微图案化表面的制备以及细胞间接触影响干细胞分化的研究
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摘要
调控细胞行为、尤其细胞黏附和干细胞分化是再生医学领域的一个研究重点,涉及到细胞生物学、医学、材料学等学科知识。迄今已有许多研究考察了生物材料模拟细胞外基质的物理、化学等特性去控制细胞的黏附,进而调控细胞的生命活动。但对细胞与细胞之间接触如何影响干细胞分化的研究则相对很少,已有研究的结论也有待确证,且不能定量给出接触程度与分化程度之间的关系。这并非因为细胞间接触对细胞生命活动不重要,在很大程度上是由于缺乏必要的研究技术手段,很难排除细胞密度变化导致的细胞自身分泌的因子浓度变化等因素的干扰。
传统的细胞研究方式,比如在培养板上研究细胞,难以克服细胞迁移等问题,新发展起来的微图案技术则可以实现细胞定位,有助于研究细胞间接触等影响细胞生命活动的相关问题。本论文尝试了多种微图案制备方法,最终从中寻找到了一种能长时间阻止细胞迁移的微图案。我们以此首次定量考察了细胞接触程度对于干细胞定向分化的影响。我们的这些实验技术和方法,以及细胞研究结论不仅丰富了细胞学知识,也为细胞学研究提供了新的手段和途径；对再生医学领域里面诸如组织修复材料的设计、干细胞调控等提供了一些基本的实验和理论知识。
本论文的主要创新性研究包括以下几方面：
1.尝试了多种微图案制备方法,包括在PLGA膜上制备微拓扑形貌、PEG接枝表面制备有细胞黏附反差的化学微图案、PEG水凝胶形成的微凹坑图案、PEG水凝胶表面的化学微图案等。每种方法都反复摸索了详细的制备条件,根据细胞定位实验,从中确定了PEG水凝胶表面的化学微图案能够长时间控制细胞黏附位置,特别是阻止了细胞的迁移等运动,为后续的干细胞研究奠定了基础。其它几种方法制备的微图案,尽管不能长时间限制细胞的黏附位置,但也有各自的特点,适合于相应的细胞研究,例如微拓扑形貌可以调节细胞铺展；PEG接枝的表面可以考察短时间内的细胞形态、黏附、迁移等问题。
2.建立了利用光学显微镜照片分析细胞内碱性磷酸酶活性的半定量分析方法。骨髓基质干细胞被定位在微图案上后成骨分化,但在同一微图案上面存在不同的细胞接触状况,比如有的细胞处于孤立状态；有的接触了一个细胞；有的接触了两个,乃至多个不等的细胞,它们的成骨分化程度存在差异,却又难以用直接测吸光度的方法来判别。比照分光光度法,我们通过染色、拍照,测量细胞灰度值,并根据吸光值计算公式,定量分析了不同细胞接触情况下的干细胞成骨分化水平。虽然我们是针对骨髓基质干细胞的成骨分化所建立的分析方法,但这个方法同样适用于其它的,能够通过染色来定性、定量分析的研究中。
3.利用之前确定的微图案制备技术以及建立的半定量分析方法,我们考察了细胞接触对大鼠骨髓基质干细胞成骨分化和成脂分化的影响。我们在同一基底材料表面利用不同黏附圆岛导致不同细胞接触程度的技术排除了细胞密度变化导致因子浓度不同等因素的干扰。我们的结论确证了细胞接触能够促进干细胞定向分化,并首次发现这种促进作用与细胞接触程度成正比。我们还发现缝隙连接是相关细胞接触的重要因素,但并非唯一因素。
The relationship between cell communication and differentiation is a fundamental. problem of Cell Biology, which is closely related to Biomaterials and Regenerative Medicine. As cell studies are concerned, while differentiation of stem cells has been paid much attention to during the latest decade, relatively little is focused upon the relationship between cell differentiation and communication. Straightforward cell-cell contact is the most popular way of cell-cell interaction. It is, however, very hard to rule out the effects of soluble factors due to paracrine of cells and the effects of different concentrations of nutrients during cell culture, if one just examines differentiation of stem cells under a series of seeding concentration. An unambiguous research approach is thus desired.
Among several types of techniques for fabricating micropatterns on different substrates, we eventually determined a micropattern which can localized cells for a long time. Based upon the micropatterning technique, the effect of cell-cell contact on lineage differentiation of rat bone marrow stem cells (rMSC) was revealed semi-quantitatively. Our methodology and results not only augment fundamental knowledge of Cell Biology, but also offer innovative means and instruments for cell research as well as for regenerative medicine.
The main innovative results are listed as follows:
1. To find a technique to prepare micropattern of adhesive contrast with a background resistant to cell adhesion for a long time. Considering that differentiation of stem cells must proceed for at least several days, an excellent adhesion-resistant background is necessary. We developed several methods to prepare micropatterns, including topographic PLGA film, a self-assembly monolayer (SAM) of poly(ethylene glycol) (PEG) molecules on glass surface, micropits formed with PEG hydrogel, micropattern on PEG hydrogel surface. Eventually, a micropattern prepared on PEG hydrogel surface was found to meet the requirement, which made examination of differentiation of localized stem cells available.
2. To establish a semi-quantitative analysis method to evaluate the osteogenesis level of stem cells. By using grey values on different adhesion microislands on micrographs, we established a semi-quantitative analysis of the activity of the expressed alkaline phosphatase (ALP). This method is likely to be applied in other semi-quantitative analysis of optical micrographs of stained samples.
3. To put forward a unique methodology to examine the effects of cell-cell contact between stem cells per se on their lineage differentiation while ruling out the interference of soluble factors or cell seeding concentration etc. MSCs from neonatal Sprague Dawley (SD) rats are employed as demonstration. During osteogenesis, the cells are well localized on the micropatterns which prevent or ensure cell-cell contact persistently. Both osteogenic and adipogenic differentiations were found to be regulated by cell-cell contact, isolated cells exhibited less significant differentiation than paired or aggregated cells. For those stem cells in contact, extent of differentiation was fairly linearly related to extent of contact characterized by coordination number. Additionally, we revealed the existence of some unknown cues besides gap junction responsible for such effects of cell-cell contact. While cell studies based upon patterned surface have been reported in many literatures, this is, to the best of our knowledge, the first time to semi-quantitatively investigate the relationship between extent of differentiation of stem cells and extent of cell-cell contact.
传统的细胞研究方式,比如在培养板上研究细胞,难以克服细胞迁移等问题,新发展起来的微图案技术则可以实现细胞定位,有助于研究细胞间接触等影响细胞生命活动的相关问题。本论文尝试了多种微图案制备方法,最终从中寻找到了一种能长时间阻止细胞迁移的微图案。我们以此首次定量考察了细胞接触程度对于干细胞定向分化的影响。我们的这些实验技术和方法,以及细胞研究结论不仅丰富了细胞学知识,也为细胞学研究提供了新的手段和途径；对再生医学领域里面诸如组织修复材料的设计、干细胞调控等提供了一些基本的实验和理论知识。
本论文的主要创新性研究包括以下几方面：
1.尝试了多种微图案制备方法,包括在PLGA膜上制备微拓扑形貌、PEG接枝表面制备有细胞黏附反差的化学微图案、PEG水凝胶形成的微凹坑图案、PEG水凝胶表面的化学微图案等。每种方法都反复摸索了详细的制备条件,根据细胞定位实验,从中确定了PEG水凝胶表面的化学微图案能够长时间控制细胞黏附位置,特别是阻止了细胞的迁移等运动,为后续的干细胞研究奠定了基础。其它几种方法制备的微图案,尽管不能长时间限制细胞的黏附位置,但也有各自的特点,适合于相应的细胞研究,例如微拓扑形貌可以调节细胞铺展；PEG接枝的表面可以考察短时间内的细胞形态、黏附、迁移等问题。
2.建立了利用光学显微镜照片分析细胞内碱性磷酸酶活性的半定量分析方法。骨髓基质干细胞被定位在微图案上后成骨分化,但在同一微图案上面存在不同的细胞接触状况,比如有的细胞处于孤立状态；有的接触了一个细胞；有的接触了两个,乃至多个不等的细胞,它们的成骨分化程度存在差异,却又难以用直接测吸光度的方法来判别。比照分光光度法,我们通过染色、拍照,测量细胞灰度值,并根据吸光值计算公式,定量分析了不同细胞接触情况下的干细胞成骨分化水平。虽然我们是针对骨髓基质干细胞的成骨分化所建立的分析方法,但这个方法同样适用于其它的,能够通过染色来定性、定量分析的研究中。
3.利用之前确定的微图案制备技术以及建立的半定量分析方法,我们考察了细胞接触对大鼠骨髓基质干细胞成骨分化和成脂分化的影响。我们在同一基底材料表面利用不同黏附圆岛导致不同细胞接触程度的技术排除了细胞密度变化导致因子浓度不同等因素的干扰。我们的结论确证了细胞接触能够促进干细胞定向分化,并首次发现这种促进作用与细胞接触程度成正比。我们还发现缝隙连接是相关细胞接触的重要因素,但并非唯一因素。
The relationship between cell communication and differentiation is a fundamental. problem of Cell Biology, which is closely related to Biomaterials and Regenerative Medicine. As cell studies are concerned, while differentiation of stem cells has been paid much attention to during the latest decade, relatively little is focused upon the relationship between cell differentiation and communication. Straightforward cell-cell contact is the most popular way of cell-cell interaction. It is, however, very hard to rule out the effects of soluble factors due to paracrine of cells and the effects of different concentrations of nutrients during cell culture, if one just examines differentiation of stem cells under a series of seeding concentration. An unambiguous research approach is thus desired.
Among several types of techniques for fabricating micropatterns on different substrates, we eventually determined a micropattern which can localized cells for a long time. Based upon the micropatterning technique, the effect of cell-cell contact on lineage differentiation of rat bone marrow stem cells (rMSC) was revealed semi-quantitatively. Our methodology and results not only augment fundamental knowledge of Cell Biology, but also offer innovative means and instruments for cell research as well as for regenerative medicine.
The main innovative results are listed as follows:
1. To find a technique to prepare micropattern of adhesive contrast with a background resistant to cell adhesion for a long time. Considering that differentiation of stem cells must proceed for at least several days, an excellent adhesion-resistant background is necessary. We developed several methods to prepare micropatterns, including topographic PLGA film, a self-assembly monolayer (SAM) of poly(ethylene glycol) (PEG) molecules on glass surface, micropits formed with PEG hydrogel, micropattern on PEG hydrogel surface. Eventually, a micropattern prepared on PEG hydrogel surface was found to meet the requirement, which made examination of differentiation of localized stem cells available.
2. To establish a semi-quantitative analysis method to evaluate the osteogenesis level of stem cells. By using grey values on different adhesion microislands on micrographs, we established a semi-quantitative analysis of the activity of the expressed alkaline phosphatase (ALP). This method is likely to be applied in other semi-quantitative analysis of optical micrographs of stained samples.
3. To put forward a unique methodology to examine the effects of cell-cell contact between stem cells per se on their lineage differentiation while ruling out the interference of soluble factors or cell seeding concentration etc. MSCs from neonatal Sprague Dawley (SD) rats are employed as demonstration. During osteogenesis, the cells are well localized on the micropatterns which prevent or ensure cell-cell contact persistently. Both osteogenic and adipogenic differentiations were found to be regulated by cell-cell contact, isolated cells exhibited less significant differentiation than paired or aggregated cells. For those stem cells in contact, extent of differentiation was fairly linearly related to extent of contact characterized by coordination number. Additionally, we revealed the existence of some unknown cues besides gap junction responsible for such effects of cell-cell contact. While cell studies based upon patterned surface have been reported in many literatures, this is, to the best of our knowledge, the first time to semi-quantitatively investigate the relationship between extent of differentiation of stem cells and extent of cell-cell contact.
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