Materials exploitation of the biointerface to control MSC quality and niche phenotype

利用生物界面材料开发来控制 MSC 质量和生态位表型

• 批准号: BB/N018419/1
• 负责人: Matthew Dalby
• 金额: $ 59.24万
• 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: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN018419%2F1
• 关键词: Materials; exploitation; biointerface; control; MSC

We understand that stem cells hold the key to curing many degenerative conditions. Currently lacking, however, are the technologies that will open up use of stem cells for regenerative therapies. In the body, in their niches, adult stem cells are controlled by their environment - a complex mixture of proteins, sugars and other cells. This environmental control allows stem cell growth with maintenance of stem cell phenotype (the cells observable characteristics). However, when we take stem cells out of the body and grow them in the lab they don't have these environmental controls and so quickly loose stem cell characteristics, making it hard to grow large numbers of clinically useful stem cells.In this project we will refine a material that we use to arrange proteins and cells in a particular way to allow stem cell growth. First, we will investigate mesenchymal stem cells (MSCs) from bone marrow. MSCs are responsible for provision of bone, cartilage, ligament and tendon cells. We will improve on our ability to grow these cells in the lab and will understand how the cells regulate themselves so that we can identify drugs and drug targets that we can exploit to improve growth in larger-scale stem cell cultures. Further we will develop our technology to allow culture without animal products so that the cells are clinically relevant for use in humans. However, in this project, rather than investigating MSC use in skeletal regeneration, we wish to see if we can maintain their ability to modulate the immune system for longer. MSCs have exciting potential to be used almost as a drug along with transplants as they can modulate immune responses to help prevent transplant rejection. The blood transfusion service are investigating this possibility and we will work with them using our approaches to expand high quality MSCs with immune modulatory capacity retained. Further, we will use our materials systems to investigate haematopoietic stem cell (HSC - stem cells that make blood cells) maintenance. In the bone marrow, HSCs stick to MSCs and this preserves their stem cell characteristics. In the lab HSCs don't proliferate and rapidly loose their stem cell phenotype. HSCs are important as they are central to a widely used stem cell therapy - the bone marrow transplant that remains a successful tool in the fight against conditions such as leukaemia. In leukaemia, HSC progeny cells that go on to make blood cells (red blood cells that carry oxygen around the body and white blood cells that fight infections) become diseased. Thus, bone marrow, that contains stem cells, can be moved from a healthy donor to a recipient who has had their own, diseased, stem cells killed. The donated stem cells have the ability to repopulate the blood of the recipient with disease free cells. This is an amazing example of the ability of a few stem cells to repopulate and regenerate.There are, however, some major drawbacks. Firstly, this is a one donor to one recipient therapy and the ability to match recipients with tissue-matched donors is very limited. While there have been advances, such as use of mobilised peripheral blood stem cells, supply still falls far short of demand and this severely limits the therapy that can be offered.While it is very ambitious to say that we believe our technology can be used to grow HSCs in the lab, we believe we can take the first steps towards this. Our aim is to bioengineer niche environments using MSCs and our novel materials. By controlling the characteristics of the MSCs we will increase the number of HSC sticking to them. This achieved, we will investigate HSC phenotype maintenance and look for the tempting possibility of HSC growth.Understanding stem cells and unlocking their potential is one of the major challenges of this century. This project aims both to improve understanding and unlock potential.

我们了解，干细胞是治愈许多退化条件的关键。然而，目前缺乏的是将使用干细胞用于再生疗法的技术。在体内，在其壁ches中，成年干细胞受其环境控制 - 蛋白质，糖和其他细胞的复杂混合物。这种环境控制允许干细胞表型（可观察到的细胞特征）维持干细胞的生长。但是，当我们将干细胞从体内取出并在实验室中生长时，它们没有这些环境控制，并且很快就会松散干细胞特征，因此很难生长大量的临床有用的干细胞。在这个项目中，我们将完善我们用来以特定方式排列蛋白质和细胞的材料，以允许干细胞生长。首先，我们将研究骨髓中的间充质干细胞（MSC）。 MSC负责提供骨骼，软骨，韧带和肌腱细胞。我们将提高我们在实验室中生长这些细胞的能力，并了解细胞如何调节自身，以便我们可以鉴定出可以利用的药物和药物靶标，以改善大型干细胞培养物的生长。此外，我们将开发我们的技术，以允许没有动物产品的文化，以使细胞在临床上与人类使用相关。但是，在这个项目中，我们希望查看是否可以保持其更长更长的免疫系统调节免疫系统的能力，而不是研究MSC使用。 MSC具有令人兴奋的潜力，几乎可以用作药物以及移植物，因为它们可以调节免疫反应以帮助防止移植排斥。输血服务正在研究这种可能性，我们将使用我们的方法与他们合作，以扩大保留免疫调节能力的高质量MSC。此外，我们将使用我们的材料系统研究造血干细胞（HSC - 使血细胞的干细胞）维持。在骨髓中，HSC坚持使用MSC，这保留了其干细胞特征。在实验室中，HSC不会扩散并快速松散其干细胞表型。 HSC很重要，因为它们对于广泛使用的干细胞疗法至关重要 - 骨髓移植仍然是与白血病等疾病的成功工具。在白血病中，继续使血细胞（在人体周围携带氧气的红细胞和对抗感染的白细胞）的HSC后代细胞发病。因此，包含干细胞的骨髓可以从健康的供体转移到患有自己的，患病的干细胞杀死的接受者。捐赠的干细胞具有无疾病细胞的血液重新填充受体的血液。这是一些干细胞重新填充和再生能力的一个了不起的例子。但是，有一些主要缺点。首先，这是一个接受者疗法的一个捐助者，并且能够与组织匹配的供体匹配接受者的能力非常有限。尽管有进步，例如使用动员的外围血干细胞，但供应仍然远远远没有需求，这严重限制了可以提供的疗法。虽然我们相信我们的技术可以用来在实验室中发展HSC，但我们相信我们可以采取第一步。我们的目的是使用MSC和我们的新型材料生物工程生态裂环境。通过控制MSC的特征，我们将增加粘在其上的HSC的数量。实现这一目标，我们将研究HSC表型维持，并寻找HSC生长的诱人可能性。理解干细胞并解锁其潜力是本世纪的主要挑战之一。该项目旨在提高理解并解锁潜力。

项目成果

Hurdles to uptake of mesenchymal stem cells and their progenitors in therapeutic products.

• DOI: 10.1042/bcj20190382
• 发表时间: 2020-09-18
• 期刊: The Biochemical journal
• 作者: Childs PG;Reid S;Salmeron-Sanchez M;Dalby MJ
• 通讯作者: Dalby MJ

Overcoming BCR::ABL1 dependent and independent survival mechanisms in chronic myeloid leukaemia using a multi-kinase targeting approach.

• DOI: 10.1186/s12964-023-01363-2
• 发表时间: 2023-11-29
• 期刊: CELL COMMUNICATION AND SIGNALING
• 影响因子: 8.4
• 作者: Busch, Caroline;Mulholland, Theresa;Zagnoni, Michele;Dalby, Matthew;Berry, Catherine;Wheadon, Helen
• 通讯作者: Wheadon, Helen

Receptor control in mesenchymal stem cell engineering

• DOI: 10.1038/natrevmats.2017.91
• 发表时间: 2018-03-01
• 期刊: NATURE REVIEWS MATERIALS
• 影响因子: 83.5
• 作者: Dalby, Matthew J.;Garcia, Andres J.;Salmeron-Sanchez, Manuel
• 通讯作者: Salmeron-Sanchez, Manuel

Customizable, engineered substrates for rapid screening of cellular cues.

• DOI: 10.1088/1758-5090/ab5d3f
• 发表时间: 2020-02-07
• 期刊: Biofabrication
• 影响因子: 9
• 作者: Huethorst E;Cutiongco MF;Campbell FA;Saeed A;Love R;Reynolds PM;Dalby MJ;Gadegaard N
• 通讯作者: Gadegaard N

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