异基因骨髓间充质干细胞早期局部移植修复碱烧伤角膜的研究
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摘要
目的进行骨髓间充质干细胞(bone marrow mesenchymal stem cells,MMSCs)的分离、纯化和鉴定;研究MMSCs同种异基因移植后的生存状况和对受体免疫状态的影响,探讨局部结膜下行MMSCs异基因移植用于治疗眼表创伤疾病的可行性;研究局部结膜下行MMSCs异基因移植修复中、重度碱烧伤角膜的可行性,并探讨其可能的发生机制。
方法
1.幼年SD大鼠10只。采用贴壁筛选法分离SD大鼠骨髓的间充质干细胞,反复传代对细胞进行扩增、纯化。鉴定:显微镜下观察各代细胞的形态、排列形式;选择第三代贴壁细胞,诱导其向脂肪样细胞、骨样细胞分化;流式细胞术检测细胞表面的免疫分子CD29、CD44、CD90、CD31、CD34、CD45的表达。
2.成年SD大鼠20只,MMSCs移植组10只,培养液对照组10只。体外DiI荧光标记MMSCs。表面麻醉下在鼻侧、颞侧结膜下各注入100μl的DiI-MMSCs细胞悬液,密度为5×10~3个/μl;对照组10只,同样方法注入200μL的DMEM-F12培养液。移植后4周共聚焦荧光显微镜下(DAPI复染细胞核)追踪MMSCs在体内存活情况,观察受体鼠生长状况和角膜、虹膜、晶体等眼部情况,RT-PCR法比较两组大鼠角膜免疫分子MHC-Ⅱ的mRNA的表达差异。
3.建立中度和重度角膜碱烧伤模型。中度角膜碱烧伤的MMSCs移植分组:模型+MMSCs移植组40只(其中CM-DiI标记的MMSC移植为10只),烧伤后1小时移植,细胞浓度为5×10~3个/μl;模型+培养液组(对照组)30只。移植后3天、2周、4周观察角膜透明度、新生血管。移植后4周行角膜组织HE染色、免疫荧光法共聚焦显微镜下观察MMSCs的迁移,角膜上皮细胞特异性标记CK12、Cx43的表达及分布。RT-PCR法检测EGF、IL-RA的表达。Western blotting分析E-cadherin的表达。
重度角膜碱烧伤的MMSCs移植分组:模型+MMSC移植组28只(其中CM-DiI荧光标记MMSCs移植为10只);模型+培养液组(对照组)18只。移植后3天、2周、4周观察角膜透明度、新生血管。移植后4周行角膜组织HE染色、免疫荧光法共聚焦显微镜下观察角膜上皮细胞特异性标记CK12、Cx43的表达及分布。RT-PCR分析IL-1RA的表达。
结果
1.贴壁细胞呈间质细胞特性:呈梭形,漩涡状排列。Von Kossa染色、油红染色贴壁细胞呈骨样细胞及脂肪样细胞分化。流式细胞仪显示细胞表面的免疫分子的表达:CD29(99.19%)、CD44(98.34%)、CD90(97.94%),;CD31(0.15%)、CD34(0.69%)、CD45(1.21%)。
2.移植4周后大量的DiI-MMSCs存活于结膜下、角膜缘,结构完整,生长良好。受体鼠全身情况良好,眼局部无排斥反应发生。RT-PCR结果显示受体鼠角膜表达MHC-Ⅱ,对照组未表达。
3.中度角膜碱烧伤的MMSCs移植结果:与对照组比较,移植后2周、4周移植组角膜透明度改善(P＜0.05)、新生血管减少(P＜0.05)。HE染色显示角膜上皮层有3-4层细胞,基质层可见少量新生血管,炎性细胞。共聚焦显微镜下见角膜缘处DiI-MMSCs少量表达CK12、Cx43;近角膜中央处存在MMSCs,未表达CK12、Cx43;角膜中央未见MMSCs。2周和4周时移植组EGF、IL-1RA高表达,其中2周时EGF的表达和IL-1RA的表达差异明显。4周时E-cadherin低表达,3天和2周时未见表达E-cadherin。
重度角膜碱烧伤的MMSCs移植结果:与对照组比较,4周时移植组角膜新生血管减少(P＜0.05),而透明度未见改善。HE染色显示上皮层中少量基底细胞,新生血管较少,少量炎细胞浸润。共聚焦荧光显微镜下见角膜缘处少量DiI-MMSCs,未表达CK12、Cx43。角膜近中央区和中央区未见迁移的MMSCs。RT-PCR显示,移植组2周、4周时IL-1RA高表达,其中2周时差异明显。
结论
1.本实验从骨髓中分离的贴壁细胞为骨髓间充质干细胞,纯度高。贴壁筛选和反复传代法是一种较理想的骨髓间充质干细胞的提纯方法。
2.局部结膜下行MMSCs异基因移植用于治疗眼表创伤疾病是安全可行的,有利于创建一种细胞来源广泛、无免疫排斥、微创的治疗眼表创伤疾病的新手段。
3.早期局部结膜下行异基因MMSCs移植可以抑止碱烧伤角膜表面新生血管生成,促进中度碱烧伤角膜修复。MMSCs发生迁移和分化,取决于局部微环境的改变。MMSCs的作用机制并非通过分化为相应的靶细胞来修复损伤,而主要通过调节细胞生长因子的分泌,改善残余细胞所处的微环境,促进残余细胞的生长来发挥修复作用。
Purpose The mesenchymal stem cells from femur and tibia of SD rats were isolated, purified and identified.The purpose of present study was to study the survival of marrow mesenchymal stem cells(MMSCs)and the immune status of recipient after allogenetic transplantation of MMSCs,and to investigate whether the local allogenetic transplantation of MMSCs and its reconstruction on alkali burned rat corneal surface are feasible.
Method
1.The MMSCs from femur and tibia of SD rats were isolated,passaged, amplified and puritied by adheresion-screening method.Cell morphology were observed by microscope.MMSCs are induced toward differentiation of Adipose-like cells and bone-like cells.The flow cytometry was utilized to detect the expression of CD29、CD44、CD90、CD31、CD34、CD45 molecule.
2.Twenty Adult Sprague-Dawley(SD)rats were randomly devided into transplantation group(10 rats)and control group(10 rats).MMSCs were labeled by DiI fluorescent.The cell suspension containing 5×10~3 cells/μL MMSCs was injected On the nasal and temporal subconjunctica in the right eyes of 10 SD rats,and the culture medium was used in a same way in other 10 SD rats as control.At 4 weeks after transplantation,the survivals of DiI-labled MMSCs were invastigated under the confocal microscope,and recipient growth and ocular manifestations were clinically observed.The expression of MHC-ⅡmRNA between two groups were compared.
3.MMSCs(5×10~3 cells/μL)allotransplantation for moderate alkali Burned 40 Rats Corneal Surface(DiI-MMSCs allotransplantation for 10 rats),and culture medium for moderate alkali Burned 30 Rats Corneal Surface(control group)were performed.After allogenetic MMSCs transplantation,rat cornea clarity and neovascularization in transplantation group and control group were observed.At the 4th week after DiI-labled MMSCs transplantation,expression and distribution of corneal epithelial cell specific marker CK12、Cx43 were observed by confocal microscopy.Expression of EGF and IL-1RA were compared by RT-PCR,and E-cadherin by Western blotting between transplantation group and control group at 3d, 2w and 4w.
MMSCs(5×10~3 cells/μL)allotransplantation for moderate alkali Burned 28 Rats Corneal Surface(DiI-MMSCs allotransplantation for 10 rats),and culture medium for moderate alkali Burned 1 Rats Corneal Surface(control group)were performed.After allogenetic MMSCs transplantation,rat cornea clarity and neovacularization in transplantation group and control group were observed.At the 4th week after DiI-labled MMSCs transplantation,expression and distribution of comeal epithelial cell specific marker CK12、Cx43 were observed,by confocal microscopy.Expression of IL-1RA were compared by RT-PCR between transplantation group and control group at 3d,2w and 4w.
Result
1.Cutured adherent cells present spindle fibroblast-like growth and swirl-like arrangement.Red adipose vacuole in endochylema was showed in adipose-like cell and black calcium salts deposition was found in bone-like cells differentiated by MMSCs.Cultured adherent cells presented positive expression for CD29(99.19%), CD44(98.34%),CD90(97.94%)and absent expression of CD31(0.15%),CD34(0.69 %),CD45(1.21%).
2.A lots of MMSCs labled by DiI were seen under the limbal and subconjunctiva in the 4th week after transplantation.No obvious abnormality was found in the eyes during the clinical observation.MHC-ⅡmRNA was expressed in cornea of allograft group compared with the control group.
3.In MMSCs allotransplantation for moderate alkali burned rat corneal surface,compared with the control group,corneas in transplantation group at the 4th week presented reduction in vascularity(P＜0.05)and obvious improvement in clarity(P＜0.05).HE staining showed three to four layer cells in epithelial lamina and less neovascularization and inflammatory cells in stroma.A lot of DiI-labled MMSCs appeared in cornea limbus,which express CK12 and Cx43,and them in near central region which no express CK12 and Cx43,and not in central region.By RT-PCR, corneas in transplantation group expressed more EGF and IL-1RA than in control group at the 2w and 4w.,and most discrepancy at the 2w.By Western blotting, corneas in transplantation group expressed small amounts E-cadherin at the 4w.
In MMSCs allotransplantation for severe alkali burned rat corneal surface, compared with the control group,corneas in transplantation group at the 4th week presented reduction in vascularity(P＜0.05)and no obvious improvement in clarity.HE staining showed less basal cells in epithelial lamina and less NV and Inflammatory cells in stroma.A lot of DiI-labled MMSCs appeared in cornea limbus,which expressed no CK12 and Cx43 and not in central region or near central region of cornea by confocal microscopy.By RT-PCR,corneas in transplantation group expressed more IL-1RA than in control group at the 2w and 4w.,and most discrepancy at the 2w.
Conclusion
1.Adherent cells from femur and tibia of SD rats are identificated as MMSCs based on cell morphology,differentiation and cell surface immune molecule. adheresion-screening and passage are good method for MMSCs purification.
2.local allogenetic transplantation of MMSCs is safe and feasible.It is a new,no immunologic rejection and less injury way on ocular surface diseases treatment.
3.Allogenetic MMSCs after early being subconjunctivally transplanted into moderate alkali Burned Rat Cornea,can reconstruct rat corneal surface.It is effective on inhibition angiogenesis of severe alkali burned cat Cornea.MMSCs migration and differentiation rely on microenvironment.MMSCs repair cornea surface by regulating cytokines and promoting residuary cells proliferation,not differentiating into injuryed cells.
方法
1.幼年SD大鼠10只。采用贴壁筛选法分离SD大鼠骨髓的间充质干细胞,反复传代对细胞进行扩增、纯化。鉴定:显微镜下观察各代细胞的形态、排列形式;选择第三代贴壁细胞,诱导其向脂肪样细胞、骨样细胞分化;流式细胞术检测细胞表面的免疫分子CD29、CD44、CD90、CD31、CD34、CD45的表达。
2.成年SD大鼠20只,MMSCs移植组10只,培养液对照组10只。体外DiI荧光标记MMSCs。表面麻醉下在鼻侧、颞侧结膜下各注入100μl的DiI-MMSCs细胞悬液,密度为5×10~3个/μl;对照组10只,同样方法注入200μL的DMEM-F12培养液。移植后4周共聚焦荧光显微镜下(DAPI复染细胞核)追踪MMSCs在体内存活情况,观察受体鼠生长状况和角膜、虹膜、晶体等眼部情况,RT-PCR法比较两组大鼠角膜免疫分子MHC-Ⅱ的mRNA的表达差异。
3.建立中度和重度角膜碱烧伤模型。中度角膜碱烧伤的MMSCs移植分组:模型+MMSCs移植组40只(其中CM-DiI标记的MMSC移植为10只),烧伤后1小时移植,细胞浓度为5×10~3个/μl;模型+培养液组(对照组)30只。移植后3天、2周、4周观察角膜透明度、新生血管。移植后4周行角膜组织HE染色、免疫荧光法共聚焦显微镜下观察MMSCs的迁移,角膜上皮细胞特异性标记CK12、Cx43的表达及分布。RT-PCR法检测EGF、IL-RA的表达。Western blotting分析E-cadherin的表达。
重度角膜碱烧伤的MMSCs移植分组:模型+MMSC移植组28只(其中CM-DiI荧光标记MMSCs移植为10只);模型+培养液组(对照组)18只。移植后3天、2周、4周观察角膜透明度、新生血管。移植后4周行角膜组织HE染色、免疫荧光法共聚焦显微镜下观察角膜上皮细胞特异性标记CK12、Cx43的表达及分布。RT-PCR分析IL-1RA的表达。
结果
1.贴壁细胞呈间质细胞特性:呈梭形,漩涡状排列。Von Kossa染色、油红染色贴壁细胞呈骨样细胞及脂肪样细胞分化。流式细胞仪显示细胞表面的免疫分子的表达:CD29(99.19%)、CD44(98.34%)、CD90(97.94%),;CD31(0.15%)、CD34(0.69%)、CD45(1.21%)。
2.移植4周后大量的DiI-MMSCs存活于结膜下、角膜缘,结构完整,生长良好。受体鼠全身情况良好,眼局部无排斥反应发生。RT-PCR结果显示受体鼠角膜表达MHC-Ⅱ,对照组未表达。
3.中度角膜碱烧伤的MMSCs移植结果:与对照组比较,移植后2周、4周移植组角膜透明度改善(P＜0.05)、新生血管减少(P＜0.05)。HE染色显示角膜上皮层有3-4层细胞,基质层可见少量新生血管,炎性细胞。共聚焦显微镜下见角膜缘处DiI-MMSCs少量表达CK12、Cx43;近角膜中央处存在MMSCs,未表达CK12、Cx43;角膜中央未见MMSCs。2周和4周时移植组EGF、IL-1RA高表达,其中2周时EGF的表达和IL-1RA的表达差异明显。4周时E-cadherin低表达,3天和2周时未见表达E-cadherin。
重度角膜碱烧伤的MMSCs移植结果:与对照组比较,4周时移植组角膜新生血管减少(P＜0.05),而透明度未见改善。HE染色显示上皮层中少量基底细胞,新生血管较少,少量炎细胞浸润。共聚焦荧光显微镜下见角膜缘处少量DiI-MMSCs,未表达CK12、Cx43。角膜近中央区和中央区未见迁移的MMSCs。RT-PCR显示,移植组2周、4周时IL-1RA高表达,其中2周时差异明显。
结论
1.本实验从骨髓中分离的贴壁细胞为骨髓间充质干细胞,纯度高。贴壁筛选和反复传代法是一种较理想的骨髓间充质干细胞的提纯方法。
2.局部结膜下行MMSCs异基因移植用于治疗眼表创伤疾病是安全可行的,有利于创建一种细胞来源广泛、无免疫排斥、微创的治疗眼表创伤疾病的新手段。
3.早期局部结膜下行异基因MMSCs移植可以抑止碱烧伤角膜表面新生血管生成,促进中度碱烧伤角膜修复。MMSCs发生迁移和分化,取决于局部微环境的改变。MMSCs的作用机制并非通过分化为相应的靶细胞来修复损伤,而主要通过调节细胞生长因子的分泌,改善残余细胞所处的微环境,促进残余细胞的生长来发挥修复作用。
Purpose The mesenchymal stem cells from femur and tibia of SD rats were isolated, purified and identified.The purpose of present study was to study the survival of marrow mesenchymal stem cells(MMSCs)and the immune status of recipient after allogenetic transplantation of MMSCs,and to investigate whether the local allogenetic transplantation of MMSCs and its reconstruction on alkali burned rat corneal surface are feasible.
Method
1.The MMSCs from femur and tibia of SD rats were isolated,passaged, amplified and puritied by adheresion-screening method.Cell morphology were observed by microscope.MMSCs are induced toward differentiation of Adipose-like cells and bone-like cells.The flow cytometry was utilized to detect the expression of CD29、CD44、CD90、CD31、CD34、CD45 molecule.
2.Twenty Adult Sprague-Dawley(SD)rats were randomly devided into transplantation group(10 rats)and control group(10 rats).MMSCs were labeled by DiI fluorescent.The cell suspension containing 5×10~3 cells/μL MMSCs was injected On the nasal and temporal subconjunctica in the right eyes of 10 SD rats,and the culture medium was used in a same way in other 10 SD rats as control.At 4 weeks after transplantation,the survivals of DiI-labled MMSCs were invastigated under the confocal microscope,and recipient growth and ocular manifestations were clinically observed.The expression of MHC-ⅡmRNA between two groups were compared.
3.MMSCs(5×10~3 cells/μL)allotransplantation for moderate alkali Burned 40 Rats Corneal Surface(DiI-MMSCs allotransplantation for 10 rats),and culture medium for moderate alkali Burned 30 Rats Corneal Surface(control group)were performed.After allogenetic MMSCs transplantation,rat cornea clarity and neovascularization in transplantation group and control group were observed.At the 4th week after DiI-labled MMSCs transplantation,expression and distribution of corneal epithelial cell specific marker CK12、Cx43 were observed by confocal microscopy.Expression of EGF and IL-1RA were compared by RT-PCR,and E-cadherin by Western blotting between transplantation group and control group at 3d, 2w and 4w.
MMSCs(5×10~3 cells/μL)allotransplantation for moderate alkali Burned 28 Rats Corneal Surface(DiI-MMSCs allotransplantation for 10 rats),and culture medium for moderate alkali Burned 1 Rats Corneal Surface(control group)were performed.After allogenetic MMSCs transplantation,rat cornea clarity and neovacularization in transplantation group and control group were observed.At the 4th week after DiI-labled MMSCs transplantation,expression and distribution of comeal epithelial cell specific marker CK12、Cx43 were observed,by confocal microscopy.Expression of IL-1RA were compared by RT-PCR between transplantation group and control group at 3d,2w and 4w.
Result
1.Cutured adherent cells present spindle fibroblast-like growth and swirl-like arrangement.Red adipose vacuole in endochylema was showed in adipose-like cell and black calcium salts deposition was found in bone-like cells differentiated by MMSCs.Cultured adherent cells presented positive expression for CD29(99.19%), CD44(98.34%),CD90(97.94%)and absent expression of CD31(0.15%),CD34(0.69 %),CD45(1.21%).
2.A lots of MMSCs labled by DiI were seen under the limbal and subconjunctiva in the 4th week after transplantation.No obvious abnormality was found in the eyes during the clinical observation.MHC-ⅡmRNA was expressed in cornea of allograft group compared with the control group.
3.In MMSCs allotransplantation for moderate alkali burned rat corneal surface,compared with the control group,corneas in transplantation group at the 4th week presented reduction in vascularity(P＜0.05)and obvious improvement in clarity(P＜0.05).HE staining showed three to four layer cells in epithelial lamina and less neovascularization and inflammatory cells in stroma.A lot of DiI-labled MMSCs appeared in cornea limbus,which express CK12 and Cx43,and them in near central region which no express CK12 and Cx43,and not in central region.By RT-PCR, corneas in transplantation group expressed more EGF and IL-1RA than in control group at the 2w and 4w.,and most discrepancy at the 2w.By Western blotting, corneas in transplantation group expressed small amounts E-cadherin at the 4w.
In MMSCs allotransplantation for severe alkali burned rat corneal surface, compared with the control group,corneas in transplantation group at the 4th week presented reduction in vascularity(P＜0.05)and no obvious improvement in clarity.HE staining showed less basal cells in epithelial lamina and less NV and Inflammatory cells in stroma.A lot of DiI-labled MMSCs appeared in cornea limbus,which expressed no CK12 and Cx43 and not in central region or near central region of cornea by confocal microscopy.By RT-PCR,corneas in transplantation group expressed more IL-1RA than in control group at the 2w and 4w.,and most discrepancy at the 2w.
Conclusion
1.Adherent cells from femur and tibia of SD rats are identificated as MMSCs based on cell morphology,differentiation and cell surface immune molecule. adheresion-screening and passage are good method for MMSCs purification.
2.local allogenetic transplantation of MMSCs is safe and feasible.It is a new,no immunologic rejection and less injury way on ocular surface diseases treatment.
3.Allogenetic MMSCs after early being subconjunctivally transplanted into moderate alkali Burned Rat Cornea,can reconstruct rat corneal surface.It is effective on inhibition angiogenesis of severe alkali burned cat Cornea.MMSCs migration and differentiation rely on microenvironment.MMSCs repair cornea surface by regulating cytokines and promoting residuary cells proliferation,not differentiating into injuryed cells.
引文
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