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RUNX1对牙髓干细胞的增殖及成骨、成脂分化的影响

崔钰嘉, 郭黛墨, 孙建勋, 杨月翼, 谢静, 张德茂

崔钰嘉, 郭黛墨, 孙建勋, 等. RUNX1对牙髓干细胞的增殖及成骨、成脂分化的影响[J]. 四川大学学报(医学版), 2021, 52(3): 416-422. DOI: 10.12182/20210560101
引用本文: 崔钰嘉, 郭黛墨, 孙建勋, 等. RUNX1对牙髓干细胞的增殖及成骨、成脂分化的影响[J]. 四川大学学报(医学版), 2021, 52(3): 416-422. DOI: 10.12182/20210560101
CUI Yu-jia, GUO Dai-mo, SUN Jian-xun, et al. The Roles of RUNX1 in the Proliferation and Osteogenic and Adipogenic Differentiation of Dental Pulp Stem Cells[J]. Journal of Sichuan University (Medical Sciences), 2021, 52(3): 416-422. DOI: 10.12182/20210560101
Citation: CUI Yu-jia, GUO Dai-mo, SUN Jian-xun, et al. The Roles of RUNX1 in the Proliferation and Osteogenic and Adipogenic Differentiation of Dental Pulp Stem Cells[J]. Journal of Sichuan University (Medical Sciences), 2021, 52(3): 416-422. DOI: 10.12182/20210560101

RUNX1对牙髓干细胞的增殖及成骨、成脂分化的影响

基金项目: 国家自然科学基金(No. 81600840、No. 81771047、No. 82001062)和四川大学华西口腔医院探索与研发项目(No. RD-02-201912)资助
详细信息
    通讯作者:

    张德茂: E-mail:demao.zhang666@foxmail.com

The Roles of RUNX1 in the Proliferation and Osteogenic and Adipogenic Differentiation of Dental Pulp Stem Cells

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  • 摘要:
      目的  研究Runt相关转录因子1(Runt-related transcription factor 1,RUNX1)对牙髓干细胞(dental pulp stem cell,DPSC)增殖、成骨向分化、成脂向分化的作用。
      方法  转染建携带目的基因RUNX1和绿色荧光蛋白(GFP)的慢病毒载体至DPSC 48 h后,通过荧光标记GFP和Western blot确定转染效率。过表达 RUNX1后,CCK-8法和克隆形成实验检测DPSC增殖能力和克隆形成能力,流式细胞术检测DPSC细胞周期。转染沉默 RUNX1的siRNA至DPSC 。矿化诱导后,通过碱性磷酸酶活性检测和茜素红染色,观察过表达/沉默RUNX1对DPSC成骨向分化的影响;成脂诱导后,通过油红O染色,观察过表达/沉默RUNX1对DPSC成脂向分化的影响。
      结果  转染慢病毒后 RUNX1蛋白在DPSC中过表达,荧光检测示慢病毒转染成功,稳定表达GFP蛋白的细胞均在70%以上。过表达RUNX1后DPSC细胞增殖速度增快、克隆形成能力增强、S期细胞比例增加(P<0.05)。RUNX1过表达后DPSC的碱性磷酸酶活性和矿化结节形成能力增强,脂滴减少(P<0.05);RUNX1敲低后DPSC的碱性磷酸酶活性和矿化结节形成能力减弱,脂滴增加(P<0.05)。
      结论  RUNX1促进DPSC增殖和成骨向分化,抑制DPSC成脂向分化。

     

    Abstract:
      Objective  To investigate the influence of Runt-related transcription factor 1 (RUNX1) on the proliferation, osteogenic differentiation and adipogenic differentiation of dental pulp stem cells (DPSC) in vitro.
      Methods  DPSCs were transfected through lentiviral vector carrying the target gene RUNX1 and green fluorescent protein (GFP). After 48 h, transfection efficiency was determined with the fluorescent marking of GFP and Western blot. The effect of the overexpression of RUNX1 on DPSC proliferation and colony formation was determined with CCK-8 and colony formation assay; cell cycle of DPSC was detected by flow cytometry. RUNX1 siRNA was transfected into the DPSCs. After mineralized induction, the effect of RUNX1 overexpression/silencing on the osteogenetic differentiation of DPSC was tested by alkaline phosphatase (ALP) staining and alizarin red staining. After adipogenic induction, oil red O staining was done in order to observe the effect of overexpression/silencing of RUNX1 on the adipogenic differentiation of DPSC.
      Results  RUNX1 protein was overexpressed in DPSC after lentiviral transfection. Fluorescent test showed successful transfection of lentiviral transfection and over 70% of the cells showed stable expression of GFP protein. The proliferation and colony-formation efficiency of DPSC was enhanced significantly and the proportion of DPSCs in the S phase was significantly increased in the RUNX1-overexpessed group (P<0.05). ALP activity and mineralized nodule formation ability increased, while lipid droplets decreased in the RUNX1-overexpessed group (P<0.05). ALP activity and mineralized nodule formation ability decreased, while lipid droplets increased in the RUNX1 knockdown group (P<0.05).
      Conclusion  RUNX1 promotes DPSC proliferation and osteogenic differentiation while it inhibits DPSC adipogenic differentiation.

     

  • 随着我国社会人口的老龄化,老年人股骨颈坏死、关节炎的发病人数逐年增加[1-2]。全髋关节置换术是治疗股骨颈坏死和慢性难治性髋关节疼痛的常用手术之一。术后常用X线、CT及MRI进行复查。X线是评价金属植入物位置、稳定性的基本方式,但其重叠影像会影响髋关节解剖细节的显示;MRI检查时间长、禁忌证多,且金属植入物会影响磁场均匀性导致植入物周围组织显示欠佳[3]。CT可以对金属植入物本身的情况、植入物与周围组织的关系、周围软组织的变化等进行评估,在关节置换术后的复查中具有不可替代的作用[4-6]。但是,植入物的金属伪影会对CT图像产生影响。伪影是由人体组织和金属植入物的密度差异引起的,产生的原因包括光子饥饿效应、射线束硬化效应以及散射线等[7]。传统的滤波反投影(filter backup projection,FBP)是CT的基础算法,其缺点是在CT图像中极大地增加了金属植入物的射线硬化效应,使图像伪影重、噪声大。金属伪影校正(metal artifact correction,MACTM)是联影公司研发的重建算法,在减少金属伪影的同时,能够保留金属植入物的信息及邻近组织的解剖细节。本研究探讨MAC技术在全髋关节置换术后CT复查中的应用,旨在提高全髋关节置换术后的CT图像质量。

    回顾性收集2018年12月−2020年3月由于全髋关节置换术后在四川大学华西医院行髋关节CT复查患者的资料。纳入标准:①全髋关节置换术后;②CT复查在联影uCT780上进行,且扫描方案与1.2所述一致。排除标准:①运动伪影严重,影响诊断;②金属植入物脱位或术后关节间隙完全融合,无法进行测量分析。最后收集72例患者资料,其中男33例,女39例,年龄21~84岁,平均年龄(56.05±13.03)岁。其中,在本院手术者41例,外院手术31例。因本研究为回顾性研究,故没有进行伦理审查。

    所有患者均采用联影公司uCT780行髋关节CT螺旋扫描。患者仰卧位头先进,身体正中矢状面垂直并对准床面中线,尽量保持两侧髋关节对称。扫描范围从髋臼上缘5 cm至金属植入物下缘5 cm,包括全双髋关节及金属植入物,扫描方向从头到足侧。扫描参数:管电压140 kV、管电流量180 mAs、准直器160 mm×0.5 mm、矩阵512×512、螺距0.9875,球管旋转时间0.8 s,重建层厚1 mm、层间距0.8 mm、窗宽400 Hu、窗位30 Hu。所有患者扫描后分别采用FBP和MACTM两种算法对图像进行重建。

    将FBP和MACTM的1 mm图像载入UIDeal67工作站,勾画兴趣区(region of interest,ROI)并进行测量。每个患者均选取3个层面,分别为髋臼上缘层面、髋臼中心层面、髋臼下缘层面,勾画金属高低密度伪影区、金属髋关节间隙、金属旁骨组织、腰大肌、膀胱及对侧臀部皮下脂肪的ROI,ROI大小为50~70 mm2,其中金属髋关节间隙ROI大小为10~20 mm2。测量ROI内的CT图像中各组织与X线衰减系数相当的对应值(CT值X)及图像噪声(CT值的标准差,standard deviation,SD) [8-9],计算3个层面平均值。以对侧臀部皮下脂肪CT值(CT值脂肪)和SD脂肪为参考,计算金属旁骨组织、腰大肌以及膀胱的信噪比(signal to noise ratio,SNR)和对比噪声比(contrast to noise rati,CNR)。两组图像测量时层面一致,ROI大小及位置完全复制[10]。ROI放置如图1。SNR=CT值X/SD脂肪,CNR=(CT值X-CT值脂肪)/SD脂肪

    图  1  患者男,65岁,右髋关节置换术后1周CT复查FBP(A)和MAC(B)后处理算法图像中ROI的设置(重建1 mm图像)
    Figure  1.  Male patient,65 years old, one week after right hip arthroplasty, CT review of FBP (A) and MAC (B) post-processing algorithm image in ROI settings (reconstructed 1 mm image)
    ROI were placed close to the metal implant, in the hypo- and hyperdense region (green ROIs), hip joint space (red ROI), adjacent bone (blue ROI), psoas muscle (yellow ROI), bladder (black ROI), subcutaneous fat of contralateral buttocks (orange ROI).

    由2名放射科医师(分别有5年和8年的骨关节影像诊断经验)采用盲法对两组1 mm重建图像进行主观评分,两位医师意见不一致时通过协商达成一致意见。评分为5分制,评分标准[11-12]:5分,图像没有伪影,金属植入物外形、位置、间隙以及金属周围组织清晰显示,图像质量佳;4分,图像少量伪影,金属植入物外形、位置、间隙以及金属周围组织能够识别,图像质量较好;3分,图像有伪影,金属植入物外形、位置、间隙以及金属周围组织部分可见,图像质量一般;2分,图像较多伪影,金属植入物外形、位置、间隙以及金属周围组织少部分可见,图像质量较差;1分,图像大量伪影,金属植入物外形、位置、间隙以及金属周围组织不可见,图像质量差。

    采用Kologorov-Smirnov进行计量资料的正态性检验,满足正态分布的资料用$\bar x \pm s$表示,不满足正态分布的计量资料用中位数(P25, P75)表示。根据是否满足正态分布,选择配对样本t检验或Wilcoxon秩检验比较FBP组和MAC组的金属高低密度伪影区和金属髋关节间隙的CT值、噪声,金属旁骨组织、腰大肌与膀胱的SNR和CNR,以及两组之间的主观评分,P<0.05为差异有统计学意义。采用Kappa检验评价2名医师间主观评分的一致性,Kappa值为0表示无一致性,Kappa值<0.40为一致性较差,0.40≤Kappa值<0.75为一致性中等,Kappa值≥0.75为一致性较好。

    MACTM组金属高密度伪影区ROI平均CT值比FBP组减少了146.42 Hu(95%CI:124.554~168.285),即降低了38.19%,差异有统计学意义(P<0.05)。MACTM组平均噪声值比FBP组减少了18.05(95%CI:13.962~22.138),即降低25.35%,差异有统计学意义(P<0.05)。见表1

    表  1  两组图像金属高低密度伪影区、金属髋关节间隙的CT值和图像噪声比较
    Table  1.  Comparison of CT value and image noise in hypo- and hyperdensity metal artifact areas, metal hip joint space between the two groups
    GroupnCT value/HuImage noise value
    Hyperdense
    artifacst region
    Hypodense
    artifacst region
    Metal hip
    joint space
    Hyperdense
    artifacst region
    Hypodense
    artifacst region
    Metal hip
    joint space
    FBP 72 383.39±145.34 −313.82±137.25 134.97±272.62 71.20±55.25 59.91±27.38 172.21±90.53
    MACTM 72 236.97±173.47 −163.90±15.74 38.50±112.60 53.15±47.13 41.68±17.46 89.82±79.28
    t 13.352 −8.834 3.397 8.803 6.520 8.777
    P <0.05 <0.05 <0.05 <0.05 <0.05 <0.05
    下载: 导出CSV 
    | 显示表格

    MACTM组金属低密度伪影区ROI平均CT值比FBP组增加了149.92 Hu(95%CI:183.753~116.077),即增加47.77%,差异有统计学意义(P<0.05)。MACTM组平均噪声值比FBP组减少了18.24(95%CI:12.660~23.813),即降低30.44%,差异有统计学意义(P<0.05)。见表1

    金属髋关节间隙中,MACTM组CT值比FBP组减少了96.46 Hu(95%CI:39.837~153.098),即降低了71.47%,差异有统计学意义(P<0.05)。MACTM组平均噪声值比FBP组减少了82.38 (95%CI:63.671~101.104),即降低了47.84% ,差异有统计学意义(P<0.05)。见表1

    MACTM组金属旁骨组织、腰大肌及膀胱的SNR和CNR均高于FBP组,差异均有统计学意义(P<0.05)。见表2

    表  2  两组图像金属旁骨组织、腰大肌及膀胱的SNR和CNR比较
    Table  2.  Comparison of SNR and CNR in the adjacent bone tissue, psoas muscle and bladder
    GroupnSNRCNR
    Adjacent bone tissue
    (median (P25, P75))
    Psoas muscle
    ($\bar x \pm s$)
    Bladder
    ($\bar x \pm s$)
    Adjacent bone tissue
    (median (P25, P75))
    Psoas muscle
    (median (P25, P75))
    Bladder
    ($\bar x \pm s$)
    FBP 72 2.50 (0.63, 5.58) 2.79±2.23 −1.07±1.98 7.94 (5.03, 12.75) 8.78 (5.61, 12.18) 5.81±3.68
    MACTM 72 3.22 (2.01, 5.77) 3.23±1.99 −0.46±1.91 9.58 (6.22, 9.58) 9.77 (7.33, 13.54) 7.16±3.89
    t/Z −2.870 −2.258 −3.309 −2.911 −4.019 −4.083
    P 0.004 0.045 <0.05 <0.05 <0.05 <0.05
    下载: 导出CSV 
    | 显示表格

    2名医师对两组图像主观评分一致性检验中,FBP组的Kappa值为0.72,具有中等一致性,MAC组Kappa值为0.85,具有良好的一致性。FBP组图像评分在3分及以上者3例,MACTM组图像评分3分及以上者为37例。两组的主观评分差异具有统计学意义(Z=−6.564,P<0.05),且MACTM组主观评分〔4(3, 4)〕优于FBP组〔3(2, 3)〕,由图2可见,MACTM组金属伪影较少,金属植入物结构显示更加明显,图像质量较好。

    图  2  患者女,52岁,全髋关节置换术后半年
    Figure  2.  Female patient, 52 years old, 6 months after right hip replacement
    A is an FBP reconstructed 1 mm image with a subjective score of 2; B is a MACTM reconstructed 1 mm image with a subjective score of 4.

    CT是全髋关节置换术后评价髋关节情况的重要手段,但常规CT图像上金属伪影严重干扰了金属植入物及周围组织的显示。因此,减少金属植入物的伪影一直是全髋关节置换术后CT影像研究的热点[13-15]。常见的去伪影算法包括投影插值算法、迭代重建算法及混合算法[16-17]。投影插值算法[18]通过由金属物体产生的投影被替换为来自不包含任何金属的相邻投影的插值信号,能有效减少金属伪影,但金属本身和金属周围结构的信息容易丢失,导致图像信息不全。迭代重建算法[19]能在投影数少、数据不完全和低辐射剂量条件下,得到高质量、低噪声的图像,但耗时较长,且在重建时易缺失组织边界锐利度。MACTM是联影公司最近研发的金属伪影校正技术,结合了插值和迭代算法的优势,基本原理是先通过图像域分割找到金属,再对金属图像正投影,找到被金属破坏的投影数据,通过插值和加权的方法最大程度上修复投影数据,最后对矫正后的投影数据反投影,得到校正图像。MACTM通过考虑金属的密度和形状,由此设计算法,以充分保留金属边缘信息,同时抑制伪影和噪声。

    全髋关节置换术后CT复查的图像经常显示金属伪影严重的区域主要位于髋臼附近,而既往文献[20-22]大多数只测量了金属伪影最严重的单一层面。为了更加全面的对髋臼周围的金属伪影进行评价,本研究以髋臼窝为中心,分别选择上、中、下3个层面进行测量。在每个层面的CT图像中,光子饥饿效应和散射效应主要产生高密度伪影,严重的衰减结构之间光束硬化效应主要产生低密度伪影,故金属植入物的伪影常表现为放射状高密度影和星条状低密度暗区[23]。通过对层面中伪影最严重区域,即金属高低密度伪影区进行测量,可以量化评估MACTM对金属伪影的影响。本研究结果发现,金属高密度伪影区MAC组CT值较FBP组降低了38.19%,噪声降低了25.35%;金属低密度伪影区MACTM组CT值增加了47.77%,噪声降低了30.44%。其原因是由于金属高密度伪影中,金属植入物相邻的低对比度结构很容易被伪影遮挡,MACTM通过数据校准、去噪,能减少光子饥饿引起的细小条纹伪影,使金属高密度伪影区CT值降低,图像噪声降低。同时,利用原始数据进行插值补偿,消除了大部分阴影,提高了金属低密度伪影区的CT值。因此,MACTM图像中金属高密度伪影区和金属低密度伪影区的CT值均有改善,图像中的噪声明显降低,此结果与LAUKAMP等[24]对于高低密度伪影区CT值和噪声值的研究结果相似。

    除了测量金属高、低密度伪影区的CT值和图像噪声之外,本研究还对金属髋关节间隙进行了测量,这是因为髋关节间隙是骨科医生关注的重点,但是目前的去金属伪影的研究少有对关节间隙的分析测量。众所周知,CT检查能够详细显示髋关节结构,可以有效评估术后并发症,主要包括骨溶解、金属植入物松动、植入物周围骨折、关节周围积液等[25],其中骨溶解是髋关节翻修手术的常见原因之一,多由人工关节界面磨损颗粒导致[26-27]。清晰的金属髋关节间隙图像,可以充分显示磨损颗粒,有助于评价骨溶解,所以本研究选择髋关节间隙作为研究重点,旨在解决临床问题。结果显示,使用MAC后金属髋关节间隙CT值降低了71.47%,噪声值降低了47.84%,说明通过MACTM可以去除部分金属伪影的干扰,使CT图像能够更加直观的展示金属髋关节间隙的结构和形貌,呈现金属植入物磨损的程度,有助于临床医生分析假体的使用情况及预估其使用年限。

    相较于国内许多关于金属伪影的研究只量化比较CT值和噪声值[28-29],本研究还对金属旁组织的SNR和CNR进行了测量和评价。这是因为金属植入物周围组织的SNR和CNR不仅可以反映伪影对周围组织的影响程度,而且能反映整体的CT图像质量。研究结果显示MACTM重建后金属髋关节旁的骨组织、腰大肌以及膀胱的SNR和CNR均高于FBP组,差异有统计学意义,说明通过抑制伪影和噪声,MACTM能够保护和恢复金属髋关节旁骨组织、肌肉及盆腔的对比度,较为清晰的显示金属植入物周围组织的影像特点,对于明确金属髋关节置换术后疼痛与功能的病因有重要的辅助作用,尤其对金属髋关节置换术后伴有盆腔疾病的患者[30-31],如膀胱肿瘤等,MACTM重建可以更好的显示盆腔的解剖结构。同时,主观评分结果也证实了MACTM组图像优于FBP组(P<0.05)。

    本研究存在一些不足。首先,金属髋关节置换术中常见的两个主要成分是钛合金和钴铬合金,但由于纳入的部分患者为院外手术,手术材料未知,所以没有对不同金属材料进行分类;其次,由于纳入的样本量较少,没有对双侧髋关节置换的患者进行单独分析;再次,没有对MACTM是否会引入其它伪影进行研究。

    综上所述,MACTM不需要特殊CT硬件设备的支持,在常规CT扫描后,即可快速重建,操作简便,在全髋关节置换术后的CT复查中可以有效去除金属植入物的伪影,使关节间隙显示清晰,改善整体图像质量,在评估术后并发症方面具有重要的临床价值。

  • 图  1   慢病毒和siRNA转染DPSC后RUNX1的表达

    Figure  1.   The expression of RUNX1 protein after transfection of DPSC with overexpressing lentivirus and siRNA

    A: Fluorescence microscope images of DPSC after transfection with overexpressing lentivirus (×100). The effect of RUNX1 transduction is the radio of DPSC in green to DPSC in bright field; B, C: Western blot analysis and protein quantification showing up-regulation of RUNX1 protein in DPSC after transfection with overexpressing lentivirus; D, E: Western blot analysis and protein quantification showing down-regulation of RUNX1 protein in DPSC after transfection with siRNA. *P<0.05, n=3.

    图  2   过表达RUNX1对DPSC增殖的影响

    Figure  2.   The effect of RUNX1 overexpression on proliferation of DPSC

    A: Growth curve of DPCs (n=5); B: Colony formation assay; C: Cell cycle of DPSC detected by flow cytometry; D: Quantitative analysis of cell cycle distributions in C (n=3). *P<0.05, vs. DPSC and GFP.

    图  3   RUNX1在DPSC中过表达后的矿化和成脂表型

    Figure  3.   The phenotype of osteogenic differentiation and adipogenic differentiation after RUNX1 overexpression in DPSC

    A, B: ALP staining and quantitative analysis showing enhanced osteogenesis in DPSC by over-expressed RUNX1; C, D: Alizarin staining and quantitative analysis showing the enhanced mineralization capacity in DPSC by over-expressed RUNX1; E, F: Oil red O staining and quantitative analysis showing weakened adipogenesis in DPSC by over-expressed RUNX1 (×400). *P<0.05, n=3.

    图  4   RUNX1在DPSC中敲低后的矿化和成脂表型

    Figure  4.   The phenotype of osteogenic differentiation and adipogenic differentiation after RUNX1 knockdown in DPSC

    A, B: ALP staining and quantitative analysis showing weakened osteogenesis in DPSC by knocking down RUNX1; C, D: Alizarin staining and quantitative analysis showing the weakened mineralization capacity in DPSC by knocking down RUNX1; E, F: Oil red O staining and quantitative analysis showing enhanced adipogenesis in DPSC by knocking down RUNX1 (×400). *P<0.05, n=3.

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  • 收稿日期:  2021-03-04
  • 修回日期:  2021-04-11
  • 网络出版日期:  2021-05-18
  • 发布日期:  2021-05-19

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