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中，我们已经超越了身体的用处。结构性成分患有关节炎或骨质疏松症，并且器官可提供降低的效率，并通过退行过程损害或患病。我们生活在历史上令人兴奋的时刻，我们都期望释放干细胞的潜力将有助于满足这些紧急再生需求。然而，胚胎干细胞仍然陷入伦理辩论中，并且还存在与其使用相关的临床问题（包括缺乏免疫特权，可能导致不良免疫反应，以及形成畸胎瘤的可能性，这是一种癌症）。成年干细胞提供了与骨髓（例如骨髓捐赠获得的）或脂肪组织（例如通过吸脂术获得的），可提供有吸引力的自体（即来自患者的）多元细胞来源的脂肪组织（例如，从患者获得）。成人干细胞的主要障碍是在实验室中标准培养过程中它们的快速和自发分化（即，它们从体内迅速停止充当干细胞）。当我们对干细胞成熟并设计成成熟的细胞类型（例如成纤维细胞）或细胞系（例如HELA细胞）之前，开发了当前的细胞培养物质。因此，我们目前缺乏用于自体干细胞生长的良好平台。在过去的几年中，包括我们自己在内的研究人员已经了解到，MSC的生长和差异化受细胞粘附材料和一致的“规则”的方式控制。材料科学的发展提出了有利于MSC增长或有益于分化的表面，但是不能控制两者。在我们的体内，干细胞位于专门的位置（称为“壁niches”）中，以控制其生长以允许干细胞供应在整个生命中存在于组织中，并且还调节对组织需求的响应。同样，再次认为细胞粘附是干细胞的小裂调节的关键。在这里，我们将开发高新颖的材料，这些材料最初支持多能MSC的生长（乘法），然后可以在用户控制下切换以打开所需的分化类型，以生成身体的“功能”细胞。为此，我们将使用酶（生物催化剂）裂解自我更新表面（这将通过使用控制化学的粘附和使用纳米级空间信息（即小型化学模式）并揭示潜在的分化表面（不同的化学表面（不同的化学表面来控制差异粘附，从而驱动茎细胞效果）。用户可以简单地将这种酶添加到细胞介质（其食物）中。然后，我们将走得更远，将开关放在单元控制下。随着细胞在培养物中变得稠密（汇合）的蛋白质（及其酶的谱）变化，我们将利用这一点，以找到可以从促进生长的底物转变为诱导的诱导底物的酶，只有在细胞发展到大数量之后，这些技术才能成为MSC生长和分化的平台。这将是动态的，因为它们的天然生态位是动态的，这将是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.

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

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

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

Improving cartilage phenotype from differentiated pericytes in tunable peptide hydrogels.

• DOI: 10.1038/s41598-017-07255-z
• 发表时间: 2017-07-31
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Alakpa EV;Jayawarna V;Burgess KEV;West CC;Péault B;Ulijn RV;Dalby MJ
• 通讯作者: Dalby MJ