Designing synthetic matrices for enhanced organoid development: A step towards better disease understanding

神经病理学的严重衰弱效应，从阿尔茨海默氏症等神经退行性疾病到多发性硬化症等神经炎性自身免疫性疾病，以及对神经系统的创伤性损伤，继续深刻地影响着许多人的生活。目前对这些疾病的了解很少，导致可用的治疗方法有限，失去了许多高质量的生命年。了解人脑发育对于创造有效方法来修正这些病理是至关重要的。然而，目前的人脑体外模型过于粗糙，因为与它们目前拥有的体内模型相比有明显的不同。提高我们在这一领域的知识，为理解神经发育障碍提供了希望，并提供了一种通过改善对神经组织再生的理解来减轻其影响的方法。目前，我的研究重点是建立早期大脑发育的模型，以促进对神经病理学的理解。该模型是基于HiPSCs产生的神经上皮类器官。为了模拟周围脑组织的自然条件，我将这些有机化合物嵌入到一种合成的可调水凝胶中，这是我在过去两年开发和优化的。在这种情况下，有机物质微环境与活体条件更相关，允许调节，控制有机物质形态，并成为探索大脑发育错综复杂的有力工具。早期大脑发育始于神经管的形成，其中神经板经历折叠和闭合，最终形成大脑和脊髓。随着大脑的成熟，它呈现出一种不同的结构，不同的区域表现出不同程度的僵硬。我们推测，这种僵硬的梯度，结合三维环境，在重建神经管模式方面发挥了关键作用。此外，Wnt信号/β-连环蛋白通路在这一过程中起着至关重要的作用。Wnt梯度对于前后分化是必不可少的。此外，细胞外基质的刚性增加也会影响Wnt的激活。因此，建立一个能够精确控制僵硬梯度、材料软化和生物分子靶向释放的模型对于构建体外模型至关重要。参与这个交换计划，并将受控僵硬梯度与Wnt信号的精确控制相结合，将产生一个更健壮和更可靠的重复性模型，用于研究大脑发育和疾病建模。对英国-加拿大的好处：在不久的将来，我们预计将发表一篇基于我们的初步数据的手稿，该手稿建立在我们的初步数据的基础上，该手稿建立在Gentleman实验室关于ECM僵硬如何影响神经上皮器官中神经元生成的初步数据的基础上。我们即将进行的研究将集中于确定硬度梯度是否可以激活WNT信号并影响类器官图案。随后，我们将进一步研究在均匀水凝胶中使用微球控制释放的WNT模式。展望未来，我们的目标是推进最佳疾病特异性模型的开发。例如，研究涉及细胞外基质异常的疾病，如髓鞘变性，最好使用完全合成的生物材料进行。将3D打印与合成基质和有机体技术相结合，为在这种情况下创建更有效的模型带来了巨大的希望。这种更深入的理解将为开发受损组织的再生策略铺平道路，特别是在生物打印具有开创性前景的领域。

The severely debilitating effects of neuropathology, from neurodegenerative disorders, like Alzheimer's to neuro-inflammatory autoimmune conditions, such as Multiple Sclerosis, and traumatic damage to the nervous system continue to profoundly affect the lives of many. These illnesses are poorly understood at present, resulting in limited therapeutics to be available and many good quality life years lost.Understanding human brain development is of paramount importance to create pathways to effective approaches that amend these pathologies. However, current in vitro models of the human brain are too crude, given the marked distinctions In comparison to in vivo models they currently possess. Improving our knowledge in this domain, holds promise for comprehending neurodevelopmental disorders and provide a way to mitigate its effects through improved understanding of neural tissue regeneration.At present, my research is focused on modelling early brain development to advance understanding of neuropathologies. The model is based on neuroepithelial organoids generated from hiPSCs. To mimic the natural conditions of the surrounding brain tissue, I embed these organoids in a synthetic tunable hydrogel, which I've developed and optimized in the past two years. In this way, the organoids microenvironment is more relevant to that of in vivo conditions, allowing tunability, controlling organoid morphology, and serving as a potent instrument for probing the intricacies of brain development.Early brain development begins with the formation of the neural tube, wherein the neural plate undergoes folding and closure to eventually give rise to the brain and spinal cord. As the brain matures, it displays a heterogeneous structure, with distinct regions exhibiting varying degrees of stiffness. We postulate that this gradient of stiffness, combined with the three-dimensional environment, plays a key role in recreating neural tube patterning. Additionally, the Wnt signaling/beta-catenin pathway is critical in patterning this process. The Wnt gradient is indispensable for anterior-posterior differentiation. Moreover, the activation of Wnt can be influenced by increased stiffness of the extracellular matrix. Hence, establishing a model that allows precise control of stiffness gradients, material softening, and the targeted release of biomolecules is critical for constructing in vitro models.Taking part in this exchange program and integrating a controlled stiffness gradient with precise control of Wnt signaling will result in a more robust and reliably reproducible model for studying brain development and disease modelling.Benefits to UK-Canada: In the near future, we anticipate publishing a manuscript that builds upon our preliminary data regarding how ECM stiffness impacts neuron generation in neuroepithelial organoids from Gentleman's lab. Our upcoming research will focus on determining whether a stiffness gradient can activate WNT signaling and influence organoid patterning. Subsequently, we will further investigate WNT patterning using controlled release with microbeads in uniform hydrogels.Looking ahead, we aim to advance the development of optimal disease-specific models. For instance, the study of disorders involving extracellular matrix irregularities, such as myelin degeneration, is best conducted using fully synthetic biomaterials. Combining 3D printing with synthetic matrices and organoid technologies holds great promise for creating a more effective model in this context.This deeper understanding will pave the way for developing regenerative strategies for damaged tissue, particularly in areas where bioprinting shows groundbreaking promise.