不同微环境对骨髓间充质干细胞分化为产胰岛素细胞的影响
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摘要
糖尿病是常见的慢性疾病,全世界患病率约6%。患者常需要终身注射胰岛素治疗,但胰岛素注射疗法对血糖的控制并不理想,无法阻止糖尿病肾病、冠心病、糖尿病眼病等并发症的发生和发展。最近几年胰岛移植的成功表明了通过补充缺乏的β细胞可以治愈糖尿病。但供体来源缺乏和移植排斥阻碍了胰岛细胞移植的广泛应用。
干细胞作为一类具有极强自我更新及多向分化潜能的细胞,已经逐渐成为人们寻找胰岛β细胞替代物的新的细胞资源。由于骨髓间充质干细胞(MSCs)具有多向分化和很强的增殖能力,具有用于细胞治疗的巨大潜能。它们可以分化为神经细胞、脂肪细胞、平滑肌细胞、骨骼肌细胞、心肌细胞、软骨细胞和产胰岛素细胞等。但是由骨髓间充质干细胞诱导分化而来的产胰岛素细胞(IPCs),其胰岛素分泌量不足正常胰腺β细胞的1%。如何促进MSCs分化为较成熟的IPCs成为亟待解决的关键问题。目前认为其分化机制,主要是微环境因素通过一定的信号转导通路传递,转录因子抑制或激活,启动关键基因表达的结果。
本研究的目标是:探索不同微环境下对大鼠MSCs体外分化为IPCs的影响,在糖尿病大鼠体内微环境下MSCs是否还可以分化为IPCs,为糖尿病细胞替代治疗提供理想的种子细胞。
大鼠MSCs的体外分离培养和生物学特征:利用贴壁法分离纯化大鼠MSCs,传代培养于含10%胎牛血清的DMEM培养液中;通过倒置显微镜、电镜、免疫细胞化学分析大鼠MSCs的生物学特征。结果显示原代和传代培养MSCs均保持较强的增殖能力,形态为均一的成纤维样细胞。超微结构显示了干细胞的幼稚特征,免疫细胞化学显示CD34阴性,CD44阳性。结论:采用我们的方法,可以获得生长稳定,扩增较快和纯度较高的MSCs。
不同微环境对大鼠MSCs体外分化为IPCs的影响:采用第三代MSCs,用不同的微环境进行诱导,对照组诱导剂为含有角朊细胞生长因子、胰岛素铁硒传递蛋白(ITS)、尼克酰胺的无血清DMEM/F12培养基、实验组在对照组基础上添加胰腺条件培养液;对诱导后细胞进行光、电镜观察,双硫腙和免疫细胞化学等进行鉴定,并行体外葡萄糖刺激实验,测定细胞分泌胰岛素及C-肽功能。结果表明,实验组及对照组均可诱导分化为IPCs,但实验组分化而成的IPCs在数量及功能上均好于对照组。结论:大鼠胰腺提取物模拟的微环境能促进大鼠MSCs体外诱导分化为较高质量的IPCs。
在糖尿病大鼠体内微环境下MSCs分化为IPCs的潜能:通过腹腔注射链脲佐菌素(STZ)诱导健康SD大鼠建立糖尿病模型;将MSCs及由MSCs诱导分化来的IPCs注射到糖尿病模型大鼠的肾包膜下,检测移植前后血糖、体重、尿量、生存时间变化,当移植大鼠血糖开始下降后,行荷移植物肾切除术去除移植物,继续观察血糖变化,看是否有血糖反跳,以评价其治疗糖尿病的效果,结合标本免疫组织化学染色,观察移植入的MSCs在糖尿病大鼠体内是否分化为IPCs。结果:将MSCs及IPCs移植到大鼠肾包膜下后,大鼠的血糖水平下降,糖尿病症状得到控制,生存时间明显延长。免疫组化显示移植入的MSCs分化为胰岛素染色阳性细胞。结论:在糖尿病大鼠体内微环境下MSCs可以分化为IPCs。
综上所述,大鼠MSCs在不同的体外及体内微环境下均可特异诱导分化为IPCs,而大鼠胰腺提取物模拟的微环境能促进大鼠MSCs体外诱导分化为IPCs;将大鼠MSCs和IPCs移植入糖尿病大鼠模型体内能够明显改善糖尿病症状,延长其生存时间。虽然骨髓间充质干细胞在安全而有效地运用于临床治疗之前还有许多基本的问题有待解决,但它为我们解决移植治疗糖尿病中供体缺乏问题方面提供了一条新的途经。
Diabetes mellitus is a devastating chronic disease and over 6% of the population is affected worldwide. The diabetic are necessary to inject insulin in their lifetime, but it is not ideal to inject insulin since insulin can't prevent the development of diseases derived form diabetes, such as kidney diseases, coronary heart disease, eye diseases,etc. The success achieved over last few years with islet transplantation suggests that diabetes can be cured by the replenishment of deficientβcells. However, the lack of donor organs and transplant rejection hinder the application of pancreatic islet transplantation.
Stem cells ,which have the capacity for both self-renewal and multilineage differentiation into any type of cell, becoming the new source of islet cell replacement. Bone marrow mesenchymal stem cells(MSCs) have great ability of multi-directional differentiation and reproductive activity that make them potentially useful for cell therapy. A number of protocols have been described to induce MSCs to neuronal cells,adipocytes,smooth muscle myocytes,skeletal muscle myocytes,cartilage cells and insulin-producing cells(IPCs).The IPCs induced from MSCs can secrete insulin,but their secretory volume was less than 1% that of a normalβcells. How to promote MSCs differentiating into IPCs become the critical issue should be solved. The recent study have shown that the differentiation mechanism is the result of key gene expression through a definite signal transmitting passway and inhibition or activation of transcription factor induced by microenviroment factors.
In this study,we try to explore the impact of different microenvironment on differentiating rat bone marrow MSCs into IPCs in vitro,then to study the capacity of MSCs differentiating into IPCs in diabetic rat’s microenviroment in vivo,and to provide suitable“seed”cells for replacement therapy of diabetes mellitus.
Isolation, cultivation and biological features of rat MSCs in vitro:MSCs were isolated from rat bone marrow,purified by their adhesive process onto the culture dish,serial subcultivated on dulbecco’s modified eagle medium with 10% fetal bovine serum;The changes of cell morphology and the ultrastructure were observed, cell surface markers CD34、CD44 were detected by immunocytochemistry. The results show both primary and passage MSCs have maintained highly proliferative capacity.They have homogeneous fibrocyte-like shap under light microscope. The ultrastructure showed the young cell nature of stem cell. The cells were negative for CD34, while positive for CD44 by immunocytochemistry staining.Conclusion: MSCs can be cultured stably、expanded quickly and have higher purity with our method.
The Impact of different microenvironments on the differentiating rat MSCs into IPCs: Third descended MSCs cells were then cultivated in vitro mimicking different microenvironments,in which control group was cultivated in serum free DMEM/F12 medium including keratinocyte growth factor(KGF)、ITS and Nicotinamide, while experimental group was cultivated in serum free DMEM/F12 medium in which the rat pancreatic extract was added. During the cultivation period the cells were taken for light and electron microscopy at different time points, identified by dithizone(DTZ) and immunocytochemistry. The glucose stimulation test was performed in vitro and the levels of insulin and C-peptide in response to the different glucose concentration was assayed. The results show MSCs could differentiat into IPCs both in the control group and the experimental group. The IPCs harvested from experiment group had greater number and better function than that from control group . Conclusion :The microenvironment in which the rat pancreatic extract added could promote the rat bone marrow MSCs to differentiate into better IPCs in vitro。
The capacity of MSCs differentiating into IPCs in diabetic rat’s microenviroment in vivo: The rat MSCs and IPCs induced from MSCs were transplanted under the renal capsule of STZ induced SD rat. Blood glucose levels, weight, urine and survival rate were monitored. when rat’s blood glucose levels begin to descend,grafts were then removed by unilateral nephrectomy. The blood glucoses level was monitored to investgate whether euglycemia reversal happenned, and we have immunohistochemistry staining to observe wherether the MSCs of transplanted could differentiate into IPCs. The result show MSCs and IPCs by injection into the renal capsule of STZ induced diabetic SD rat could decrease its blood glucose level and prolonged survival time. Immunohistochemistry also confirmed that the MSCs of transplanted were strongly positive for insulin. Conclusion: MSCs can differentiating into IPCs in diabetic rat’s microenviroment in vivo.
In summary, the present study provides evidence that rat MSCs have the capacity to differentiate into IPCs under different microenvironments both in vitro and in vivo. The microenvironment in which the rat pancreatic extract added could promote the rat bone marrow MSCs to differentiate into better IPCs in vitro. MSCs and IPCs transplanted into the renal capsule of STZ induced diabetic SD rats could decrease their blood glucose level and prolong their survival time. Obviously, there are still a number of fundamental questions about MSCs need to be answered before they can be safely and effectively used in clinical setting, but it provides us a new solution to deal with the shortage of beta cells for therapy of type 1 diabetes.
干细胞作为一类具有极强自我更新及多向分化潜能的细胞,已经逐渐成为人们寻找胰岛β细胞替代物的新的细胞资源。由于骨髓间充质干细胞(MSCs)具有多向分化和很强的增殖能力,具有用于细胞治疗的巨大潜能。它们可以分化为神经细胞、脂肪细胞、平滑肌细胞、骨骼肌细胞、心肌细胞、软骨细胞和产胰岛素细胞等。但是由骨髓间充质干细胞诱导分化而来的产胰岛素细胞(IPCs),其胰岛素分泌量不足正常胰腺β细胞的1%。如何促进MSCs分化为较成熟的IPCs成为亟待解决的关键问题。目前认为其分化机制,主要是微环境因素通过一定的信号转导通路传递,转录因子抑制或激活,启动关键基因表达的结果。
本研究的目标是:探索不同微环境下对大鼠MSCs体外分化为IPCs的影响,在糖尿病大鼠体内微环境下MSCs是否还可以分化为IPCs,为糖尿病细胞替代治疗提供理想的种子细胞。
大鼠MSCs的体外分离培养和生物学特征:利用贴壁法分离纯化大鼠MSCs,传代培养于含10%胎牛血清的DMEM培养液中;通过倒置显微镜、电镜、免疫细胞化学分析大鼠MSCs的生物学特征。结果显示原代和传代培养MSCs均保持较强的增殖能力,形态为均一的成纤维样细胞。超微结构显示了干细胞的幼稚特征,免疫细胞化学显示CD34阴性,CD44阳性。结论:采用我们的方法,可以获得生长稳定,扩增较快和纯度较高的MSCs。
不同微环境对大鼠MSCs体外分化为IPCs的影响:采用第三代MSCs,用不同的微环境进行诱导,对照组诱导剂为含有角朊细胞生长因子、胰岛素铁硒传递蛋白(ITS)、尼克酰胺的无血清DMEM/F12培养基、实验组在对照组基础上添加胰腺条件培养液;对诱导后细胞进行光、电镜观察,双硫腙和免疫细胞化学等进行鉴定,并行体外葡萄糖刺激实验,测定细胞分泌胰岛素及C-肽功能。结果表明,实验组及对照组均可诱导分化为IPCs,但实验组分化而成的IPCs在数量及功能上均好于对照组。结论:大鼠胰腺提取物模拟的微环境能促进大鼠MSCs体外诱导分化为较高质量的IPCs。
在糖尿病大鼠体内微环境下MSCs分化为IPCs的潜能:通过腹腔注射链脲佐菌素(STZ)诱导健康SD大鼠建立糖尿病模型;将MSCs及由MSCs诱导分化来的IPCs注射到糖尿病模型大鼠的肾包膜下,检测移植前后血糖、体重、尿量、生存时间变化,当移植大鼠血糖开始下降后,行荷移植物肾切除术去除移植物,继续观察血糖变化,看是否有血糖反跳,以评价其治疗糖尿病的效果,结合标本免疫组织化学染色,观察移植入的MSCs在糖尿病大鼠体内是否分化为IPCs。结果:将MSCs及IPCs移植到大鼠肾包膜下后,大鼠的血糖水平下降,糖尿病症状得到控制,生存时间明显延长。免疫组化显示移植入的MSCs分化为胰岛素染色阳性细胞。结论:在糖尿病大鼠体内微环境下MSCs可以分化为IPCs。
综上所述,大鼠MSCs在不同的体外及体内微环境下均可特异诱导分化为IPCs,而大鼠胰腺提取物模拟的微环境能促进大鼠MSCs体外诱导分化为IPCs;将大鼠MSCs和IPCs移植入糖尿病大鼠模型体内能够明显改善糖尿病症状,延长其生存时间。虽然骨髓间充质干细胞在安全而有效地运用于临床治疗之前还有许多基本的问题有待解决,但它为我们解决移植治疗糖尿病中供体缺乏问题方面提供了一条新的途经。
Diabetes mellitus is a devastating chronic disease and over 6% of the population is affected worldwide. The diabetic are necessary to inject insulin in their lifetime, but it is not ideal to inject insulin since insulin can't prevent the development of diseases derived form diabetes, such as kidney diseases, coronary heart disease, eye diseases,etc. The success achieved over last few years with islet transplantation suggests that diabetes can be cured by the replenishment of deficientβcells. However, the lack of donor organs and transplant rejection hinder the application of pancreatic islet transplantation.
Stem cells ,which have the capacity for both self-renewal and multilineage differentiation into any type of cell, becoming the new source of islet cell replacement. Bone marrow mesenchymal stem cells(MSCs) have great ability of multi-directional differentiation and reproductive activity that make them potentially useful for cell therapy. A number of protocols have been described to induce MSCs to neuronal cells,adipocytes,smooth muscle myocytes,skeletal muscle myocytes,cartilage cells and insulin-producing cells(IPCs).The IPCs induced from MSCs can secrete insulin,but their secretory volume was less than 1% that of a normalβcells. How to promote MSCs differentiating into IPCs become the critical issue should be solved. The recent study have shown that the differentiation mechanism is the result of key gene expression through a definite signal transmitting passway and inhibition or activation of transcription factor induced by microenviroment factors.
In this study,we try to explore the impact of different microenvironment on differentiating rat bone marrow MSCs into IPCs in vitro,then to study the capacity of MSCs differentiating into IPCs in diabetic rat’s microenviroment in vivo,and to provide suitable“seed”cells for replacement therapy of diabetes mellitus.
Isolation, cultivation and biological features of rat MSCs in vitro:MSCs were isolated from rat bone marrow,purified by their adhesive process onto the culture dish,serial subcultivated on dulbecco’s modified eagle medium with 10% fetal bovine serum;The changes of cell morphology and the ultrastructure were observed, cell surface markers CD34、CD44 were detected by immunocytochemistry. The results show both primary and passage MSCs have maintained highly proliferative capacity.They have homogeneous fibrocyte-like shap under light microscope. The ultrastructure showed the young cell nature of stem cell. The cells were negative for CD34, while positive for CD44 by immunocytochemistry staining.Conclusion: MSCs can be cultured stably、expanded quickly and have higher purity with our method.
The Impact of different microenvironments on the differentiating rat MSCs into IPCs: Third descended MSCs cells were then cultivated in vitro mimicking different microenvironments,in which control group was cultivated in serum free DMEM/F12 medium including keratinocyte growth factor(KGF)、ITS and Nicotinamide, while experimental group was cultivated in serum free DMEM/F12 medium in which the rat pancreatic extract was added. During the cultivation period the cells were taken for light and electron microscopy at different time points, identified by dithizone(DTZ) and immunocytochemistry. The glucose stimulation test was performed in vitro and the levels of insulin and C-peptide in response to the different glucose concentration was assayed. The results show MSCs could differentiat into IPCs both in the control group and the experimental group. The IPCs harvested from experiment group had greater number and better function than that from control group . Conclusion :The microenvironment in which the rat pancreatic extract added could promote the rat bone marrow MSCs to differentiate into better IPCs in vitro。
The capacity of MSCs differentiating into IPCs in diabetic rat’s microenviroment in vivo: The rat MSCs and IPCs induced from MSCs were transplanted under the renal capsule of STZ induced SD rat. Blood glucose levels, weight, urine and survival rate were monitored. when rat’s blood glucose levels begin to descend,grafts were then removed by unilateral nephrectomy. The blood glucoses level was monitored to investgate whether euglycemia reversal happenned, and we have immunohistochemistry staining to observe wherether the MSCs of transplanted could differentiate into IPCs. The result show MSCs and IPCs by injection into the renal capsule of STZ induced diabetic SD rat could decrease its blood glucose level and prolonged survival time. Immunohistochemistry also confirmed that the MSCs of transplanted were strongly positive for insulin. Conclusion: MSCs can differentiating into IPCs in diabetic rat’s microenviroment in vivo.
In summary, the present study provides evidence that rat MSCs have the capacity to differentiate into IPCs under different microenvironments both in vitro and in vivo. The microenvironment in which the rat pancreatic extract added could promote the rat bone marrow MSCs to differentiate into better IPCs in vitro. MSCs and IPCs transplanted into the renal capsule of STZ induced diabetic SD rats could decrease their blood glucose level and prolong their survival time. Obviously, there are still a number of fundamental questions about MSCs need to be answered before they can be safely and effectively used in clinical setting, but it provides us a new solution to deal with the shortage of beta cells for therapy of type 1 diabetes.
引文
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1. Diabetes Control and Complication Trial Research Group.The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.N Engl J Med 1993;329:977-986
2. UK Prospective Diabetes Study Group.Intensive blood glucose control with sulphonvlureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes(UKPDS 33) . Lancet 1998;352:837-853
3. Shapiro AM,Lakey JR,Ryan EA,et al. Islet transplantation in seven patients with type I diabetes mellitus using a glucocorticoid-free immunosupp- ressive regimen.[J] New Engl JMed, 2000,343(4): 230-238.
4. Hess D,Li L , Martin M,et al.Bone mallow-derived stem cells initiate pancreatic regeneration[J].Nat Biotechnol,2003;2l(7):763-770.
5. Ianus A, Holz GG,Theise ND, Hussain MA: In vivo derivation of glucosecompetent pancreatic endocrine cells from bone marrow without evidence of cell fusion.2003,J Clin Invest 111:843-850.
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