Ultrastable targeted multifunctional hybrid nanomaterials for long-term stem cell tracking

用于长期干细胞追踪的超稳定靶向多功能混合纳米材料

• 批准号: EP/H046143/1
• 负责人: Matthew Rosseinsky
• 金额: $ 197.21万
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FH046143%2F1
• 关键词: Ultrastable; targeted; multifunctional; hybrid; nanomaterials

Stem cell science is beginning to realise its potential, with many patients now benefiting from novel stem cell therapies, usually involving transplantation of the patient's own bone marrow-derived stem cells. However, to make further progress in stem cell medicine so that more patients can benefit from these pioneering therapies, technological developments are required so that the behaviour of the stem cells can be closely monitored following transplantation. Stem cell monitoring is crucial, because, if the cells migrate to other organs and tissues besides the target organ, they could cause serious health problems for the patient. Apart from these important safety issues, stem cell monitoring is also necessary to help us understand how the cells mediate their positive effects. In this project, we aim to develop the technology to monitor stem cells using a non-invasive method called magnetic resonance imaging (MRI) that will not cause harm to the patient. The technology we propose is based on tracking superparamagnetic iron oxide nanoparticles, or 'SPIONs'. The main advantage of SPIONs is that, because of their nanoscale dimensions, they can be easily introduced into cells without detrimental side effects. Furthermore, because iron is a natural substance in the human body and indeed an important nutrient, as it is an essential component of the oxygen-carryng molecule, haemoglobin, it is unlikely to cause any harm to patients and iron oxides have previously been established to be biocompatible.A major obstacle that currently prevents the use of SPIONs for stem cell tracking is that in most cases they are not retained by the stem cells for more than a few weeks. Therapeutic or adverse effects of the stem cells would potentially manifest well beyond two weeks and, therefore, there is a strong need for a step change technology enabling cell tracking for much longer periods following transplantation. One of the reasons why cellular retention of SPIONs is so poor is that upon entry into the cells, the SPIONs become localised in a cellular compartment called the endosome, which due to its acid environment, causes the SPIONs to degrade. A further reason is that the cells use a process called 'retro-endocytosis' to actively remove the contents of endosomes back into the extracellular space. This project addresses the challenge in an interdisciplinary collaboration between physical scientists and stem cell biologists. We will design and chemically synthesise novel coatings for the SPIONs that will protect them from degradation and prevent them from being retro-endocytosed. To identify the most effective coatings, we will use a new imaging technology developed by our group that allows us to monitor the retention time of the SPIONs within single cells in a culture dish. In the final stages of the project we will select the most promising SPIONs to label mouse bone marrow-derived stem cells, which are known to promote recovery from kidney damage. These labelled stem cells will then be transplanted into mice that have damaged kidneys, and we will use MRI to monitor the behaviour of the stem cells over a prolonged time course.We predict that the novel SPIONs generated during the course of this project will make a significant impact on our ability to track stem cells in the long-term (several months) following transplantation. Although bone marrow-derived stem cells are the focus of the current project, we anticipate that the novel SPIONs will be of use to the wider stem cell community, due to their adaptability for labelling other clinically relevant stem cell types, such as embryonic stem cells, which are expected to enter clinical trials in the UK next year for the treatment of age-related macular degeneration. Furthermore, the SPIONs could be used to label various stem cells types that have potential for the treatment of conditions such as Parkinson's Disease, Diabetes and Heart Disease.

干细胞科学开始认识到其潜力，许多患者现在受益于新型干细胞疗法，通常涉及患者自身骨髓干细胞的移植。然而，为了在干细胞医学方面取得进一步进展，使更多患者能够从这些开创性疗法中受益，需要技术发展，以便能够在移植后密切监测干细胞的行为。干细胞监测至关重要，因为如果细胞迁移到目标器官以外的其他器官和组织，可能会给患者带来严重的健康问题。除了这些重要的安全问题之外，干细胞监测也有必要帮助我们了解细胞如何介导其积极作用。在这个项目中，我们的目标是开发一种技术，使用一种称为磁共振成像（MRI）的非侵入性方法来监测干细胞，这种方法不会对患者造成伤害。我们提出的技术基于跟踪超顺磁性氧化铁纳米粒子，或“SPION”。 SPION 的主要优点是，由于其纳米级尺寸，它们可以很容易地引入细胞中，而不会产生有害的副作用。此外，由于铁是人体内的天然物质，而且确实是一种重要的营养物质，因为它是携氧分子血红蛋白的重要组成部分，因此不太可能对患者造成任何伤害，而且氧化铁此前已被证实具有生物相容性。目前阻止使用 SPION 进行干细胞追踪的一个主要障碍是，在大多数情况下，它们不会被干细胞保留超过几周。干细胞的治疗或副作用可能会在两周后显现出来，因此，迫切需要一种阶跃改变技术，能够在移植后更长时间地进行细胞跟踪。 SPION 的细胞保留如此差的原因之一是，在进入细胞后，SPION 定位在称为内体的细胞区室中，由于其酸性环境，导致 SPION 降解。另一个原因是细胞使用一种称为“逆转录内吞作用”的过程来主动将内体的内容物移回细胞外空间。该项目解决了物理科学家和干细胞生物学家之间跨学科合作的挑战。我们将为 SPION 设计和化学合成新型涂层，以保护它们不被降解并防止它们被逆内吞。为了确定最有效的涂层，我们将使用我们小组开发的新成像技术，该技术使我们能够监测培养皿中单个细胞内 SPION 的保留时间。在该项目的最后阶段，我们将选择最有前途的 SPION 来标记小鼠骨髓干细胞，众所周知，这些干细胞可以促进肾脏损伤的恢复。然后，这些标记的干细胞将被移植到肾脏受损的小鼠体内，我们将使用 MRI 来长期监测干细胞的行为。我们预测，在该项目过程中产生的新型 SPION 将对我们在移植后长期（几个月）追踪干细胞的能力产生重大影响。尽管骨髓干细胞是当前项目的重点，但我们预计新型 SPION 将用于更广泛的干细胞群体，因为它们能够标记其他临床相关干细胞类型，例如胚胎干细胞，预计明年将在英国进入临床试验，用于治疗年龄相关性黄斑变性。此外，SPION 可用于标记具有治疗帕金森病、糖尿病和心脏病等疾病潜力的各种干细胞类型。

项目成果

Multimodal stem cell imaging and tracking

多模式干细胞成像和追踪

• 发表时间: 2017
• 期刊: ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY
• 作者: Ashraf Sumaira

Poly[2-(methacryloyloxy)ethylphosphorylcholine]-coated iron oxide nanoparticles: synthesis, colloidal stability and evaluation for stem cell labelling

• DOI: 10.1039/c2cc34420c
• 发表时间: 2012-01-01
• 期刊: CHEMICAL COMMUNICATIONS
• 影响因子: 4.9
• 作者: Peacock, Anita K.;Cauet, Solene I.;Rosseinsky, Matthew J.
• 通讯作者: Rosseinsky, Matthew J.

SPIONs for cell labelling and tracking using MRI: magnetite or maghemite?

• DOI: 10.1039/c7bm00515f
• 发表时间: 2017-12-19
• 期刊: Biomaterials science
• 影响因子: 6.6
• 作者: Barrow M;Taylor A;Fuentes-Caparrós AM;Sharkey J;Daniels LM;Mandal P;Park BK;Murray P;Rosseinsky MJ;Adams DJ
• 通讯作者: Adams DJ

MS-1 magA: Revisiting Its Efficacy as a Reporter Gene for MRI.

• DOI: 10.1177/1536012116641533
• 发表时间: 2016
• 期刊: Molecular imaging
• 影响因子: 2.8
• 作者: Pereira SM;Williams SR;Murray P;Taylor A
• 通讯作者: Taylor A

Nanoparticles for imaging, sensing, and therapeutic intervention.

• DOI: 10.1021/nn500962q
• 发表时间: 2014-04-22
• 期刊: ACS NANO
• 影响因子: 17.1
• 作者: Bogart, Lara K.;Pourroy, Genevieve;Murphy, Catherine J.;Puntes, Victor;Pellegrino, Teresa;Rosenblum, Daniel;Peer, Dan;Levy, Raphael
• 通讯作者: Levy, Raphael