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.

我们知道干细胞是治疗许多退行性疾病的关键。然而，目前缺乏的是将干细胞用于再生治疗的技术。在体内，在它们的生态位中，成体干细胞受它们的环境——一种由蛋白质、糖和其他细胞组成的复杂混合物——的控制。这种环境控制允许干细胞生长与维持干细胞表型（细胞的可观察特征）。然而，当我们将干细胞从体内取出并在实验室中培养它们时，它们没有这些环境控制，因此很快就会失去干细胞的特性，这使得很难培养出大量临床有用的干细胞。在这个项目中，我们将改进一种材料，我们用它来以一种特定的方式排列蛋白质和细胞，以允许干细胞生长。首先，我们将研究骨髓间充质干细胞（MSCs）。骨髓间充质干细胞负责提供骨、软骨、韧带和肌腱细胞。我们将提高我们在实验室中培养这些细胞的能力，并将了解细胞如何调节自己，这样我们就可以识别药物和药物靶点，我们可以利用这些药物和靶点来促进大规模干细胞培养的生长。我们将进一步发展我们的技术，使我们的细胞在没有动物产品的情况下进行培养，从而使这些细胞在临床上适用于人类。然而，在这个项目中，我们不是研究MSC在骨骼再生中的应用，而是希望看看我们是否能更长时间地保持它们调节免疫系统的能力。骨髓间充质干细胞具有令人兴奋的潜力，几乎可以作为一种药物与移植一起使用，因为它们可以调节免疫反应，帮助防止移植排斥。输血服务机构正在研究这种可能性，我们将利用我们的方法与他们合作，扩大保留免疫调节能力的高质量间充质干细胞。此外，我们将使用我们的材料系统来研究造血干细胞（HSC -造血干细胞）的维持。在骨髓中，造血干细胞粘附在间充质干细胞上，这就保留了它们的干细胞特性。在实验室中，造血干细胞不会增殖并迅速失去其干细胞表型。造血干细胞很重要，因为它们是广泛使用的干细胞疗法的核心——骨髓移植仍然是对抗白血病等疾病的成功工具。在白血病中，造血干细胞的后代细胞继续制造血细胞（在体内携带氧气的红细胞和抵抗感染的白细胞）。因此，含有干细胞的骨髓可以从健康的供体转移到已经杀死了患病干细胞的接受者身上。捐献的干细胞有能力将无病细胞重新填充到接受者的血液中。这是一些干细胞再生能力的一个惊人例子。然而，也有一些主要的缺点。首先，这是一个供体对一个受体的治疗，将受体与组织匹配的供体相匹配的能力非常有限。虽然已经取得了一些进展，例如使用动员的外周血干细胞，但供应仍然远远不足，这严重限制了可以提供的治疗。虽然说我们相信我们的技术可以在实验室中用于培养造血干细胞是非常雄心勃勃的，但我们相信我们可以迈出第一步。我们的目标是利用间充质干细胞和我们的新材料来生物工程生态位环境。通过控制间充质干细胞的特性，我们将增加粘附在其上的HSC的数量。实现了这一点，我们将研究HSC表型维持并寻找HSC生长的诱人可能性。了解干细胞并释放其潜力是本世纪的主要挑战之一。该项目旨在增进了解并释放潜力。

项目成果

Customizable, engineered substrates for rapid screening of cellular cues.

可定制的工程基材，用于快速筛选细胞提示。

• 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

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

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

Designing stem cell niches for differentiation and self-renewal.

设计用于分化和自我更新的干细胞生态位。

• DOI: 10.1098/rsif.2018.0388
• 发表时间: 2018-08
• 期刊: Journal of the Royal Society, Interface
• 作者: Donnelly H;Salmeron-Sanchez M;Dalby MJ
• 通讯作者: Dalby MJ

Nacre Topography Produces Higher Crystallinity in Bone than Chemically Induced Osteogenesis

• DOI: 10.1021/acsnano.7b01044
• 发表时间: 2017-07-01
• 期刊: ACS NANO
• 影响因子: 17.1
• 作者: Alakpa, Enateri V.;Burgess, Karl E. V.;Cusack, Maggie
• 通讯作者: Cusack, Maggie