冻存人源永生化肝细胞微囊用于生物人工肝治疗的研究
摘要
背景
每年因肝脏疾病死亡的人数呈现持续增加趋势。人工肝作为治疗肝衰竭的有效手段成为近些年的研究热点,其目标为帮助病患等待适宜的供体器官或自体肝再生。我国在非生物型人工肝支持系统领域已经取得较大进步,但生物型人工肝系统的研究与国外发达国家相比尚有差距。
目的
本课题组拟选择功能最佳的人源性永生化肝细胞制作微囊,以大规模于液氮中冻存后,在新型生物人工肝支持系统中检测肝衰竭病人血浆对肝细胞的毒性作用以及肝细胞对肝衰竭病人血浆的清除效果,为生物型人工肝的临床试验奠定基础。
方法
1.永生化人源肝细胞的功能评价。利用MTT、实时定量PCR、免疫荧光和Western blot及ELISA等检测增殖及功能。
2.将反应器流化培养的永生化肝细胞系微囊与静态培养肝细胞系微囊、二维培养肝细胞作对比,比较细胞中与功能相关Ⅰ相酶、Ⅱ相酶和特异性核受体基因、CYP450蛋白表达的变化。检测肝细胞生存率及白蛋白分泌和尿素合成确定冻存条件、冻存时间以及复苏孵育条件并且评价微囊化肝细胞大规模冻存效果。
3.体外初步评价生物人工肝的有效性。收集肝衰竭病人血浆,将复苏并孵育后的肝细胞微囊加入到肝衰竭病人血浆中培养24h,观察肝衰竭病人血浆对微囊内肝细胞活性和功能的影响以及肝衰竭病人血浆内重要物质成分的变化。
结果
1HepLi3细胞增殖能力最好,可以进行大规模的培养,获得高数量的细胞,而且其在功能上明显优于其他永生化肝细胞。
2.微囊化和流化培养的肝细胞在培养过程中保持很好的活性；微囊化的培养方式可以促进肝细胞特异基因及蛋白的表达；此种培养方式可能是通过抑制细胞内磷酸激酶活性来提高肝细胞特异性功能的。
3.确定微囊制作完成孵育2h后进行冻存操作；冻存复苏后孵育2h,其功能可恢复很好,且将体积扩大到50毫升不会影响肝细胞的冻存后的功能。
4.肝衰竭病人血浆造成肝细胞活率下降12%,但不影响其作为种子细胞的应用。而且微囊化肝细胞系可以改变肝衰竭病人血浆中物质成分,促进其体内内环境的稳定,为其临床应用奠定基础。
结论
1.本实验室制作的HepLi3可作为生物人工肝的种子细胞有效发挥肝特异性功能。
2.确定了微囊的制作,肝细胞冻存及复苏的条件,并探究蛋白激酶的抑制可能是微囊化促进肝细胞功能的原因。
3.大规模冻存微囊化肝细胞后,细胞活性保持良好,可以为生物人工肝提供种子细胞库。
4.利用肝衰竭病人血浆及生物反应器证明冻存后的微囊化肝细胞可降低重肝血浆中的谷丙转氨酶和直接胆红素。
Background
The number of deaths caused by liver diseases, especially late stage liver failure, continues to an increasing trend annually. Artificial liver becomes a research hotspot in recent years, which is designed to "bridge" patients to liver transplantation or spontaneous recovery. Many non-bioartificial liver support systems have been investigated over the past30years, and recent developments appear promising, but there are still gaps compared with developed countries for bioartificial liver system research.
Aim
This study is to choose the immortalized hepatocytes with best functions, encapsulate them and culture these microspheres with patients'plasma in our bioartificial support system after cryopreservation in large scale.
Methods
1. The functional evaluation of immortalized human hepatocyte. Cell proliferation was detected by MTT and functions were extamined by Real-time quantitative PCR. immunofluoresence, Western blot, drug metabolizing capacity and ELISA.
2. Fluidized microencapsulated hepatocyte cell lines were compared with the two-dimensional cultured hepatocytes and microencapsulated cells on the changes of gene and protein expression of phase I enzymes, II phase enzyme and specific nuclear receptors. Cryopreservation and recovery conditions of microencapsulated hepatocytes and the effection of large scale cryopreservation were optimized by the synthesis of ALB and urea.
3. The evaluation of effectiveness of bioartificial liver. The patient's plasma was collected. Microencapsulated hepatocyte cells were recovered after crypopreservation and added in the optimized bioreactor to be cultured with the plasma for24h. The effect of plasma on activity and functions of cells and the changes of small molecules in the plasma were determined.
Results
1. HepLi3cells were better according to their better proliferation, available to large-scale cultivation and liver functions.
2. The microencapsulated hepatocytes maintained high activity during the fluidization culture. And this condition could improve the expression of liver specific genes and protein, which may enhance cells'functions through suppressing kinases.
3.2hours incubation before and after the cryopreservation were determined, during which the number of recovered alive cells was more than50%. Forethemore, the cryopreservation volume expansion did not affect the liver functions.
4. HepLi3cells as seeded cells after cryopreservation were used for treating plasma from liver failure patients. Microencapsulated cells could stable the environment of patients which may improve their conditions.
Conclusion
1. HepLi3was the better seeded cells for BAL.
2. Optimized the production of microcapsules, liver cell cryopreservation and recovery conditions, protein kinases surpression may be the mechnism of promoting liver cell functions in microcapsulated culture.
3. The microencapsulated hepatocytes maintained high activity after large scale cryopreservation. They could be offered as seeded cells resource for BAL system.
4. BAL was proved to remove toxic substances, effectively improve the environment of patients by using microencapsulated HepLi3.
每年因肝脏疾病死亡的人数呈现持续增加趋势。人工肝作为治疗肝衰竭的有效手段成为近些年的研究热点,其目标为帮助病患等待适宜的供体器官或自体肝再生。我国在非生物型人工肝支持系统领域已经取得较大进步,但生物型人工肝系统的研究与国外发达国家相比尚有差距。
目的
本课题组拟选择功能最佳的人源性永生化肝细胞制作微囊,以大规模于液氮中冻存后,在新型生物人工肝支持系统中检测肝衰竭病人血浆对肝细胞的毒性作用以及肝细胞对肝衰竭病人血浆的清除效果,为生物型人工肝的临床试验奠定基础。
方法
1.永生化人源肝细胞的功能评价。利用MTT、实时定量PCR、免疫荧光和Western blot及ELISA等检测增殖及功能。
2.将反应器流化培养的永生化肝细胞系微囊与静态培养肝细胞系微囊、二维培养肝细胞作对比,比较细胞中与功能相关Ⅰ相酶、Ⅱ相酶和特异性核受体基因、CYP450蛋白表达的变化。检测肝细胞生存率及白蛋白分泌和尿素合成确定冻存条件、冻存时间以及复苏孵育条件并且评价微囊化肝细胞大规模冻存效果。
3.体外初步评价生物人工肝的有效性。收集肝衰竭病人血浆,将复苏并孵育后的肝细胞微囊加入到肝衰竭病人血浆中培养24h,观察肝衰竭病人血浆对微囊内肝细胞活性和功能的影响以及肝衰竭病人血浆内重要物质成分的变化。
结果
1HepLi3细胞增殖能力最好,可以进行大规模的培养,获得高数量的细胞,而且其在功能上明显优于其他永生化肝细胞。
2.微囊化和流化培养的肝细胞在培养过程中保持很好的活性；微囊化的培养方式可以促进肝细胞特异基因及蛋白的表达；此种培养方式可能是通过抑制细胞内磷酸激酶活性来提高肝细胞特异性功能的。
3.确定微囊制作完成孵育2h后进行冻存操作；冻存复苏后孵育2h,其功能可恢复很好,且将体积扩大到50毫升不会影响肝细胞的冻存后的功能。
4.肝衰竭病人血浆造成肝细胞活率下降12%,但不影响其作为种子细胞的应用。而且微囊化肝细胞系可以改变肝衰竭病人血浆中物质成分,促进其体内内环境的稳定,为其临床应用奠定基础。
结论
1.本实验室制作的HepLi3可作为生物人工肝的种子细胞有效发挥肝特异性功能。
2.确定了微囊的制作,肝细胞冻存及复苏的条件,并探究蛋白激酶的抑制可能是微囊化促进肝细胞功能的原因。
3.大规模冻存微囊化肝细胞后,细胞活性保持良好,可以为生物人工肝提供种子细胞库。
4.利用肝衰竭病人血浆及生物反应器证明冻存后的微囊化肝细胞可降低重肝血浆中的谷丙转氨酶和直接胆红素。
Background
The number of deaths caused by liver diseases, especially late stage liver failure, continues to an increasing trend annually. Artificial liver becomes a research hotspot in recent years, which is designed to "bridge" patients to liver transplantation or spontaneous recovery. Many non-bioartificial liver support systems have been investigated over the past30years, and recent developments appear promising, but there are still gaps compared with developed countries for bioartificial liver system research.
Aim
This study is to choose the immortalized hepatocytes with best functions, encapsulate them and culture these microspheres with patients'plasma in our bioartificial support system after cryopreservation in large scale.
Methods
1. The functional evaluation of immortalized human hepatocyte. Cell proliferation was detected by MTT and functions were extamined by Real-time quantitative PCR. immunofluoresence, Western blot, drug metabolizing capacity and ELISA.
2. Fluidized microencapsulated hepatocyte cell lines were compared with the two-dimensional cultured hepatocytes and microencapsulated cells on the changes of gene and protein expression of phase I enzymes, II phase enzyme and specific nuclear receptors. Cryopreservation and recovery conditions of microencapsulated hepatocytes and the effection of large scale cryopreservation were optimized by the synthesis of ALB and urea.
3. The evaluation of effectiveness of bioartificial liver. The patient's plasma was collected. Microencapsulated hepatocyte cells were recovered after crypopreservation and added in the optimized bioreactor to be cultured with the plasma for24h. The effect of plasma on activity and functions of cells and the changes of small molecules in the plasma were determined.
Results
1. HepLi3cells were better according to their better proliferation, available to large-scale cultivation and liver functions.
2. The microencapsulated hepatocytes maintained high activity during the fluidization culture. And this condition could improve the expression of liver specific genes and protein, which may enhance cells'functions through suppressing kinases.
3.2hours incubation before and after the cryopreservation were determined, during which the number of recovered alive cells was more than50%. Forethemore, the cryopreservation volume expansion did not affect the liver functions.
4. HepLi3cells as seeded cells after cryopreservation were used for treating plasma from liver failure patients. Microencapsulated cells could stable the environment of patients which may improve their conditions.
Conclusion
1. HepLi3was the better seeded cells for BAL.
2. Optimized the production of microcapsules, liver cell cryopreservation and recovery conditions, protein kinases surpression may be the mechnism of promoting liver cell functions in microcapsulated culture.
3. The microencapsulated hepatocytes maintained high activity after large scale cryopreservation. They could be offered as seeded cells resource for BAL system.
4. BAL was proved to remove toxic substances, effectively improve the environment of patients by using microencapsulated HepLi3.
引文
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