半侧颜面发育不全患者骨髓间充质干细胞生物学行为及免疫调控能力的研究
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摘要
半侧颜面发育不全疾病（Hemifacial Microsomia，HFM），是继唇腭裂后，临床上较常见的一类颌面部发育畸形疾病。由于该病畸形主要涉及颌面部，对患者的日常生活和心理健康都造成了严重影响。
对该疾病的诊断和治疗一直都是影像学、正畸学和颌面外科学关注的要点。但由于该病临床表型复杂且病因不明，在诊断中除了详细的家族史、既往史采集外还需详细的检查。近几年，随着现代口腔医学的快速发展和正畸正颌联合治疗的推广，对HFM患者的治疗已经逐渐完善化和系统化。
对于该病致病原因一直也是讨论的热点，目前尚无结论，但大多的研究都认为HFM可能为多种病因，包括基因缺陷、致畸剂及血管畸形等。其中多数研究都证实该病是由于基因突变引起的遗传性疾病。而致病基因的确定也成了亟待解决的问题，研究者曾提出多种基因，但后期的研究均一一推翻，最近有学者又提出TCOF1为致病基因的可能性，但是否明确还需进一步证实。
众所周知，BMMSCs作为一类重要的间充质干细胞在生长发育过程中起到重要的作用。目前的研究证明，BMMSCs不仅在骨形成方面，而且在免疫调控方面都有着重要的作用。而越来越多的研究都证实基因的缺陷以及微环境的改变均可以影响干细胞的生物学行为，分化及功能，从而导致发育的缺陷，因此，疾病干细胞的研究对遗传性疾病的研究有着重要的作用。
研究目的
1．通过病史采集、临床检查，观察和分析患者颌面部发育的异常表现。
2．验证以往文献报道的TCOF1基因为该病致病基因的准确性。
3．探讨患者患侧与健康侧颌骨hBMMSCs的生物学行为和多向分化能力的差异。
4．探讨患侧与健康侧颌骨hBMMSCs的免疫调控能力的差异。
研究方法
1．我们经统一的诊断标准，经过全面和详尽的问诊，临床检查，收集HFM患者14例，并运用OMENS分类法通过对临床特征和器官受累情况进行分类。在患者及家属知情同意情况下，我们抽取患者静脉血2ml，提取全基因组DNA，对目前报道的可疑致病基因TCOF1的26个外显子进行测序，验证其正确性。
2．在患者及家属知情和不影响患者手术效果的情况下，我们在患者进行正颌手术过程中，取得患者颌骨健康侧和患侧的组织，利用组织块方法分离培养hBMMSCs。并以正常人的下颌骨hBMMSCs作为正常对照组，首先利用流式细胞技术检测表面分子的表达，然后对各组细胞的生物学行为进行比较。通过克隆集落形成实验、MTT检测和EDU检测细胞增殖能力。进行成神经诱导后，通过免疫细胞化学实验从蛋白水平上检测hBMMSCs多向分化能力。Real time-PCR和Western Blot检测分析成骨成脂诱导后标志性基因的表达。并且将不同组hBMMSCs与TA/TCP混合后植入裸鼠皮下，8周后取材，进行组织学观察，HE染色观测体内类骨质形成情况。
3．利用ELISA检测上述各组hBMMSCs培养液上清的INF-γ、IL-6、IL-10及IL-17的表达，并通过Real time RT-PCR检测这些验证因子在各组hBMMSCs中的表达变化。我们把各组hBMMSCs和T淋巴细胞进行直接共培养，检测共培养后的T淋巴细胞的周期，观察各组细胞对T淋巴细胞增殖的影响情况。构建DSS炎症性结肠炎小鼠模型，并于模型建立的第三天一次性注射各组hBMMSC，每日观察小鼠的体重，大便，疾病发生状况，并于第十天处死小鼠后，对其结肠进行病理学观察，以确定各组hBMMSC对小鼠模型的治疗情况。
实验结果
1．由于HFM疾病临床表现复杂，且发病表型与多个其他颌面遗传病相似，我们经过详尽检查，收集14例患者，运用OMENS对其临床表型进行分类后，我们发现即使同一患者，其各个器官的受累程度也各不相同。通过对可疑基因TCOF1的26个外显子测序，将测得的基因序列进行核酸序列的同源性比较分析，排除SNP位点，我们认为TCOF1并非为HFM的致病基因。
2．分离培养的各组颌骨hBMMSCs间充质细胞表面标志物表达阳性。克隆集落、MTT、EDU检测、流式细胞检测结果显示患者患侧hBMMSCs的增殖能力减弱，低于正常对照组和患者健侧的hBMMSCs。成骨、成脂、成软骨诱导分化证明，培养的hBMMSCs具有多向分化能力。而通过对各组细胞的比较，发现各组细胞在成神经分化方面无明显差异，而成脂和成骨诱导后，从RNA水平和蛋白水平，都观察到患者患侧hBMMSCs的分化能力明显弱于正常对照组和患者健侧组的hBMMSCs，而后两组能力相当。
3．利用ELISA检测各组hBMMSCs培养上清的炎症因子表达水平发现患者患侧hBMMSCs的表达水平较高，而Real time RT-PCR对hBMMSCs的RNA水平检测也得到了类似的结果。我们将与各组hBMMSCs共培养后的T细胞做周期检测，发现患者患侧hBMMSCs对T细胞的增殖的抑制作用不及正常对照组细胞和患者健侧细胞。而通过hBMMSCs治疗DSS炎症性结肠炎模型鼠，我们观察到患者患侧hBMMSCs的免疫抑制能力下降，而患者健侧细胞则表现出与正常对照组相似的能力。
结论：
通过对病例的研究，我们发现即使同一HFM患者，其各个器官的受累程度也不尽相同。之前文献中所报道的TCOF1基因并不是HFM的致病基因，而其致病基因还有待进一步探讨。患者健康侧hBMMSCs的增殖与正常对照组相似，患者患侧hBMMSCs的增值能力降低。患者患侧hBMMSCs的成脂和成骨分化能力明显弱于正常对照组和患者健侧组的hBMMSCs，而后两组能力相当。患者患侧hBMMSCs的成神经能力与健侧及正常对照组无差异。经实验发现患者患侧hBMMSCs的免疫调节能力下降，而患者健侧细胞则表现出与正常对照组相似的能力。
Hemifacial microsomia, following cleft lip and palate, is a common clinicalmaxillofacial malformation disease. Deformity mainly related to maxillofacial region, thedisease seriously affect the patient's daily life and mental health.
The diagnosis and treatment of the disease have been focused by imaging,orthodontics and maxillofacial surgery. However, due to the complex clinicalmanifestations and unknown etiology, the diagnosis in addition to the collection ofdetailed family history and personal medical history is depend on detailed clinicalexamination. In recent years, with the rapid development of Stomatology, orthodontics andorthognathic surgery, the treatment of HFM patients has been promoted.
The cause of the disease has been also a hot topic.There is no conclusion, but most ofthe researchers believe that HFM is possiblely caused by a variety of causes, including genetic defects, teratogenic, and vascular malformations. Most studies confirmed that thedisease is a hereditary disease due to genetic mutations. And the determination of thecausative gene has become an urgent problem. Researchers have proposed a variety ofgenes, but were overthrew by the later study. Some scholars have recently proposedTCOF1as disease gene, but whether explicitly need further confirmed.
As we all know, BMMSCs play an important role in the process of growth anddevelopment. The current study has been proved, BMMSCs not only in bone formation,but also plays an important role in immune regulation. Increasing number of studies haveconfirmed that a defect in the gene as well as the microenvironment changes can influencethe biological behavior, differentiation and function of stem cells, resulting indevelopmental defects. Now studying on stem cells from patients has been veryimportant on genetic diseases research.
Objectives
1. To collecte patients with Hemifacial microsomia.
2. To verify TCOF1gene for the accuracy of the genes that cause the disease.
3. To explore the difference of the biological behavior and differentiation capacitybetween hBMMSCs from the affected jaw and healthy side.
4. To explore the difference of immune regulatory capacity between hBMMSCs fromaffected maxillary and unaffected side.
Methods
1. We unified diagnostic criteria after comprehensive and exhaustive inquiry andclinical examination, resulting in a collection of14HFM patients using OMENSclassification based on the clinical features and organ involvement. In the case of patientsand their families informed consent, we extracted the patients2ml vein, extracted thegenome-wide DNA, and verified the reported suspicious pathogenic genes TCOF1bysequencing its26exons.
2. In the case of patients and their families informed, we harvested the tissue ofaffected side and the unaffected side of mandibular, tissue blocks were isolated andcultured hBMMSCs. And with normal mandible hBMMSCs as normal control group, the difference of the cells in each group was studied. Flow cytometry expression of surfacemolecules; clone colony formation, MTT, EDU detection, cell cycle, apoptosis analysiswere performed to detect cell proliferation ability. Osteogenic, adipogenic, and neuralinduction detection hBMMSCs multipotent differentiation capacity. Real time-PCR andWestern Blot analysis were performed to detect the osteogenic and adipogenic iconicgenes expression. As well as the different groups hBMMSCs TA/TCP mixed implantedsubcutaneously into nude mice, harvested after8weeks, fixed decalcified the two weeksparaffin-embedded sections, HE staining observation to detect in vivo osteoid formation.
3.Using an ELISA to detect the above groups’ hBMMSCs culture supernatant ofINF-γ, IL-6, IL-10and IL-17expression, Real time RT-PCR was performed to explore theexpression changes of these validation factors in each group. We co-cultured hBMMSCsdirectly with T lymphocytes, examined the T lymphocytes cycle after co-culture, andobserved the proliferation of cells in each group of T lymphocytes. The DSS ulcerativecolitis mouse model was built, and hBMMSCs were injected once on the third day afterthe model building. Mice were observed daily about the body weight, stool, disease status.Mice were killed on the tenth day, and the colonic pathology was observed in order todetermine the outcome of hBMMSC treatment.
Results
1. Due to the complexity of the HFM disease and its similarity with the phenotype ofmultiple other Maxillofacial genetic disease, we collected14patients using the OMENSclassification after detailed examination. We found that even in the same patients, theextent of involvement of various organs was different. Measured by exon sequencing, wecompared the nucleic acid sequence homology and exclude the SNP loci. In conclusion,we do not think TCOF1is the pathogenic gene of HFM.
2. Each group of the mandible hBMMSCs expressed the mesenchymal surfacemarkers, without expressing hematopoietic markers. Clonal colony, MTT, EDU detection,flow cytometry results show the proliferation capacity of hBMMSCs from affected sidewas lower than that of normal controls. Osteogenic, adipogenic, and induced todifferentiate into cartilage had proved that cultured hBMMSCs hold the ability to multi-differentiation. Comparison of the cells in each group and found no significantdifferences between groups of cells’ neural differentiation. However, after osteogenic andadipogenic induction, the differentiation capacity of hBMMSCs from affected side wasweaker than the normal controls from the RNA and protein levels. The differentiationcapacity between hBMMSCs frome normal side of HFM patients and normal people werefairly consistent.
3. Using ELISA to detect the culture supernatant of each group hBMMSCs, the levelof expression of inflammatory cytokines of hBMMSCs frome affected side wassignificantly higher. Real time RT-PCR detecting RNA levels of hBMMSCs also obtainedsimilar results. We detected the T-cells cycle co-cultured with hBMMSCs. The resultsshowed that the inhibitory effect on T cell proliferation caused by hBMMSCs fromaffected side was less than the normal control groups. Treating ulcerative colitis modelmice by different types of hBMMSCs, we observed that the immune suppression ability ofhBMMSCs from affected side was declined, while the immune suppression ability ofhBMMSCs frome normal side of HFM patients was similar with that of hBMMSCs fromenormal people.
Conclusion
Through case studies, we found that even same patient with HFM, its degree ofinvolvement of the various organs was not consistent. TCOF1gene reported by studieswere not the virulence gene of HFM, and the virulence gene must be explored further.The proliferation of hBMMSCs from patients’ health side is similar to normal controlgroup, while the proliferation of hBMMSCs from patients’ affected side was relativelylower. The osteogenic and adipogenic differentiation capacity of hBMMSCs from affectedside was weaker than the normal controls. The osteogenic and adipogenic differentiationcapacity between hBMMSCs frome normal side of HFM patients and normal people werefairly consistent. No significant differences between groups of cells’ neural differentiationin each group was found. The immune suppression ability of hBMMSCs from affectedside was declined, while the immune suppression ability of hBMMSCs frome normal sideof HFM patients was similar with that of hBMMSCs frome normal people.
对该疾病的诊断和治疗一直都是影像学、正畸学和颌面外科学关注的要点。但由于该病临床表型复杂且病因不明，在诊断中除了详细的家族史、既往史采集外还需详细的检查。近几年，随着现代口腔医学的快速发展和正畸正颌联合治疗的推广，对HFM患者的治疗已经逐渐完善化和系统化。
对于该病致病原因一直也是讨论的热点，目前尚无结论，但大多的研究都认为HFM可能为多种病因，包括基因缺陷、致畸剂及血管畸形等。其中多数研究都证实该病是由于基因突变引起的遗传性疾病。而致病基因的确定也成了亟待解决的问题，研究者曾提出多种基因，但后期的研究均一一推翻，最近有学者又提出TCOF1为致病基因的可能性，但是否明确还需进一步证实。
众所周知，BMMSCs作为一类重要的间充质干细胞在生长发育过程中起到重要的作用。目前的研究证明，BMMSCs不仅在骨形成方面，而且在免疫调控方面都有着重要的作用。而越来越多的研究都证实基因的缺陷以及微环境的改变均可以影响干细胞的生物学行为，分化及功能，从而导致发育的缺陷，因此，疾病干细胞的研究对遗传性疾病的研究有着重要的作用。
研究目的
1．通过病史采集、临床检查，观察和分析患者颌面部发育的异常表现。
2．验证以往文献报道的TCOF1基因为该病致病基因的准确性。
3．探讨患者患侧与健康侧颌骨hBMMSCs的生物学行为和多向分化能力的差异。
4．探讨患侧与健康侧颌骨hBMMSCs的免疫调控能力的差异。
研究方法
1．我们经统一的诊断标准，经过全面和详尽的问诊，临床检查，收集HFM患者14例，并运用OMENS分类法通过对临床特征和器官受累情况进行分类。在患者及家属知情同意情况下，我们抽取患者静脉血2ml，提取全基因组DNA，对目前报道的可疑致病基因TCOF1的26个外显子进行测序，验证其正确性。
2．在患者及家属知情和不影响患者手术效果的情况下，我们在患者进行正颌手术过程中，取得患者颌骨健康侧和患侧的组织，利用组织块方法分离培养hBMMSCs。并以正常人的下颌骨hBMMSCs作为正常对照组，首先利用流式细胞技术检测表面分子的表达，然后对各组细胞的生物学行为进行比较。通过克隆集落形成实验、MTT检测和EDU检测细胞增殖能力。进行成神经诱导后，通过免疫细胞化学实验从蛋白水平上检测hBMMSCs多向分化能力。Real time-PCR和Western Blot检测分析成骨成脂诱导后标志性基因的表达。并且将不同组hBMMSCs与TA/TCP混合后植入裸鼠皮下，8周后取材，进行组织学观察，HE染色观测体内类骨质形成情况。
3．利用ELISA检测上述各组hBMMSCs培养液上清的INF-γ、IL-6、IL-10及IL-17的表达，并通过Real time RT-PCR检测这些验证因子在各组hBMMSCs中的表达变化。我们把各组hBMMSCs和T淋巴细胞进行直接共培养，检测共培养后的T淋巴细胞的周期，观察各组细胞对T淋巴细胞增殖的影响情况。构建DSS炎症性结肠炎小鼠模型，并于模型建立的第三天一次性注射各组hBMMSC，每日观察小鼠的体重，大便，疾病发生状况，并于第十天处死小鼠后，对其结肠进行病理学观察，以确定各组hBMMSC对小鼠模型的治疗情况。
实验结果
1．由于HFM疾病临床表现复杂，且发病表型与多个其他颌面遗传病相似，我们经过详尽检查，收集14例患者，运用OMENS对其临床表型进行分类后，我们发现即使同一患者，其各个器官的受累程度也各不相同。通过对可疑基因TCOF1的26个外显子测序，将测得的基因序列进行核酸序列的同源性比较分析，排除SNP位点，我们认为TCOF1并非为HFM的致病基因。
2．分离培养的各组颌骨hBMMSCs间充质细胞表面标志物表达阳性。克隆集落、MTT、EDU检测、流式细胞检测结果显示患者患侧hBMMSCs的增殖能力减弱，低于正常对照组和患者健侧的hBMMSCs。成骨、成脂、成软骨诱导分化证明，培养的hBMMSCs具有多向分化能力。而通过对各组细胞的比较，发现各组细胞在成神经分化方面无明显差异，而成脂和成骨诱导后，从RNA水平和蛋白水平，都观察到患者患侧hBMMSCs的分化能力明显弱于正常对照组和患者健侧组的hBMMSCs，而后两组能力相当。
3．利用ELISA检测各组hBMMSCs培养上清的炎症因子表达水平发现患者患侧hBMMSCs的表达水平较高，而Real time RT-PCR对hBMMSCs的RNA水平检测也得到了类似的结果。我们将与各组hBMMSCs共培养后的T细胞做周期检测，发现患者患侧hBMMSCs对T细胞的增殖的抑制作用不及正常对照组细胞和患者健侧细胞。而通过hBMMSCs治疗DSS炎症性结肠炎模型鼠，我们观察到患者患侧hBMMSCs的免疫抑制能力下降，而患者健侧细胞则表现出与正常对照组相似的能力。
结论：
通过对病例的研究，我们发现即使同一HFM患者，其各个器官的受累程度也不尽相同。之前文献中所报道的TCOF1基因并不是HFM的致病基因，而其致病基因还有待进一步探讨。患者健康侧hBMMSCs的增殖与正常对照组相似，患者患侧hBMMSCs的增值能力降低。患者患侧hBMMSCs的成脂和成骨分化能力明显弱于正常对照组和患者健侧组的hBMMSCs，而后两组能力相当。患者患侧hBMMSCs的成神经能力与健侧及正常对照组无差异。经实验发现患者患侧hBMMSCs的免疫调节能力下降，而患者健侧细胞则表现出与正常对照组相似的能力。
Hemifacial microsomia, following cleft lip and palate, is a common clinicalmaxillofacial malformation disease. Deformity mainly related to maxillofacial region, thedisease seriously affect the patient's daily life and mental health.
The diagnosis and treatment of the disease have been focused by imaging,orthodontics and maxillofacial surgery. However, due to the complex clinicalmanifestations and unknown etiology, the diagnosis in addition to the collection ofdetailed family history and personal medical history is depend on detailed clinicalexamination. In recent years, with the rapid development of Stomatology, orthodontics andorthognathic surgery, the treatment of HFM patients has been promoted.
The cause of the disease has been also a hot topic.There is no conclusion, but most ofthe researchers believe that HFM is possiblely caused by a variety of causes, including genetic defects, teratogenic, and vascular malformations. Most studies confirmed that thedisease is a hereditary disease due to genetic mutations. And the determination of thecausative gene has become an urgent problem. Researchers have proposed a variety ofgenes, but were overthrew by the later study. Some scholars have recently proposedTCOF1as disease gene, but whether explicitly need further confirmed.
As we all know, BMMSCs play an important role in the process of growth anddevelopment. The current study has been proved, BMMSCs not only in bone formation,but also plays an important role in immune regulation. Increasing number of studies haveconfirmed that a defect in the gene as well as the microenvironment changes can influencethe biological behavior, differentiation and function of stem cells, resulting indevelopmental defects. Now studying on stem cells from patients has been veryimportant on genetic diseases research.
Objectives
1. To collecte patients with Hemifacial microsomia.
2. To verify TCOF1gene for the accuracy of the genes that cause the disease.
3. To explore the difference of the biological behavior and differentiation capacitybetween hBMMSCs from the affected jaw and healthy side.
4. To explore the difference of immune regulatory capacity between hBMMSCs fromaffected maxillary and unaffected side.
Methods
1. We unified diagnostic criteria after comprehensive and exhaustive inquiry andclinical examination, resulting in a collection of14HFM patients using OMENSclassification based on the clinical features and organ involvement. In the case of patientsand their families informed consent, we extracted the patients2ml vein, extracted thegenome-wide DNA, and verified the reported suspicious pathogenic genes TCOF1bysequencing its26exons.
2. In the case of patients and their families informed, we harvested the tissue ofaffected side and the unaffected side of mandibular, tissue blocks were isolated andcultured hBMMSCs. And with normal mandible hBMMSCs as normal control group, the difference of the cells in each group was studied. Flow cytometry expression of surfacemolecules; clone colony formation, MTT, EDU detection, cell cycle, apoptosis analysiswere performed to detect cell proliferation ability. Osteogenic, adipogenic, and neuralinduction detection hBMMSCs multipotent differentiation capacity. Real time-PCR andWestern Blot analysis were performed to detect the osteogenic and adipogenic iconicgenes expression. As well as the different groups hBMMSCs TA/TCP mixed implantedsubcutaneously into nude mice, harvested after8weeks, fixed decalcified the two weeksparaffin-embedded sections, HE staining observation to detect in vivo osteoid formation.
3.Using an ELISA to detect the above groups’ hBMMSCs culture supernatant ofINF-γ, IL-6, IL-10and IL-17expression, Real time RT-PCR was performed to explore theexpression changes of these validation factors in each group. We co-cultured hBMMSCsdirectly with T lymphocytes, examined the T lymphocytes cycle after co-culture, andobserved the proliferation of cells in each group of T lymphocytes. The DSS ulcerativecolitis mouse model was built, and hBMMSCs were injected once on the third day afterthe model building. Mice were observed daily about the body weight, stool, disease status.Mice were killed on the tenth day, and the colonic pathology was observed in order todetermine the outcome of hBMMSC treatment.
Results
1. Due to the complexity of the HFM disease and its similarity with the phenotype ofmultiple other Maxillofacial genetic disease, we collected14patients using the OMENSclassification after detailed examination. We found that even in the same patients, theextent of involvement of various organs was different. Measured by exon sequencing, wecompared the nucleic acid sequence homology and exclude the SNP loci. In conclusion,we do not think TCOF1is the pathogenic gene of HFM.
2. Each group of the mandible hBMMSCs expressed the mesenchymal surfacemarkers, without expressing hematopoietic markers. Clonal colony, MTT, EDU detection,flow cytometry results show the proliferation capacity of hBMMSCs from affected sidewas lower than that of normal controls. Osteogenic, adipogenic, and induced todifferentiate into cartilage had proved that cultured hBMMSCs hold the ability to multi-differentiation. Comparison of the cells in each group and found no significantdifferences between groups of cells’ neural differentiation. However, after osteogenic andadipogenic induction, the differentiation capacity of hBMMSCs from affected side wasweaker than the normal controls from the RNA and protein levels. The differentiationcapacity between hBMMSCs frome normal side of HFM patients and normal people werefairly consistent.
3. Using ELISA to detect the culture supernatant of each group hBMMSCs, the levelof expression of inflammatory cytokines of hBMMSCs frome affected side wassignificantly higher. Real time RT-PCR detecting RNA levels of hBMMSCs also obtainedsimilar results. We detected the T-cells cycle co-cultured with hBMMSCs. The resultsshowed that the inhibitory effect on T cell proliferation caused by hBMMSCs fromaffected side was less than the normal control groups. Treating ulcerative colitis modelmice by different types of hBMMSCs, we observed that the immune suppression ability ofhBMMSCs from affected side was declined, while the immune suppression ability ofhBMMSCs frome normal side of HFM patients was similar with that of hBMMSCs fromenormal people.
Conclusion
Through case studies, we found that even same patient with HFM, its degree ofinvolvement of the various organs was not consistent. TCOF1gene reported by studieswere not the virulence gene of HFM, and the virulence gene must be explored further.The proliferation of hBMMSCs from patients’ health side is similar to normal controlgroup, while the proliferation of hBMMSCs from patients’ affected side was relativelylower. The osteogenic and adipogenic differentiation capacity of hBMMSCs from affectedside was weaker than the normal controls. The osteogenic and adipogenic differentiationcapacity between hBMMSCs frome normal side of HFM patients and normal people werefairly consistent. No significant differences between groups of cells’ neural differentiationin each group was found. The immune suppression ability of hBMMSCs from affectedside was declined, while the immune suppression ability of hBMMSCs frome normal sideof HFM patients was similar with that of hBMMSCs frome normal people.
引文
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