CAREER: Building bone marrow

1254738哈雷造血是指人体所有的血液和免疫细胞都是从少量的造血干细胞(HSCs)中产生的。这些活动发生在骨髓中被称为“小生境”的独特部分。指导HSC长期不活动、自我更新或分化以产生血液和免疫细胞等行为所需的遗传信息包含在其DNA中，但需要来自利基的外部信号来触发这些事件。虽然造血干细胞每天负责产生近1万亿个造血细胞，如血小板和免疫细胞，但这一过程中的突变是导致白血病等造血病理的原因。然而，很难研究骨髓内的这些事件。该项目的长期目标是构建一种人造骨髓，为在实验室培养造血干细胞提供正确的利基信号序列。这样的工具将是变革性的，因为它将允许人们解开定义HSC利基的线索网络，以及工程变体，以帮助一系列造血和癌症生物学研究。为此，该团队创建了一个骨髓生物芯片平台，将HSC利基环境的复杂性降低为一系列可管理的离散信号，我们可以在三维生物材料中有选择地定义这些离散信号。这种生物芯片可以从骨髓中分离出少量的造血干细胞，以确定的增量操纵这些细胞周围的利基信号，并跟踪它们的反应。在这个项目中，我们将绘制三类重要的生态位信号的组合--骨髓的结构组成、支持性的生态位细胞和生物分子线索--如何影响两种关键行为，即自我更新和分化的启动。这些知识对于定义如何将利基信号改造成生物材料以控制HSC活动的所有阶段至关重要。通过一个协调的研究和教育计划，该项目将直接支持一些重要的外展计划。针对早期小学、中学和本科生的外展工作将被用来扩大对科学和工程的参与。在该项目期间开发的工具将作为免疫学-生物学-工程学学科交汇处正在进行的和未来的研究项目的基础。

1254738 HarleyHematopoiesis is the process where all the body's blood and immune cells are generated from a small number of hematopoietic stem cells (HSCs). These events take place in unique parts of the bone marrow termed 'niches'. The genetic information required to direct HSC behaviors such as long-term inactivity, self-renewal, or differentiation to produce blood and immune cells is contained within its DNA, but external signals from the niche are required to trigger these events. And while HSCs are responsible for producing nearly one trillion hematopoietic cells per day such as platelets and immune cells, mutations in this process are responsible for hematopoietic pathologies such as leukemia. However, it is difficult to study these events inside the bone marrow. The long-term goal of this project is to build an artificial bone marrow that provides the correct sequence of niche signals to grow HSCs in the laboratory. Such a tool would be transformative because it would allow one both untangle the web of cues that define HSC niches as well as engineer variants to assist a range of hematopoietic and cancer biology studies. To that end, the group has created a bone marrow biochip platform that reduces the complexity of HSC niches to a manageable series of discrete signals that we can selectively define within a threedimensional biomaterial. This biochip allows to isolate small numbers of HSCs from the bone marrow, manipulate the niche signals surrounding these cells in defined increments, and track their response. This project we will chart how combinations of three important classes of niche signals -- the structural make-up of the bone marrow, supportive niche cells, and biomolecule cues -- impact two critical behaviors, self-renew versus the initiation of differentiation. Such knowledge will be critical for defining how niche signals can be engineered into a biomaterial to control all phases of HSC activity. Through a coordinated research and educational plan, this project will directly support a number of critical outreach programs. Outreach efforts targeting early elementary, secondary, and undergraduate students will be used to broaden participation in science and engineering. Tools developed during this project will serve as the foundation for ongoing and future research projects at the confluence of immunology-biology-engineering disciplines.