Dynamic surfaces to mimic mesenchymal stem cell niche functions

模拟间充质干细胞生态位功能的动态表面

• 批准号: BB/K006908/1
• 负责人: Matthew Dalby
• 金额: $ 41.61万
• 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: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FK006908%2F1
• 关键词: Dynamic; surfaces; mimic; mesenchymal; stem

We live in an ageing society and we are outliving the useful lives of our bodies. Structural components suffer with arthritis or osteoporosis and organs provide reduced efficiency and can become damaged or diseased through degenerative processes. We live at an exciting point in history where we all have the expectation that unlocking the potential of stem cells will help with these urgent regenerative demands. Embryonic stem cells remain locked in ethical debate, however, and also have clinical issues associated with their use (including lack of immune privilege, which can cause adverse immune reactions, and the possibility of teratoma formation, which is a type of cancer ). Adult stem cells provide an alternate route with mesenchymal stem cells from, for example, bone marrow (obtained by e.g. marrow donation) or fat tissue (obtained by e.g. liposuction) providing an attractive, autologous (i.e. from the patient) source of multipotent cells. A major hurdle with adult stem cells is their rapid and spontaneous differentiation during standard culture in the lab (i.e. out of the body they rapidly stop acting as stem cells). Current cell culture materials were developed before our understanding of stem cells had matured and were designed to grow mature cell types (such as fibroblasts) or cell lines (such as HeLa cells). Thus, we are currently lacking good platforms for autologous stem cell growth.In the last few years, researchers, including ourselves, have understood that MSC growth and differentiation is controlled by the way cells adhere to materials and consistent 'rules' are starting to emerge. Developments in materials science have put forwards surfaces that are either favourable for MSC growth or good for differentiation, however, but that cannot control both.In our bodies, stem cells reside in specialised locations (called 'niches') that control their growth to allow a supply of stem cells to be present in tissues throughout our lives and also regulate differentiation in response to tissue demand. It is, again, considered that cell adhesion is key to the niche regulation of stem cells.Here, we will develop highly novel materials that initially support the growth (multiplication) of multipotent MSCs, which can then be switched under user control to turn on the desired type of differentiation, to generate the mature 'functional' cells of the body. To do this, we will use enzymes (biological catalysts) to cleave the self-renewal surface (this will be made by use of adhesion controlling chemistry and use of nanoscale spatial information i.e. small chemical patterns) and reveal the underlying differentiation surface (different chemistries to control differential adhesion, and hence drive stem cell fate). Such enzymes can be simply added by the user to the cell media (their food). We will then go further and place the switch under cell control. As cells become dense in a culture (near confluence) their protein (and hence enzyme) profile changes and we will exploit this to find enzymes that can perform the switch from a growth-promoting substrate to a differentiation-inducing substrate, only after the cells have grown to large numbers.This technology will act as a platform for MSC growth and differentiation. It will be dynamic, as their natural niche is dynamic, and it will be an important step in the development of production of autologous cells with therapeutic potential.

我们生活在一个老龄化的社会，我们的身体正在失去有用的生命。结构部件患有关节炎或骨质疏松症，器官提供降低的效率，并可能通过退行性过程受损或患病。我们生活在一个激动人心的历史时刻，我们都期望释放干细胞的潜力将有助于满足这些紧迫的再生需求。然而，胚胎干细胞仍处于伦理争论中，并且也存在与其使用相关的临床问题（包括缺乏免疫特权，这可能导致不良免疫反应，以及畸胎瘤形成的可能性，这是一种癌症）。成体干细胞提供了一种替代途径，其中来自例如骨髓（通过例如骨髓捐赠获得）或脂肪组织（通过例如吸脂获得）的间充质干细胞提供了多能细胞的有吸引力的自体（即来自患者）来源。成体干细胞的一个主要障碍是它们在实验室标准培养过程中的快速和自发分化（即在体外它们迅速停止作为干细胞）。目前的细胞培养材料是在我们对干细胞的理解成熟之前开发的，并且被设计用于生长成熟的细胞类型（如成纤维细胞）或细胞系（如HeLa细胞）。因此，我们目前缺乏良好的自体干细胞生长平台。在过去的几年里，研究人员，包括我们自己，已经了解到MSC的生长和分化是由细胞粘附材料的方式控制的，并且一致的“规则”开始出现。材料科学的发展已经提出了有利于MSC生长或有利于分化的表面，但是，这两者都不能控制。在我们的身体中，干细胞驻留在专门的位置（称为“壁龛”），控制它们的生长，使干细胞的供应能够在我们的整个生命中存在于组织中，并根据组织的需求调节分化。细胞粘附被认为是干细胞生态位调节的关键。在这里，我们将开发高度新颖的材料，最初支持多能MSC的生长（增殖），然后可以在用户控制下切换到所需的分化类型，以产生身体的成熟“功能”细胞。为此，我们将使用酶（生物催化剂）来切割自我更新表面（这将通过使用粘附控制化学和使用纳米级空间信息（即小化学图案）来实现），并揭示潜在的分化表面（不同的化学物质来控制差异粘附，从而驱动干细胞命运）。这样的酶可以由用户简单地添加到细胞培养基（他们的食物）中。然后我们将进一步将开关置于单元控制之下。随着细胞在培养物中变得密集（接近融合），它们的蛋白质（因此酶）谱发生变化，我们将利用这一点来寻找只有在细胞大量生长后才能从促生长底物转换为诱导分化底物的酶。这项技术将作为MSC生长和分化的平台。这将是动态的，因为它们的自然生态位是动态的，这将是开发具有治疗潜力的自体细胞生产的重要一步。

项目成果

Tunable Supramolecular Hydrogels for Selection of Lineage-Guiding Metabolites in Stem Cell Cultures

• DOI: 10.1016/j.chempr.2016.07.001
• 发表时间: 2016-08-11
• 期刊: CHEM
• 影响因子: 23.5
• 作者: Alakpa, Enateri V.;Jayawarna, Vineetha;Dalby, Matthew J.
• 通讯作者: Dalby, Matthew J.

Mesenchymal Stem Cell Fate: Applying Biomaterials for Control of Stem Cell Behavior.

• DOI: 10.3389/fbioe.2016.00038
• 发表时间: 2016
• 期刊: Frontiers in bioengineering and biotechnology
• 影响因子: 5.7
• 作者: Anderson HJ;Sahoo JK;Ulijn RV;Dalby MJ
• 通讯作者: Dalby MJ

Scanning electron microscopical observation of an osteoblast/osteoclast co-culture on micropatterned orthopaedic ceramics.

• DOI: 10.1177/2041731414552114
• 发表时间: 2014
• 期刊: Journal of tissue engineering
• 影响因子: 8.2
• 作者: Halai M;Ker A;Meek RD;Nadeem D;Sjostrom T;Su B;McNamara LE;Dalby MJ;Young PS
• 通讯作者: Young PS

Reference Module in Materials Science and Materials Engineering. Elsevier.

材料科学和材料工程参考模块。

• 发表时间: 2017
• 作者: Anderson H

Cell-controlled dynamic surfaces for skeletal stem cell growth and differentiation.

• DOI: 10.1038/s41598-022-12057-z
• 发表时间: 2022-05-17
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Anderson, Hilary J.;Sahoo, Jugal Kishore;Wells, Julia;van Nuffel, Sebastiaan;Dhowre, Hala S.;Oreffo, Richard O. C.;Zelzer, Mischa;Ulijn, Rein V.;Dalby, Matthew J.
• 通讯作者: Dalby, Matthew J.