Nanoparticles and Nanotopography: A Nano-toolbox to Control Stem Cell Self-Renewal via miRNAs

纳米颗粒和纳米形貌：通过 miRNA 控制干细胞自我更新的纳米工具箱

• 批准号: BB/L008661/1
• 负责人: Catherine Berry
• 金额: $ 35.89万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL008661%2F1
• 关键词: Nanoparticles; Nanotopography; Nano; toolbox; Control

Mesenchymal stem cells (MSCs) are unspecialised cells that live in a localised area in the bone marrow called the 'niche'. MSCs are important as they can change (differentiate) into a variety of different cell types, including osteoblasts (bone cells), chondrocytes (cartilage cells) and adipocytes (fat cells), depending on when the body needs these cells. For several years now, researchers have been trying to identify methods of controlling how and when MSCs differentiate, so we can either keep them as they are (ie. as stem cells, for transplant studies etc) or make them become a certain tissue (eg. bone, for conditions such as osteoporosis). One well-known method available is to culture and grow the MSCs with special chemical additives that make them become a certain cell type. However this is not ideal, as you are using extra chemicals. We have established a way of growing MSCs and controlling their behaviour, simply by growing them on a particular pattern imprinted onto a material, with no chemicals. This means we can grow cultures of MSCs and either keep them self-renewing (as stem cells) or make them turn into osteoblasts to form bone. There are certain signals inside the MSC niche that control the MSC's fate. Recent studies have indicated that small sections of RNA, called microRNA (miRNA), are important in this control. In the first part of this project, we want to use our patterns to control MSC behaviour, and then look to see which miRNAs as involved in that control. Once we have identified these miRNAs, we will then see if we can do the reverse, ie. control MSC behaviour by blocking (or silencing) the particular miRNAs. We will do this by designing blockers of the miRNAs (called antagomirs), which we will deliver into the MSCs. They can be difficult to deliver, so we will guide them into cells by attaching the antagomirs onto small nanoparticles, which will function as taxis to ferry antagomirs into the MSCs. This will give us a nanoparticle tool, which can be ultimately used in clinic to induce bone formation.However, it must be noted that the MSC niche is located the bone marrow, which is a 3D tissue. Therefore, the final part of our project will look to see if we can also taxi the antagomirs into MSCs grown in 3D, and similarly control the fate of the cells therein. This will give a better idea of whether our technology would work in vivo.

间充质干细胞 (MSC) 是一种非特化细胞，生活在骨髓中称为“生态位”的局部区域。间充质干细胞很重要，因为它们可以转变（分化）成各种不同的细胞类型，包括成骨细胞（骨细胞）、软骨细胞（软骨细胞）和脂肪细胞（脂肪细胞），具体取决于身体何时需要这些细胞。几年来，研究人员一直在尝试找出控制间充质干细胞分化方式和时间的方法，这样我们既可以保持它们原样（即作为干细胞，用于移植研究等），也可以使它们成为某种组织（例如，骨骼，用于骨质疏松症等疾病）。一种众所周知的方法是用特殊的化学添加剂培养和生长间充质干细胞，使它们成为某种细胞类型。然而，这并不理想，因为您使用了额外的化学品。我们已经建立了一种培养间充质干细胞并控制其行为的方法，只需将它们按照印在材料上的特定图案进行培养即可，无需任何化学物质。这意味着我们可以培养间充质干细胞，让它们自我更新（作为干细胞），或者让它们变成成骨细胞形成骨骼。 MSC 生态位内存在某些控制 MSC 命运的信号。最近的研究表明，称为 microRNA (miRNA) 的一小段 RNA 在这种控制中非常重要。在这个项目的第一部分，我们希望使用我们的模式来控制 MSC 行为，然后看看哪些 miRNA 参与了该控制。一旦我们识别出这些 miRNA，我们就会看看是否可以做相反的事情，即。通过阻断（或沉默）特定的 miRNA 来控制 MSC 行为。我们将通过设计 miRNA 阻断剂（称为 antagomir）来实现这一目标，并将其传递到 MSC 中。它们可能很难递送，因此我们将通过将 antagomir 附着在小纳米颗粒上来引导它们进入细胞，这些纳米颗粒将充当出租车，将 antagomir 运送到 MSC 中。这将为我们提供一种纳米颗粒工具，最终可用于临床诱导骨形成。但是，必须指出的是，MSC生态位位于骨髓，这是一种3D组织。因此，我们项目的最后一部分将看看我们是否也可以将 antagomir 打入 3D 生长的 MSC 中，并类似地控制其中细胞的命运。这将使我们更好地了解我们的技术是否可以在体内发挥作用。

项目成果

Nanoparticle-antagomiR based targeting of miR-31 to induce osterix and osteocalcin expression in mesenchymal stem cells.

• DOI: 10.1371/journal.pone.0192562
• 发表时间: 2018
• 期刊: PloS one
• 影响因子: 3.7
• 作者: McCully M;Conde J;V Baptista P;Mullin M;Dalby MJ;Berry CC
• 通讯作者: Berry CC

A Quiescent, Regeneration-Responsive Tissue Engineered Mesenchymal Stem Cell Bone Marrow Niche Model via Magnetic Levitation.

通过磁悬浮的静态、再生响应性组织工程间充质干细胞骨髓生态位模型。

• DOI: 10.1021/acsnano.6b02841
• 发表时间: 2016
• 期刊: ACS nano
• 影响因子: 17.1
• 作者: Lewis EE

Significance of the balance between intracellular glutathione and polyethylene glycol for successful release of small interfering RNA from gold nanoparticles

• DOI: 10.1007/s12274-015-0828-5
• 发表时间: 2015-10-01
• 期刊: NANO RESEARCH
• 影响因子: 9.9
• 作者: McCully, Mark;Hernandez, Yulan;Berry, Catherine C.
• 通讯作者: Berry, Catherine C.

Magnetically levitated mesenchymal stem cell spheroids cultured with a collagen gel maintain phenotype and quiescence.

• DOI: 10.1177/2041731417704428
• 发表时间: 2017-01
• 期刊: Journal of tissue engineering
• 影响因子: 8.2
• 作者: Lewis NS;Lewis EE;Mullin M;Wheadon H;Dalby MJ;Berry CC
• 通讯作者: Berry CC

J_Casson_Supplementary_data - Supplemental material for Mesenchymal stem cell-derived extracellular vesicles may promote breast cancer cell dormancy

J_Casson_Supplementary_data - 间充质干细胞来源的细胞外囊泡的补充材料可能促进乳腺癌细胞休眠

• DOI: 10.25384/sage.7525211
• 发表时间: 2018
• 作者: Casson J