人骨髓间充质干细胞分化为脂肪细胞过程中的基本特征及机制研究
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摘要
肥胖的产生不仅是由于脂肪细胞增大引起的,还有另外一个重要因素是脂肪细胞数目的增加。脂肪细胞数目的增多来源于存在于脂肪组织内多潜能干细胞的成脂分化,甚至在某些因素的刺激下,其它器官的干细胞如骨髓间充质干细胞也可能会募集到脂肪组织分化为脂肪细胞。目前对于脂肪细胞分化的研究主要集中于小鼠前脂肪细胞到成熟脂肪细胞这个阶段,但是对于间充质干细胞特别是人来源的间充质干细胞如何分化为脂肪细胞这一过程了解甚少。因此,本课题研究的主要目的是观察人骨髓间充质干细胞分化为脂肪细胞过程中的基本特征,包括增殖特性和参与调控的转录因子的作用。
本课题中,我们利用密度梯度离心和贴壁培养的方法从人骨髓中成功分离了间充质干细胞。从形态上观察,体外培养的人骨髓间充质干细胞成梭形,生长比较缓慢,细胞缺乏接触抑制的特性,生长致密的克隆中心细胞成多层生长。流式细胞检测90%以上的细胞处以G0／G1期。人骨髓间充质在体外只能进行有限传代,多次传代后细胞出现复制性老化,大概能传至第12代。
进一步我们用含10%胎牛血清,0.5mM 3-异丁基-1-甲基黄嘌呤(3-isobutyl-l-methylxanthine, Mix), 1μM地塞米松(Dexamethasone, Dex),10μg/ml胰岛素(Insulin), 100μM吲哚美辛(Indo, Indomethacin)的培养液诱导细胞。按照MDI+Indo处理3天,接着胰岛素维持1天,如此反复处理细胞至12天,最后用仅含胰岛素的培养液维持至21天。细胞经诱导后绝大多数细胞分化为成熟的脂肪细胞,表现为细胞胞体由原来的梭形变为圆形,细胞内有甘油三酯聚积。同时用Real-time PCR的方法检测脂肪细胞特异性蛋白质脂肪酸结合蛋白(422／aP2)随分化的过程表达增加。另外,脂肪细胞分化密切相关的转录因子C/EBPβ在激素诱导过程中并没有显著变化,至分化后期有所下降。C/EBPα和PPARγ激素处理后表达增加。
以往的研究表明接触抑制的小鼠3T3-L1细胞分化时会重新进入细胞周期(MCE, mitotic clonal expansion有丝分裂克隆扩增),我们的研究发现人脂肪组织干细胞成脂分化时没有经历MCE。在我们的研究中,人骨髓间充质干细胞因为其生长特性,细胞在分化之前不能接触抑制和同步化,分化前后细胞计数结果表明,细胞分化处理结束后,未处理的对照组细胞数量相对诱导分化前还有一定量增加,而分化处理组的细胞数量少于对照组,并且刺激次数越多,分化细胞的比例越高,最终细胞数量与未诱导组相比增加越少。提示细胞分化时没有经过分裂。进一步我们在人骨髓间充质干细胞诱导分化24小时后加入BrdU孵育48小时,到细胞分化成熟后检测BrdU掺入和分化脂肪细胞的关系,结果显示有部分细胞掺入BrdU,说明这些细胞还在增殖,但这些细胞均没有分化为脂肪细胞,胞浆内没有脂滴出现；而有脂滴积聚的脂肪细胞其核内均没有BrdU掺入。对照的3T3-L1可见绝大多数分化的细胞有BrdU掺入。这些结果提示,人骨髓间充质干细胞与小鼠前脂肪细胞3T3-L1不同,分化时并不需要经过有丝分裂克隆扩增的调节过程。
人骨髓间充质干细胞中C/EBPβ的表达量在激素处理的过程中并没有显著的变化。但是当我们用RNA干扰的方法敲低C/EBPβ的表达后,细胞成脂分化能力显著降低,提示C／EBPp在人骨髓间充质干细胞分化为脂肪细胞的过程中是必须的。进一步我们利用腺病毒过表达系统在细胞内过表达C/EBPβ,观察到C/EBPβ联合PPARγ的激动剂吲哚美辛使脂肪细胞的分化增加,说明C/EBPβ可以促进人骨髓间充质干细胞向脂肪细胞分化,但必须依赖PPARγ的激活。过表达C/EBPα对细胞分化的影响类似于C/EBPβ的作用,可以促进细胞向脂肪细胞分化,但必须同时激活PPARγ。但是在相同MOI情况下,C/EBPα促进细胞成脂分化的作用小于C/EBPβ的作用。另外随着MOI的升高,C/EBPβ和C/EBPα均表现出抗细胞增殖和促进凋亡的作用。骨髓间充质干细胞过表达PPARγ能够促使细胞分化,并且不需要激素MDI的作用,加入PPARγ的激动剂能够增强这种效果。但是PPARγ的过表达和激活后分化细胞内的脂滴明显小于用MDI+Indo诱导分化的细胞,提示PPARγ可能起始了脂肪细胞的分化但是脂质代谢还需要其它基因激活参与。另外过表达PPARγ使微丝蛋白β-actin的表达降低,但不影响β-tubulin的表达,提示PPARγ可能通过调节细胞骨架蛋白调节脂肪细胞的分化。
我们对于人骨髓间充质干细胞分化为脂肪细胞过程中的基本特征和参与调节脂肪分化的三个转录因子C/EBPβ、C/EBPα和PPARγ的作用进行了初步探讨,至于它们通过何种方式调节脂肪细胞的分化还需要进一步实验和研究。这对于阐明人脂肪细胞分化机制,指导肥胖以及其相关疾病的治疗具有积极的意义。
The increase of adipose tissue mass associated with obesity is due to both hypertrophy and hyperplasia of adipocytes. This hyperplasia results from the differentiation of in situ multipotent stem cells present in the vascular stroma of adipose tissue. The recruitment and then differentiation of mesenchymal stem cells in bone marrow to adipose tissue contributes in part to the hyperplasia. The adipocyte differentiation from mesenchyma stem cells is usually described as two phase. The first phase is the commitment of stem cells to preadipocyte, which cannot be distinguished morphologically from its precursor cell but has lost the potential to differentiate into other cell types. In the second phase known as terminal differentiation, the pre-adipocyte will obtain the characteristics of the mature adipocyte. The terminal differentiation has been extensively characterized using preadipocyte cell lines (for example, the mouse cell lines 3T3-L1,3T3-F442A). But what happens to the earlier stage cells-mesenchymal stem cells during adipocyte differentiation is rarely known, especially for the human derived mesenchymal stem cells. The objective of our research is to charaterize the adipocyte differentiation of human mesenchymal stem cells(hMSCs) from bone marrow, including the relationship between proliferation and differentiation and the role of three key transcription factors C/EBPβ, C/EBPα, and PPARγ.
In our study, we first isolated mesenchymal stem cells from human bone marrow with Ficoll density gradient centrifugation and in vitro adherent culture method. The cultured hMSC showed typical spindle-shape phenotype. hMSC proliferated slowly, contact inhibition was not obvious, since the dense cells grows into multilayers in the central of clones. More than 90% cells were at G1/G0 phase indicated by PI staining and flowcytometry. hMSC had a limited lifespan in culture, and serial subcultivation resulted in senescence and grandually die. The cells could be subcultured to passage 12.
In order to induce hMSCs to differentiate into adipocytes, PPARy agonist (indomethacin) was added to classic adipocyte differentiation protocol (DMEM containing 10%FBS,0.5mM isobutyl methylxanthine, 1μM dexamethasone and 10μg/ml insulin:MDI), and treated repeatedly. Most cells differentiated after repeated treatment for three times. The expression of adipose-specific gene aP2 by real-time PCR increased along hormone induction. Multiple treatments resulted in increasing numbers of adipocytes. Significant increase of human C/EBP beta expression was not observed during differentiation. C/EBP alpha and PPAR gamma increased upon induction, and decreased in the terminal stage.
To examine whether MCE occures during adipocytes differentiation of hMSCs. We compared the cell number of hMSCs pre- and after differentiation. The more cells differentiate into adipocyte, the less cells would be there eventually. BrdU incorporation upon induction and detected when fully differentiation showed that the differentated hMSC were BrdU negative, while differentiated 3T3-L1 were BrdU positive. Together, hMSC did not undergo mitosis clone expansion upon adipocyte differentiation in culture condition, which was different from 3T3-L1 model.
To define the role of the three transcription factors in hMSCs. We performed gain-or loss-of function experiments. C/EBPβknockdown in hMSCs with RNAi impared the adipogenic potential, while overexpression of C/EBP(3 stimulated cells to differentiate in response to indomethacin treatment. Overexpression of C/EBPa also potentiated the adipocyte differentiation along with PPARy angonist. Overexpression of PPARy alone was enough to initiate adipocytes differentiation of hMSCs, but not stimulate fully differentiated adipocytes.
本课题中,我们利用密度梯度离心和贴壁培养的方法从人骨髓中成功分离了间充质干细胞。从形态上观察,体外培养的人骨髓间充质干细胞成梭形,生长比较缓慢,细胞缺乏接触抑制的特性,生长致密的克隆中心细胞成多层生长。流式细胞检测90%以上的细胞处以G0／G1期。人骨髓间充质在体外只能进行有限传代,多次传代后细胞出现复制性老化,大概能传至第12代。
进一步我们用含10%胎牛血清,0.5mM 3-异丁基-1-甲基黄嘌呤(3-isobutyl-l-methylxanthine, Mix), 1μM地塞米松(Dexamethasone, Dex),10μg/ml胰岛素(Insulin), 100μM吲哚美辛(Indo, Indomethacin)的培养液诱导细胞。按照MDI+Indo处理3天,接着胰岛素维持1天,如此反复处理细胞至12天,最后用仅含胰岛素的培养液维持至21天。细胞经诱导后绝大多数细胞分化为成熟的脂肪细胞,表现为细胞胞体由原来的梭形变为圆形,细胞内有甘油三酯聚积。同时用Real-time PCR的方法检测脂肪细胞特异性蛋白质脂肪酸结合蛋白(422／aP2)随分化的过程表达增加。另外,脂肪细胞分化密切相关的转录因子C/EBPβ在激素诱导过程中并没有显著变化,至分化后期有所下降。C/EBPα和PPARγ激素处理后表达增加。
以往的研究表明接触抑制的小鼠3T3-L1细胞分化时会重新进入细胞周期(MCE, mitotic clonal expansion有丝分裂克隆扩增),我们的研究发现人脂肪组织干细胞成脂分化时没有经历MCE。在我们的研究中,人骨髓间充质干细胞因为其生长特性,细胞在分化之前不能接触抑制和同步化,分化前后细胞计数结果表明,细胞分化处理结束后,未处理的对照组细胞数量相对诱导分化前还有一定量增加,而分化处理组的细胞数量少于对照组,并且刺激次数越多,分化细胞的比例越高,最终细胞数量与未诱导组相比增加越少。提示细胞分化时没有经过分裂。进一步我们在人骨髓间充质干细胞诱导分化24小时后加入BrdU孵育48小时,到细胞分化成熟后检测BrdU掺入和分化脂肪细胞的关系,结果显示有部分细胞掺入BrdU,说明这些细胞还在增殖,但这些细胞均没有分化为脂肪细胞,胞浆内没有脂滴出现；而有脂滴积聚的脂肪细胞其核内均没有BrdU掺入。对照的3T3-L1可见绝大多数分化的细胞有BrdU掺入。这些结果提示,人骨髓间充质干细胞与小鼠前脂肪细胞3T3-L1不同,分化时并不需要经过有丝分裂克隆扩增的调节过程。
人骨髓间充质干细胞中C/EBPβ的表达量在激素处理的过程中并没有显著的变化。但是当我们用RNA干扰的方法敲低C/EBPβ的表达后,细胞成脂分化能力显著降低,提示C／EBPp在人骨髓间充质干细胞分化为脂肪细胞的过程中是必须的。进一步我们利用腺病毒过表达系统在细胞内过表达C/EBPβ,观察到C/EBPβ联合PPARγ的激动剂吲哚美辛使脂肪细胞的分化增加,说明C/EBPβ可以促进人骨髓间充质干细胞向脂肪细胞分化,但必须依赖PPARγ的激活。过表达C/EBPα对细胞分化的影响类似于C/EBPβ的作用,可以促进细胞向脂肪细胞分化,但必须同时激活PPARγ。但是在相同MOI情况下,C/EBPα促进细胞成脂分化的作用小于C/EBPβ的作用。另外随着MOI的升高,C/EBPβ和C/EBPα均表现出抗细胞增殖和促进凋亡的作用。骨髓间充质干细胞过表达PPARγ能够促使细胞分化,并且不需要激素MDI的作用,加入PPARγ的激动剂能够增强这种效果。但是PPARγ的过表达和激活后分化细胞内的脂滴明显小于用MDI+Indo诱导分化的细胞,提示PPARγ可能起始了脂肪细胞的分化但是脂质代谢还需要其它基因激活参与。另外过表达PPARγ使微丝蛋白β-actin的表达降低,但不影响β-tubulin的表达,提示PPARγ可能通过调节细胞骨架蛋白调节脂肪细胞的分化。
我们对于人骨髓间充质干细胞分化为脂肪细胞过程中的基本特征和参与调节脂肪分化的三个转录因子C/EBPβ、C/EBPα和PPARγ的作用进行了初步探讨,至于它们通过何种方式调节脂肪细胞的分化还需要进一步实验和研究。这对于阐明人脂肪细胞分化机制,指导肥胖以及其相关疾病的治疗具有积极的意义。
The increase of adipose tissue mass associated with obesity is due to both hypertrophy and hyperplasia of adipocytes. This hyperplasia results from the differentiation of in situ multipotent stem cells present in the vascular stroma of adipose tissue. The recruitment and then differentiation of mesenchymal stem cells in bone marrow to adipose tissue contributes in part to the hyperplasia. The adipocyte differentiation from mesenchyma stem cells is usually described as two phase. The first phase is the commitment of stem cells to preadipocyte, which cannot be distinguished morphologically from its precursor cell but has lost the potential to differentiate into other cell types. In the second phase known as terminal differentiation, the pre-adipocyte will obtain the characteristics of the mature adipocyte. The terminal differentiation has been extensively characterized using preadipocyte cell lines (for example, the mouse cell lines 3T3-L1,3T3-F442A). But what happens to the earlier stage cells-mesenchymal stem cells during adipocyte differentiation is rarely known, especially for the human derived mesenchymal stem cells. The objective of our research is to charaterize the adipocyte differentiation of human mesenchymal stem cells(hMSCs) from bone marrow, including the relationship between proliferation and differentiation and the role of three key transcription factors C/EBPβ, C/EBPα, and PPARγ.
In our study, we first isolated mesenchymal stem cells from human bone marrow with Ficoll density gradient centrifugation and in vitro adherent culture method. The cultured hMSC showed typical spindle-shape phenotype. hMSC proliferated slowly, contact inhibition was not obvious, since the dense cells grows into multilayers in the central of clones. More than 90% cells were at G1/G0 phase indicated by PI staining and flowcytometry. hMSC had a limited lifespan in culture, and serial subcultivation resulted in senescence and grandually die. The cells could be subcultured to passage 12.
In order to induce hMSCs to differentiate into adipocytes, PPARy agonist (indomethacin) was added to classic adipocyte differentiation protocol (DMEM containing 10%FBS,0.5mM isobutyl methylxanthine, 1μM dexamethasone and 10μg/ml insulin:MDI), and treated repeatedly. Most cells differentiated after repeated treatment for three times. The expression of adipose-specific gene aP2 by real-time PCR increased along hormone induction. Multiple treatments resulted in increasing numbers of adipocytes. Significant increase of human C/EBP beta expression was not observed during differentiation. C/EBP alpha and PPAR gamma increased upon induction, and decreased in the terminal stage.
To examine whether MCE occures during adipocytes differentiation of hMSCs. We compared the cell number of hMSCs pre- and after differentiation. The more cells differentiate into adipocyte, the less cells would be there eventually. BrdU incorporation upon induction and detected when fully differentiation showed that the differentated hMSC were BrdU negative, while differentiated 3T3-L1 were BrdU positive. Together, hMSC did not undergo mitosis clone expansion upon adipocyte differentiation in culture condition, which was different from 3T3-L1 model.
To define the role of the three transcription factors in hMSCs. We performed gain-or loss-of function experiments. C/EBPβknockdown in hMSCs with RNAi impared the adipogenic potential, while overexpression of C/EBP(3 stimulated cells to differentiate in response to indomethacin treatment. Overexpression of C/EBPa also potentiated the adipocyte differentiation along with PPARy angonist. Overexpression of PPARy alone was enough to initiate adipocytes differentiation of hMSCs, but not stimulate fully differentiated adipocytes.
引文
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