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

造血系统作为理解细胞层次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，LSC）构成了了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的理想模型。尽管分别构成了最具特征的体细胞和癌症干细胞，但对调节生理性造血的基因调控网络以及这些网络在白血病发生期间如何被破坏仍然没有清楚的了解。我最感兴趣的是解剖造血中这些网络的逻辑和性质，以及它们的组成因素如何受到外部条件的影响，例如生态位衍生信号，特别是缺氧。表征这种网络和/或外在条件的影响将大大有助于理解HSC的命运决定，这可能提供对HSC离体扩增以及白血病发生的潜在机制的见解，其标志是HSC命运决定的放松管制。理解和重建（或反之亦然）天然干细胞龛和/或组织是干细胞生物学和再生医学的组成部分。重建骨髓小生境可能为体外扩增HSC提供稳定的平台。从理论上讲，这种合成系统应该提供一个平台来研究HSC的生物学，一个可靠的方法来产生足够的HSC产量用于治疗性移植，以及一个体外药理学筛选系统，可以提供新的见解靶向LSC生态位。由于骨髓的组织复杂性，并且考虑到合成形态学是一个非常年轻的领域，构建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）研究已知基因在诱导形态发生模块，ii）链接和协调特定模块到某些序列和iii）建立这样的模块和发育生物学的核心原则（例如图灵系统）之间的联系。这种复杂的基因工程至少在理论上足以产生简单的模式化组织，但也将提供一个平台来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.