Analysis of the types and functions of CD34 + cells in full-thickness skin defect wounds of normal mice and diabetic mice by single-cell RNA sequencing
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摘要:
目的 单细胞RNA测序解析普通小鼠和糖尿病小鼠全层皮肤缺损创面中CD34 +细胞的类型与功能。 方法 该研究为实验研究。构建CD34 +细胞谱系追踪小鼠，实现CD34 +细胞在荧光条件下可视化。取6只7~8周龄雄性CD34 +细胞谱系追踪小鼠（设为糖尿病组），腹腔注射链脲佐菌素构建糖尿病模型，于小鼠13周龄时在其背部制备全层皮肤缺损创面；另取6只13周龄雄性CD34 +细胞谱系追踪小鼠（设为对照组），在其背部制备全层皮肤缺损创面。伤后4 d，分别收集对照组3只小鼠和糖尿病组2只小鼠创面组织，消化制备单细胞悬液，采用荧光活化细胞分选法筛选出CD34 +细胞后进行单细胞RNA测序，采用R语言的Seurat 4.0.2程序通过降维可视化和细胞聚类分析CD34 +细胞类型并筛选注释各CD34 +细胞亚群的标记基因，对2组小鼠创面组织间CD34 +成纤维细胞（Fb）、平滑肌细胞、角质形成细胞（KC）、类软骨细胞的差异表达基因（DEG）进行京都基因与基因组百科全书（KEGG）和基因本体论（GO）富集分析，探索细胞功能。 结果 伤后4 d，2组小鼠创面组织中CD34 +细胞均包含7种细胞类型，具体为内皮细胞、Fb、KC、巨噬细胞、T细胞、平滑肌细胞和类软骨细胞，其中Fb细分为5个亚群。与对照组比较，糖尿病组小鼠创面组织中的CD34 +内皮细胞、Fb亚群1、Fb亚群4、KC、类软骨细胞占比升高，CD34 +Fb亚群2、Fb亚群3和平滑肌细胞占比下降。注释CD34 +类软骨细胞、内皮细胞、Fb亚群1、Fb亚群2、Fb亚群3、Fb亚群4、Fb亚群5、KC、巨噬细胞、平滑肌细胞、T细胞的标记基因分别为转移相关肺腺癌转录本1、脂肪酸结合蛋白4、Gremlin 1、补体成分4B、H19印记母源表达转录本、Dickkopf Wnt信号通路抑制剂2、纤维调节蛋白、角蛋白5、CD74分子、G蛋白信号调节蛋白5、可诱导T细胞共刺激分子。KEGG和GO富集分析显示，与对照组比较，糖尿病组小鼠伤后4 d创面组织中CD34 +Fb差异表达显著的DEG显著富集于炎症反应、细胞外基质（ECM）组装、细胞增殖调控、衰老相关条目（ P值均<0.05），CD34 +平滑肌细胞差异表达显著的DEG显著富集于细胞迁移、凋亡过程、转录的正调控、吞噬体等条目（ P值均<0.05），CD34 +KC差异表达显著的DEG显著富集于线粒体功能、转录、神经退行性疾病相关条目（ P值均<0.05），CD34 +类软骨细胞差异表达显著的DEG显著富集于节律调控、ECM、病毒感染等相关条目（ P值均<0.05）。 结论 CD34 +细胞在普通小鼠和糖尿病小鼠全层皮肤缺损创面愈合过程中均存在高异质性，2种小鼠创面间CD34 +细胞亚群差异表达显著的DEG显著富集的相关功能与创面愈合过程紧密相关。 Abstract:Objective To analyze the types and functions of CD34 + cells in full-thickness skin defect wounds of normal mice and diabetic mice by single-cell RNA sequencing. Methods This study was an experimental study. The CD34 + cell lineage tracing mouse was produced, and the visualization of CD34 + cells under the fluorescent condition was realized. Six male CD34 + cell lineage tracing mice aged 7-8 weeks (designated as diabetic group) were intraperitoneally injected with streptozotocin to establish a diabetic model, and full-thickness skin defect wounds were prepared on their backs when they reached 13 weeks old. Another 6 male CD34 + cell lineage tracing mice aged 13 weeks (designated as control group) were also subjected to full-thickness skin defect wounds on their backs. On post-injury day (PID) 4, wound tissue was collected from 3 mice in control group and 2 mice in diabetic group, and digested to prepare single-cell suspensions. CD34 + cells were screened using fluorescence-activated cell sorting, followed by single-cell RNA sequencing. The Seurat 4.0.2 program in the R programming language was utilized for dimensionality reduction, visualization, and cell clustering analysis of CD34 + cell types, and to screen and annotate the marker genes for each CD34 + cell subpopulation. Kyoto encyclopedia of genes and genomes (KEGG) and gene ontology (GO) enrichment analysis was performed to analyze the differentially expressed genes (DEGs) of CD34 + fibroblasts (Fbs), smooth muscle cells (SMCs), keratinocytes (KCs), and chondrocyte-like cells (CLCs) in the wound tissue of two groups of mice for exploring cellular functions. Results On PID 4, CD34 + cells in the wound tissue of both groups of mice were consisted of 7 cell types, specifically endothelial cells, Fbs, KCs, macrophages, T cells, SMCs, and CLCs. Among these, Fbs were further classified into 5 subpopulations. Compared with those in control group, the proportions of CD34 + endothelial cells, Fbs subpopulation 1, Fbs subpopulation 4, KCs, and CLCs in the wound tissue of mice were increased in diabetic group, while the proportions of CD34 + Fbs subpopulation 2, Fbs subpopulation 3, and SMCs were decreased. The marker genes for annotating CD34 + CLCs, endothelial cells, Fbs subpopulation 1, Fbs subpopulation 2, Fbs subpopulation 3, Fbs subpopulation 4, Fbs subpopulation 5, KCs, macrophages, SMCs, and T cells were respectively metastasis-associated lung adenocarcinoma transcript 1, fatty acid binding protein 4, Gremlin 1, complement component 4B, H19 imprinted maternally expressed transcript, Dickkopf Wnt signaling pathway inhibitor 2, fibromodulin, keratin 5, CD74 molecule, regulator of G protein signaling 5, and inducible T-cell co-stimulator molecule. KEGG and GO enrichment analysis revealed that, compared with those in control group, DEGs with significant differential expression (SDE) in CD34 + Fbs from the wound tissue of mice in diabetic group on PID 4 were significantly enriched in terms related to inflammatory response, extracellular matrix (ECM) organization, regulation of cell proliferation, and aging (with Pvalues all <0.05), DEGs with SDE in CD34 + SMCs were significantly enriched in terms related to cell migration, apoptotic process, positive regulation of transcription, and phagosome (with P values all <0.05), DEGs with SDE in CD34 + KCs were significantly enriched in terms related to mitochondrial function, transcription, and neurodegenerative diseases (with P values all <0.05), and DEGs with SDE in CD34 + CLCs were significantly enriched in terms related to rhythm regulation, ECM, and viral infection (with P values all <0.05). Conclusions CD34 + cells display high heterogeneity in the healing process of full-thickness skin defect wounds in both normal mice and diabetic mice. The significantly enriched functions of DEGs with SDE in CD34 + cell subpopulations in the wound tissue of the two mouse groups are closely related to the wound healing process. -
Key words:
- Wound healing /
- Skin /
- CD34 /
- Single-cell RNA sequencing /
- Cell subpopulations /
- Marker genes /
- Cellular heterogeneity /
- Cell function
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参考文献
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1 2组全层皮肤缺损小鼠伤后各时间点创面形态及伤后4 d CD34 +细胞在创面中的定位。1A、1B.分别为对照组伤后0（即刻）、4 d创面形态，图1B中创面面积缩小，表皮再上皮化；1C、1D.分别为糖尿病组伤后0、4 d创面形态，图1D创面较图1B愈合延迟，仅有较薄的新生表皮；1E、1F.分别为CD34 +细胞在对照组、糖尿病组创面中的定位以及与角蛋白14共定位，CD34 +细胞位于创面周围组织的真皮、毛囊、血管周围和部分表皮细胞以及创面新生组织，在图1F创面周围组织的毛囊中减少 Alexa Fluor 647-4'，6-二脒基-2-苯基吲哚×20；1G、1H.分别为图1E、1F中方框中图形的放大图，可见CD34表达在创面新生表皮的部分细胞中 Alexa Fluor 647-4'，6-二脒基-2-苯基吲哚×60
注：对照组小鼠为CD34+细胞谱系追踪小鼠，糖尿病组小鼠为CD34+细胞谱系追踪糖尿病小鼠；CD34+细胞呈绿色，非CD34+细胞呈红色，角蛋白14呈白色，细胞核呈蓝色
2 2组全层皮肤缺损小鼠伤后4 d创面组织中CD34 +细胞亚群及其占比。2A、2B.分别为对照组、糖尿病组创面中CD34 +细胞亚群的二维流形近似和投影云图；2C.CD34 +细胞亚群占比
注：对照组小鼠为CD34+细胞谱系追踪小鼠，糖尿病组小鼠为CD34+细胞谱系追踪糖尿病小鼠
3 总体分析2组全层皮肤缺损小鼠伤后4 d创面组织中各CD34 +细胞亚群前10高表达标记基因及注释细胞亚群的标记基因。3A.热图展示各CD34 +细胞亚群前10高表达标记基因；3B.气泡图展示注释细胞亚群的标记基因
注：对照组小鼠为CD34+细胞谱系追踪小鼠，糖尿病组小鼠为CD34+细胞谱系追踪糖尿病小鼠；图3A从左至右各列依次分别为标记类软骨细胞的线粒体编码的细胞色素C氧化酶Ⅱ（MT-CO2）、MT-CO1、MT-CO3、线粒体细胞色素b、线粒体编码的烟酰胺腺嘌呤二核苷酸：泛醌氧化还原酶核心亚基1（MT-ND1）、线粒体编码的ATP合酶膜亚基6、MT-ND4、MT-ND2、MT-ND3、转移相关肺腺癌转录本1（MALAT1），标记内皮细胞的脂肪酸结合蛋白4（FABP4）、选择素P、血小板和内皮细胞黏附分子1、水通道蛋白1、CD36分子、跨膜4 L六家族成员1、质膜小囊泡相关蛋白、清道夫受体B类成员1、含载脂蛋白L结构域1、富含亮氨酸的α-2-糖蛋白1，标记成纤维细胞（Fb）亚群1的Gremlin 1（GREM1）、胰岛素样生长因子结合蛋白1、基质金属蛋白酶3（MMP3）、细胞视黄酸结合蛋白1、Fcγ受体Ⅱb、MMP11、凝血因子ⅩⅢ A链、ⅩⅩⅢ型胶原蛋白α1（COL23A1）、羧肽酶X-M14家族成员1、血清淀粉样蛋白A3，标记Fb亚群2的补体成分4B（C4B）、羧肽酶Z、COL1A2、COL1A1、AE结合蛋白1、转化生长因子β诱导蛋白、类纤维蛋白原样蛋白2、前胶原C-内肽酶增强子2、整合素亚基β样1、导向蛋白3B抗体，标记Fb亚群3的H19印记母源表达转录本（H19）、C-X-C趋化因子配体1（CXCL1）、CXCL5、正五聚蛋白3、分泌型卷曲相关蛋白2、微纤维相关蛋白5、白细胞介素（IL）1受体类似物2、蛋白聚糖4、血小板反应蛋白4和COL4A1，标记Fb亚群4的Dickkopf Wnt信号通路抑制剂2（DKK2）、外核苷酸焦磷酸酶/磷酸二酯酶2、凝血因子Ⅱ凝血酶受体、肽酶抑制剂16、细胞色素P450家族1亚家族B成员1、生长停滞特异性1、群体凝血因子C同源物、核受体亚家族4A组成员1、弹性蛋白、结缔组织生长因子，标记Fb亚群5的纤维调节蛋白（FMOD）、Wnt抑制因子1、腱调蛋白、胆囊收缩素、胶质蛋白、Ig超家族成员10（IGSF10）和IGSF5，标记角质形成细胞的角蛋白5、分层蛋白、角蛋白17、角蛋白15、角蛋白14、半乳糖凝集素7、与外周髓磷脂蛋白22相关的P53凋亡效应物质、胎盘表达转录本1、角蛋白6a和角质蛋白连接蛋白，标记巨噬细胞的CD74分子、组织相容性Ⅱ类抗原Aα、H2-Ab1、溶菌酶2、C-C型趋化因子配体3（CCL3）、S100钙结合蛋白A9、CCL4、CD14分子、丝氨酸和CXCL3，标记平滑肌细胞的G蛋白信号调节蛋白5（RGS5）、Notch受体3、肌球蛋白重链11、11号染色体开放阅读框96、内皮素受体B型、肌球蛋白轻链9、平滑肌肌动蛋白α-2、肌球蛋白轻链激酶、富含半胱氨酸的酸性分泌蛋白类似蛋白1、转胶蛋白，标记T细胞的可诱导T细胞共刺激分子（ICOS）、IL-17A、IL-17F、RGS1、IL-2受体亚单位β、溶酶体蛋白跨膜5、胚细胞抗原、环腺苷酸反应元件调制器、液泡蛋白分拣相关蛋白37B、RGS2；图3B横坐标下1为MALAT1，2为FABP4，3为GREM1，4为C4B，5为H19，6为DKK2，7为FMOD，8为角蛋白5，9为CD74分子，10为RGS5，11为ICOS；标记Fb亚群5的3个基因与其他细胞标记基因重叠
4 2组全层皮肤缺损小鼠伤后4 d创面组织间CD34 +成纤维细胞亚群1差异表达显著的DEG的GO和KEGG富集分析。4A.糖尿病组较对照组显著上调的DEG；4B.糖尿病组较对照组显著下调的DEG
注：对照组小鼠为CD34+细胞谱系追踪小鼠，糖尿病组小鼠为CD34+细胞谱系追踪糖尿病小鼠；KEGG为京都基因与基因组百科全书，GO为基因本体论，DEG为差异表达基因；图4A横坐标从左至右对应富集条目为破骨细胞分化、白细胞介素17（IL-17）信号通路、丝裂原活化蛋白激酶信号通路、抗原处理和呈递、Janus激酶-信号转导及转录活化因子信号通路、肿瘤坏死因子信号通路、细胞因子-细胞因子受体相互作用、核糖体、流体剪切应力与动脉粥样硬化、冠状病毒疾病-新型冠状病毒感染、蛋白质同源二聚活性、肽酶活性、金属内肽酶活性、相同蛋白质结合、蛋白酶结合、金属肽酶活性、肽酶抑制剂活性、核糖体的结构成分、受体结合、蛋白质结合、活化蛋白-1转录复合物、细胞外基质、核糖体、细胞表面、细胞核、核糖核蛋白复合体、细胞质、胞质核糖体、细胞外区、细胞外间隙、正调控血管生成、动物器官再生、肽酶活性的负调控、蛋白质加工、细胞对IL-1的反应、对肽酶激素的反应、细胞迁移的正向调节、对脂多糖的反应、细胞增殖的负调控、细胞翻译；图4B横坐标从左至右对应富集条目为阿米巴病、库欣综合征、EB病毒感染、磷脂酰肌醇3-激酶-蛋白激酶B信号通路、糖尿病并发症中的晚期糖基化终末产物-晚期糖基化终末产物受体信号通路、黏着斑、人乳头瘤病毒感染、癌症中的蛋白聚糖、细胞外基质受体相互作用、蛋白质的消化和吸收、肝素结合、蛋白酶结合、相同蛋白质结合、血小板衍生生长因子结合、整合素结合、钙离子结合、蛋白质结合、胶原结合、赋予拉伸强度的细胞外基质结构成分、细胞外基质结构成分、弹性纤维、内质网、细胞表面、肌膜、肌腱、基底膜、胶原三聚体、细胞外间隙、细胞外区、细胞外基质、炎症反应的负调控、成纤维细胞生长因子受体信号通路的负调控、细胞迁移、细胞对干扰素β的反应、胶原生物合成过程、细胞-基质黏附、创面修复、细胞黏附、胶原原纤维组装、细胞外基质组装
5 2组全层皮肤缺损小鼠伤后4 d创面组织间CD34 +成纤维细胞亚群2差异表达显著的DEG的GO和KEGG富集分析。5A.糖尿病组较对照组显著上调的DEG；5B.糖尿病组较对照组显著下调的DEG
注：对照组小鼠为CD34+细胞谱系追踪小鼠，糖尿病组小鼠为CD34+细胞谱系追踪糖尿病小鼠；KEGG为京都基因与基因组百科全书，GO为基因本体论，DEG为差异表达基因；图5A横坐标从左至右对应富集条目为癌症中的微小RNA、白细胞介素17信号通路、序列特异性双链DNA结合、肽酶活性、鸟苷三磷酸酶活性、金属肽酶活性、双链DNA结合、肝素结合、高密度脂蛋白颗粒、细胞外基质（ECM）、细胞外间隙、细胞外区、衰老、细胞对过氧化氢的反应、短期记忆、胶原原纤维组装、细胞增殖调控、细胞凋亡过程的正调控、正调控血管生成、对有机环状化合物的反应、对氧化应激的反应、细胞增殖的负调控；图5B横坐标从左至右对应富集条目为代谢途径、糖胺聚糖结合、肝素结合、钙离子结合、生长因子活性、胰岛素样生长因子结合、生长因子结合、ECM结构成分、基底膜、ECM、细胞外间隙、细胞外区、内皮细胞形态发生、细胞增殖的负调控、对维生素D的反应、钙离子转运的负调控、转化生长因子β产生的正调控、对糖皮质激素的反应、细胞对环腺苷酸的反应、细胞增殖的正向调节、ECM组装、衰老
6 较对照组显著上调的糖尿病组小鼠伤后4 d全层皮肤缺损创面组织中CD34 +平滑肌细胞差异表达基因的GO和KEGG富集分析
注：对照组小鼠为CD34+细胞谱系追踪小鼠，糖尿病组小鼠为CD34+细胞谱系追踪糖尿病小鼠；KEGG为京都基因与基因组百科全书，GO为基因本体论；横坐标从左至右对应富集条目为内吞作用、流体剪切应力与动脉粥样硬化、人巨噬细胞感染、癌症中的蛋白聚糖、癌症中的发病途径、吞噬体、整合素结合、蛋白激素结合、肽酶活性、相同蛋白质结合、泛素-蛋白质连接酶结合、金属离子结合、前mRNA内含子结合、酶结合、细胞外基质结合、蛋白质结合、线粒体、RNA聚合酶Ⅱ转录因子复合物、核基质、高尔基膜、核糖核蛋白复合体、内质网、核、细胞质、核质、细胞溶质、神经元凋亡过程的正调控、神经元投射发育的负调控、细胞质微管组织、镁离子传输、细胞外基质组装、信号肽处理、转录的正调控（DNA模板）、骨骼系统发育、凋亡过程、细胞迁移
7 2组全层皮肤缺损小鼠伤后4 d创面组织间CD34 +角质形成细胞差异表达显著的差异表达基因的GO和KEGG富集分析
注：对照组小鼠为CD34+细胞谱系追踪小鼠，糖尿病组小鼠为CD34+细胞谱系追踪糖尿病小鼠；KEGG为京都基因与基因组百科全书，GO为基因本体论；横坐标从左至右对应富集条目为非酒精性脂肪肝、糖尿病性心肌病、化学致癌-活性氧、氧化磷酸化、神经退行性变的途径、脊髓侧索硬化症、亨廷顿舞蹈症、阿尔兹海默病、帕金森病、朊病毒病、烟酰胺腺嘌呤二核苷酸（泛醌）活性、核苷酸活性、核酸结合、相同蛋白质结合、单链DNA结合、大分子复合物结合、酶结合、染色质结合、RNA结合、蛋白质结合、剪切体复合物、线粒体呼吸链复合体Ⅰ、呼吸链、核糖核蛋白复合体、细胞溶质、线粒体内膜、线粒体、细胞质、核质、细胞核、线粒体电子运输、DNA复制、核糖体RNA处理、信使RNA剪切（通过剪切体）、细胞周期、转录的正调控（DNA模板）、线粒体呼吸链复合体Ⅰ组装、有氧呼吸、RNA剪切、线粒体ATP合成偶联质子转运
8 2组全层皮肤缺损小鼠伤后4 d创面组织间CD34 +类软骨细胞差异表达显著的差异表达基因的GO和KEGG富集分析
注：对照组小鼠为CD34+细胞谱系追踪小鼠，糖尿病组小鼠为CD34+细胞谱系追踪糖尿病小鼠；KEGG为京都基因与基因组百科全书，GO为基因本体论；横坐标从左至右对应富集条目为阿米巴病、化学致癌-活性氧、糖尿病并发症中晚期糖基化终末产物（AGE）-AGE受体信号、内吞作用、流体剪切应力与动脉粥样硬化、抗原处理和呈递、糖尿病性心肌病、癌症中的蛋白聚糖、爱泼斯坦-巴尔病毒感染、卡波西肉瘤相关疱疹病毒感染、染色体DNA结合、整合素结合、细胞外基质（ECM）结构成分、肽酶活性、相同蛋白质结合、酶结合、泛素蛋白连接酶结合、胶原结合、大分子复合物结合、蛋白质结合、核内小体、大分子化合物、核糖核蛋白复合体、细胞表面、细胞外区、早期内膜体、ECM、核质、细胞质、细胞核、自然杀伤细胞介导的细胞毒性的保护、对过氧化氢的反应、蛋白质磷酸化的正调控、细胞迁移的正向调控、基因表达的昼夜节律调节、染色质组装、昼夜节律的调控、内皮细胞迁移的正调控、转录的负调控（DNA模板）、节律过程
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