Combining stem cell science and tissue engineering to study the development and repair of human skeletal tissues

随着老龄化人口的不断增加，迫切需要能够简单地修复和增强因骨质疏松症和骨关节炎等疾病或因衰老或事故后丢失的骨组织的战略。虽然有许多外科技术可以用来修复骨骼和帮助骨折愈合，但非常需要开发替代的骨和软骨修复和再生策略。为了解决患者可能在一个部位缺乏骨骼的问题，外科医生可以尝试从患者的另一个部位获取并使用现有的骨(称为自体骨)，尽管可用骨量自然是有限的。其他选择包括使用来自不同个体的供体骨(称为同种异体骨)。然而，供骨存在排斥和感染的风险。组织工程学的目标是使用干细胞和前体细胞、细胞可以在其上生长和引导的支架以及必要的机械信号来制造组织和器官--包括骨组织--在实验室中创造骨组织进行移植，以取代受损或患病的组织。在我们所有的骨髓中都有干细胞(称为骨骼干细胞或间充质干细胞)，可以使用选择性标记进行分离，并可以在生长过程中产生大量细胞，同时保留它们形成骨和脂肪等各种组织的能力。同样，我们在为细胞生长创造结构(支架)方面拥有专业知识，这些支架可以量身定做，释放特定的生长因子和蛋白质，以引导和告诉干细胞生成骨骼和软骨。此外，我们知道机械信号在刺激新骨生长方面非常重要(例如，我们知道过度卧床或失重会导致骨骼丢失)。因此，应用干细胞、选择支架和使用信号提示来产生新的骨组织是目前疾病治疗和骨修复最令人兴奋和最有前途的领域之一。我们提出并结合了这些关键因素，关键是，如果我们要应对日益老龄化的人口对新骨骼形成的挑战，就迫切需要一种新的思维方式，即科学家目前如何试图创造骨骼组织。我们认为，了解骨的发育和形成是至关重要的，如果我们能够利用骨骼如何发育的信息，如果我们能够理解骨生物学，这将为我们奠定基础，并告诉我们如何修复和制造新的骨骼组织。因此，我们提出了一个雄心勃勃的研究计划，以显著推进发育生物学、干细胞、材料化学、机械信号和加载以及转化医学的最先进水平，以产生新的骨骼发育模型，可用于为骨骼修复和再生的临床使用提供骨骼修复策略的信息。为了实现我们的目标，我们将使用多学科战略，将干细胞生物学家、发育生物学家、材料科学家、机械生物学家和临床医生聚集在一起，能够从骨骼发育生物学中吸取教训，为我们的骨骼形成和修复的组织工程战略提供信息。

With an ever increasing ageing population, strategies that allow the simple repair and enhancement of bone tissue, lost due to diseases such as osteoporosis and osteoarthritis or with ageing or after an accident, are urgently needed. Whilst there are a number of surgical techniques that can be used to repair bone and to aid fracture healing, there is a great need for the development of alternative bone and cartilage repair and regeneration strategies. To try and solve the lack of bone a patient may have at one site, the surgeon can try and harvest and use existing bone from another site (known as autogenous bone) in the patient although, naturally, the amounts available to use are limited. Other options include the use of donor bone from a different individual (known as allogeneic bone). However donor bone carries risks of rejection and infection. Tissue engineering aims to make tissues and organs - including bone tissue - using stem and precursor cells, scaffolds upon which the cells can grow and be guided, and necessary mechanical cues to create bone tissue in the laboratory for transplantation to replace damaged or diseased tissues. Within all our bone marrow are stem cells (called skeletal or mesenchymal stem cells), which can be isolated using selective markers and which can be grown up to give lots of cells, while retaining their ability to form a variety of tissues like bone and fat. Similarly we have expertise in the ability to create structures (scaffolds) for the cells to grow on and these scaffolds can be tailored to release select growth factors and proteins needed to guide and tell the stem cells to make bone and cartilage. In addition, we know that mechanical cues are very important in stimulating new bone growth (for example we know excessive bed rest or weightlessness leads to loss of bone). Thus the application of stem cells, select scaffolds and the use of signalling cues to generate new bone tissue is currently one of the most exciting and promising areas for disease treatment and bone repair. We propose as well as combining these key ingredients, that, critically, a new way of thinking as to how scientists currently try to create skeletal tissue is urgently needed if we are to meet the challenges of new skeletal formation for an increasing ageing population. We propose that it is vital to understand bone development and formation and that if we can harness the information of how bone develops and if we can understand bone biology, this will set the foundation and inform us how to repair and make new skeletal tissue. Thus, we propose an ambitious programme of research to significantly advance the state-of-the-art in developmental biology, stem cells, materials chemistry, mechanical signalling and loading and translational medicine to generate new models of skeletal development that can be used to inform skeletal repair strategies for clinical use in bone repair and regeneration. To achieve our goal we will use a multidisciplinary strategy that brings together stem cell biologists, developmental biologists, materials scientists, mechanobiologists and clinicians with an ability to draw lessons from skeletal developmental biology to inform our tissue engineering strategy for skeletal formation and repair.