Engineering the bone marrow niche to control stem cell regulation, metastatic evolution and cancer dormancy

骨髓是健康和疾病的场所。在健康状况下，它产生我们赖以携带氧气和保护我们免受感染的所有血细胞。然而，产生血液并驻留在骨髓中的干细胞，即造血干细胞（HSC），会老化并可能陷入疾病状态，如发展中的白血病。吸烟和治疗身体其他部位的癌症（化疗/放疗的毒性作用）等因素可能会加速衰老，从而导致疾病的转变。此外，它形成了其他癌细胞的家园，这些癌细胞离开原始肿瘤并移动或转移到骨髓。一旦进入骨髓，它们就会休眠，躲避化疗，并在稍后的某个时候激活，形成毁灭性的骨癌。将癌细胞从休眠状态唤醒的线索在很大程度上是未知的。如果可以开发出含有人类细胞的骨髓模型，并且可以模拟实验室中利基的关键方面，如血液再生，癌症演变和休眠，这将对寻找更好的癌症治疗方法有很大帮助。我们正在开发应对这一挑战所需的材料和技术。在这项研究计划中，我们将解决三个生物医学挑战：1）HSC再生。骨髓移植（更准确地说是造血干细胞移植）是一种单供体、单受体疗法，可以治愈白血病等血液疾病。它是有限的，因为HSC不能在体外得到很好的照顾。在实验室中妥善照顾这些珍贵细胞的方法可以使这种关键疗法成为一种单供体，多受体治疗。此外，在实验室中照顾细胞的能力将打开基因修饰细胞的潜力，使我们能够治愈细胞并将其放回患者体内，从而失去对患者免疫抑制的需要。随着年龄的增长，我们的细胞会在DNA中收集突变，这些突变可能是癌症的驱动因素。生活方式的选择，如吸烟，以及其他疾病治疗的副作用也会增加细胞的突变。随着血癌的发展，骨髓改变其结构以保护这些患病的HSC。我们的3D环境将使我们能够更好地了解这种骨髓重塑过程，以及药物如何在这种更具保护性的环境中靶向癌症。这些模型还将使我们能够研究基因编辑的HSC的潜在毒性，以确保它们不会产生不必要的副作用或本身不会癌变。什么触发休眠和激活休眠知之甚少。通过将我们的3D环境置于一个可扩展的格式中，我们可以连接包括感染和免疫反应在内的其他模型，我们可以开始了解参与激活休眠癌细胞的因素。我们的愿景是由材料和工程驱动的，因为骨髓生态位富含结构和信号生物材料（蛋白质）。因此，我们将建立三个工程挑战：（1）细胞可以通过材料的刚度和粘性（粘弹性）来控制。因此，我们将开发合成生物混合材料，可以制造具有可再生的物理特性，并具有生物功能。(2)我们将开发这些材料与生长因子和生物活性代谢物相互作用，这两者都是细胞行为的强大控制器。这些材料将用于以芯片实验室（芯片）形式组装HSC微环境，以进行高含量药物和毒性筛选。(3)我们将开发实时系统来检测细胞行为的变化，例如使用拉曼和布里渊显微镜从健康到癌症的转变。我们将提供比动物模型更好的替代品。

The bone marrow is a site of health and disease. In health, it produces all of the blood cells that we rely on to carry oxygen and protect us from infection. However, the stem cells that produce the blood and that reside in the marrow, the haematopoietic stem cells (HSCs), age and can tip over into disease states, such as developing leukaemia. Factors such as smoking and treatment of cancers elsewhere in the body (toxic effects of chemotherapy/radiotherapy) can accelerate ageing, and therefore, drive the transition to disease. Further, it forms a home to other cancer cells, that leave their original tumour and move, or metastasise, to the bone marrow. Once in the marrow, they can become dormant, hiding from chemotherapies and activating sometime later to form devastating bone cancers. The cues that wake cancer cells from dormancy are largely unknown.If models of the bone marrow that contain human cells and that can mimic key facets of the niche in the lab, such as blood regeneration, cancer evolution and dormancy, can be developed it would be a big help in the search for better cancer therapies. We are developing the materials and technologies required to meet this challenge. In this programme of research, we will tackle three biomedical challenges:1) HSC regeneration. Bone marrow transplantation (more correctly HSC transplantation) is a one-donor, one-recipient therapy that can be curative for blood diseases such as leukaemia. It is limited as HSCs cannot be looked after well out of the body. Approaches to properly look after these precious cells in the lab could allow this key therapy to become a one-donor, multiple recipient treatment. Further, the ability to look after the cells in the lab would open up the potential for genetically modifying the cells to allow us to cure the cells and put them back into the patient, losing the need for patient immunosuppression.2) Cancer evolution. As we get older, our cells collect mutations in their DNA and these mutations can be drivers of cancer. Lifestyle choices such as smoking, and side effects of treatments of other diseases can also add mutations to the cells. As blood cancers develop, the bone marrow changes its architecture to protect these diseased HSCs. Our 3D environments will allow us to better understand this marrow remodelling process and how drugs can target cancers in this more protective environment. The models will also allow us to study the potential toxicity of gene-edited HSCs to make sure they don't produce unwanted side effects or are not cancerous in themselves.3) Dormancy. What triggers dormancy and activation from dormancy are poorly understood. By placing our 3D environments in a miniaturised format where we can connect other models that include infection and immune response, we can start to understand the factors involved in the activation of cancer cells from dormancy.Our vision is driven by materials and engineering, as the bone marrow niche is rich in structural and signalling biological materials (proteins). Therefore, we will establish three engineering challenges:(1) Cells can be controlled by the stiffness and viscous nature of materials (viscoelasticity). We will therefore develop synthetic-biological hybrid materials that can be manufactured to have reproducible physical properties and that have biological functionality. (2) We will develop these materials to interact with growth factors and bioactive metabolites, both of which are powerful controllers of cell behaviours. These materials will be used to assemble the HSC microenvironments in lab-on-chip (miniaturised) format to allow high-content drug and toxicity screening. (3) We will develop real-time systems to detect changes in cell behaviour, such as the transition from health to cancer using Raman and Brillouin microscopies.The use of animals in research provides poor predictivity. We will offer better than animal model alternatives.