Akt signaling pathway	13	3.258 145 363	0.014 714 234	Prkaa1、Itga4、Angpt1、Bdnf、 Lama4、Lpar1、Vegfb、Ppp2r3b、Efna4、Gng7、Spp1、Col9a3、Met
ECM-receptor interaction	6	1.503 759 398	0.016 252 600	Sdc4、Itga4、Rgd1565355、Lama4、Spp1、Col9a3
Cytokine-cytokine receptor interaction	11	2.756 892 231	0.016 582 561	Cxcl10、Cntf、Il25、Tnfsf15、Tnfrsf9、Il1r2、Il21r、Ccr7、Ltb、Cxcl13、Ccl17
IL-17 signaling pathway	6	1.503 759 398	0.020 227 194	Cxcl10、Il25、Traf3、Mmp3、Lcn2、Ccl17
Pathways in cancer	17	4.260 651 629	0.020 758 687	Ctbp1、Lama4、Lpar1、Vegfb、Gstt3、Adcy6、Dll4、Gsta4、Peg12、Traf3、Gng7、Rassf5、Ccdc6、Hmox1、E2f3、Met
Chemical carcinogenesis- DNA adducts	5	1.253 132 832	0.040 451 734	Cyp3a9、Hpgds、Gsta4、Gstt3
Cholesterol metabolism	4	1.002 506 266	0.053 168 933	Rgd1565355、Apoh、Apoc1、Apoc3
Focal adhesion	8	2.005 012 531	0.054 767 437	Itga4、Lama4、Vegfb、Spp1、Col9a3、 Pip5k1c、Met、Bcar1
Metabolic pathway	36	9.022 556 391	0.068 256 357	Mtmr2、Gldc、Mtmr14、Pde3b、Gstt3、Hexd、Ehmt1、Adcy6、Abo、Selenbp1、Cyp3a9、Hpgds、Neu4、Spp1、Hmox1、St3gal6、Ca8、Pip5k1c、Csgalnact1、Car1、Uros、Qrsl1、 Coq7、Sirt3、Nt5c3b、Akr1b10、 Cyp2u1、Gsta4、Akr1c15、P4ha3、Piga、Cat、Acot1、Idnk
Mineral absorption	4	1.002 506 266	0.072 932 376	Atp7b、Slc40a1、Hmox1、Slc39a4
Toll-like receptor signaling pathway	5	1.253 132 832	0.074 076 217	Cxcl10、Irf3、Traf3、Spp1、Tlr3
Human papillomavirus infection	11	2.756 892 231	0.079 092 324	Irf3、Itga4、Traf3、Rt1-N2、Lama4、Spp1、Col9a3、Ppp2r3b、Rt1-T24-1、Tlr3、Llgl1
Glycosphingolipid biosynthesis	3	0.751 879 699	0.081 761 102	St3gal6、Abo

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