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

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.

The beneficiaries from the research include: Recipients of future stem cell therapies Members of the wider public, including schools, interested public groups and associations, and charities UK and EU Government Departments and Agencies, such as the Nanotechnologies Issues Dialogue Group (NIDG) responsible for formulating policy for engineered nanomaterials Manufacturers of MRI contrast agents and biocoatings UK Chemical and Chemical-using Industry and broader industry sectors MRI and clinical communities Academic chemists, physicists, materials scientists, clinical engineers and stem cell biologists The appointed researchers Our current inability to monitor stem cells following transplantation raises safety concerns about their use in humans, and is a barrier to progress. By engineering SPIONs that enable long-term tracking of stem cells, we will address these important safety issues, and thus make a positive impact on the nation's health by increasing the likelihood of translating stem cell therapies to the clinic. The knowledge from the project will impact public understanding of nanomaterials, helping to overcome current concerns about such advanced medical technologies, and also inform the NIDG that has responsibility for formulating UK Government policy for engineered nanomaterials, together with the EU and WHO. UK industry will benefit from the project outputs because the advances made in multifunctional particle coatings will be disseminated by the Knowledge Centre for Materials Chemistry to manufacturers of imaging agents and biocoatings, as well as to broader chemicals-using industry sectors. This is likely to enhance UK economic competitiveness in nanoscale technologies. The MRI and clinical communities, along with academic chemists, physicists, materials scientists, clinical engineers and stem cell biologists, will benefit from the developed technology to stabilise, target and image nanoparticles within cells. The knowledge base generated by the integrated synthesis/imaging/biology approach will be of high utility to broad sectors of the bionanotechnology community. The researchers appointed to the project will benefit from research training and the supportive training environment in chemistry, cell imaging and stem cell science, which emphasises interdisciplinary working communication. The following strategies will be implemented to ensure maximal impact of project outputs, monitored and driven by our impact coordinator PM: In year 3, we will organise a 'Nanomaterials for Stem Cell Science' conference, widely advertised to encourage attendance by materials scientists, stem cell researchers, clinicians, policy-makers, representatives from industry and members of the public. The conference will include public lectures to inform the lay community of current issues relating to nanotechnology and stem cell science. To maximise commercial exploitation, we will work with the Knowledge Centre for Materials Chemistry to ensure the widest possible dissemination of project outputs to industry users. ULive Enterprises Ltd, established by the University to commercialise intellectual property generated from research activities, will protect foreground IP from the project. Dissemination of knowledge to the relevant academic, MRI and clinical communities will be achieved by presentation at conferences and timely publication in high impact journals. Engagement with the clinical community will be lead by SK, and with the MRI community by SW. SK is the media spokesperson for the project to relate science advances to clinical application for the public. Researcher training in an interdisciplinary environment will be accomplished by assigning staff primary locations plus project hotdesks in partner labs to ensure ease of communication, and via our existing regular 'BioNano' cross-disciplinary seminars, which are attended by chemists, physicists, mathematicians, biologists and clinicians.