Modelling the human bone marrow microenvironment

在造血过程中，骨髓微环境触发造血干细胞（HSC）中的特异性信号传导，诱导其分化为多种免疫谱系。在该领域的一个主要限制是缺乏人在体外模型来概括这一过程，并提供免疫细胞分化的早期步骤的机制的见解，我提出了一个创新的，多学科的方法来解码的作用，骨髓微环境中塑造细胞的身份和功能。我将通过分析单细胞基因组学数据集来定义在发育中的人类骨髓中驱动HSC向B细胞分化的基本细胞生态位。该参考文献将指导使用合成生物学工具从人诱导多能干细胞（hiPSC）工程化饲养细胞（人骨髓样基质细胞，hBMLSC）。最后，我将设计新的3D培养物来共培养我的工程饲养细胞和HSC，并诱导它们向B细胞谱系分化。我的提议将单细胞和计算技术与细胞和组织工程相结合，以提供第一个人类人工骨髓模型。这种模式有望改变血液病的研究，并为免疫治疗的新时代铺平道路。此外，实验和计算框架将指导未来使用单细胞基因组学数据改进体外模型。

During hematopoiesis, the bone marrow microenvironment triggers specific signalling in hematopoietic stem cells (HSCs), inducing their differentiation into multiple immune lineages. A main constraint in the field is the lack of human in vitro models to recapitulate this process and provide mechanistic insights into the early steps of immune cell differentiation.I propose an innovative, multidisciplinary approach to decode the role of the bone marrow microenvironment in shaping cell identity and function. I will define the essential cellular niche driving HSC to B-cell differentiation in the developing human bone marrow by analysing single-cell genomics datasets. This reference will guide the engineering of feeder cells (human bone marrow-like-stromal cells, hBMLSCs) from human induced pluripotent stem cells (hiPSCs) using synthetic biology tools. Finally, I will design novel 3D-cultures to co-culture my engineered feeder cells and HSCs, and induce their differentiation towards the B-cell lineage.My proposal combines single-cell and computational technologies with cell and tissue engineering to provide the first artificial bone marrow model in humans. This model promises to transform the study of hematological disease and pave the way to a new era in immunotherapies. In addition, the experimental and computational framework will guide the future improvement of in vitro models using single-cell genomics data.