Synthetic cell-based patterning systems and their applications in stem cell differentiation

造血系统是理解细胞等级和组织特异性干细胞特性的范例。造血干细胞和白血病干细胞（hsc, LSCs）构成了理解生理和恶性干细胞生物学方面的开创性模型，使骨髓和血液成为研究组织修复和肿瘤形成的理想模型。尽管体细胞和癌症干细胞分别是最具特征的干细胞，但对于调节生理性造血的基因调控网络，以及这些基因在白血病发生过程中是如何被破坏的，仍然没有明确的认识。我最感兴趣的是剖析造血过程中这些网络的逻辑和本质，以及它们的组成因素如何受到外部条件的影响，比如利基衍生信号，尤其是缺氧。表征这些网络和/或外部条件的影响将极大地有助于理解HSC的命运决定，这可能为HSC在体外的扩展以及白血病发生的潜在机制提供见解，其标志是对HSC命运决定的解除管制。理解和重建（或反之亦然）一个天然的干细胞生态位和/或组织是干细胞生物学和再生医学的一个组成部分。重建骨髓生态位可能为造血干细胞的体外扩增提供一个稳定的平台。理论上，这种合成系统应该为研究造血干细胞的生物学提供一个平台，为治疗性移植提供一种可靠的方法来产生足够的造血干细胞产量，并为靶向LSC利基提供一种体外药理筛选系统。由于骨髓组织的复杂性，并考虑到合成形态学是一个非常年轻的领域，建立和理解更简单的系统是首要任务。为了实现这一目标，我将热衷于I)研究诱导形态发生模块的已知基因，ii)将特定模块链接并协调成一定的序列，iii)在这些模块与发育生物学的核心原理（例如图灵系统）之间建立联系。这种复杂的基因工程足以产生，至少在理论上，简单的模式组织，但也将提供一个平台，以产生更复杂的形态发生。

he haematopoietic system serves as a paradigm for understanding cellular hierarchies and properties of tissue-specific stem cells. Haematopoietic and Leukaemic Stem Cells (HSCs, LSCs) constitute the pioneering models for understanding aspects of both physiological and malignant stem cell biology, making the bone marrow and blood the ideal models to study tissue repair and neoplasia. Albeit constituting the best characterized somatic and cancer stem cells respectively, there is still no clear understanding of the gene regulatory networks that regulate physiological haematopoiesis, and how these are corrupted during leukaemogenesis. I am most interested in dissecting the logic and the nature of these networks in haematopoiesis and how their constituent factors are affected by external conditions, such as niche-derived signals and particularly hypoxia. Characterizing such networks and/or the effect of extrinsic conditions shall substantially contribute in understanding HSC fate-decisions, which might provide insights into the expansion of HSCs ex vivo as well as into the underlying mechanisms of leukaemogenesis, whose hallmark is the deregulation of HSC fate-decisions.Understanding and recreating (or vice versa) a natural stem cell niche and/or tissue is an integral part of stem cell biology and regenerative medicine. Recreating the bone marrow niche might provide a steady platform to expand HSCs ex vivo. In theory, such synthetic system should provide a platform to study the biology of HSCs, a reliable method to generate sufficient HSC yields for curative transplantations, and an in vitro pharmacological screening system which can provide novel insights into targeting the LSC niche. Due to the tissue complexity of the bone marrow and given that synthetic morphology is a very young field, building and understanding simpler systems is of primary priority. To achieve this, I would be keen on i) investigating known genes in the induction of morphogenic modules, ii) link and coordinate specific modules into certain sequence and iii) establish a link between such modules and core principles of developmental biology (e.g. Turing's system). Such complex genetic engineering would be sufficient to generate, at least in theory, simply patterned tissues, but would also provide a platform to generate more complex morphogenesis.