Bioengineered, patient-specific bonemarrow model for studying leukemic niche interactions

用于研究白血病生态位相互作用的生物工程、患者特异性骨髓模型

• 批准号: 10536104
• 负责人: Daniel Naveed Tavakol
• 金额: $ 4.68万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-13 至 2023-07-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10536104
• 关键词: Accounting; Acute Lymphocytic Leukemia; Acute leukemia; Adherent Culture; Adult; Apoptosis; Apoptotic; BCL2 gene; Biological Assay; Biological Models; Biomedical Engineering; Blood Cells; Bone Marrow; CXCL12 gene; Cancer Model; Cell Line; Cells; Cessation of life; Chemicals; Child; Childhood Leukemia; Coculture Techniques; Development; Disease; Disease model; Drug resistance; Endothelial Cells; Engineering; Engraftment; Epigenetic Process; Experimental Leukemia; Exposure to; Fibrin; Flow Cytometry; Genetic; Goals; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Heterogeneity; Homeostasis; Human; Human Engineering; Hydrogels; IL7 gene; In Vitro; Interleukin-1 beta; Interleukin-6; Investigational Therapies; Lymphoblastic Leukemia; Lymphoid; Maintenance; Malignant - descriptor; Malignant Bone Neoplasm; Malignant Neoplasms; Marrow; Mesenchymal; Metabolic; Methodology; Modeling; Myelogenous; Nature; Organoids; Osteoblasts; Outcome; PTPRC gene; Patients; Pharmaceutical Preparations; Phenotype; Physiology; Play; Population; Prediction of Response to Therapy; Predictive Value; Research; Role; Sampling; Solid Neoplasm; Stromal Cells; Study models; Supplementation; System; TNF gene; Testing; Therapeutic; Therapeutic Human Experimentation; Tissue Engineering; Tissue Model; Tissues; Treatment Efficacy; Trichrome stain method; Tropism; Work; Xenograft Model; Xenograft procedure; acute lymphoblastic leukemia cell; biological research; bone engineering; bone scaffold; bone sialoprotein; cancer type; cell immortalization; cell stroma; cell type; cytokine; efficacy testing; high risk; human model; human tissue; improved; in vitro Model; in vivo; induced pluripotent stem cell; induced pluripotent stem cell technology; interest; leukemia; leukemic transformation; lymphoblast; mesenchymal stromal cell; microCT; molecular marker; monolayer; neoplastic cell; novel; novel therapeutics; organ on a chip; patient derived xenograft model; progenitor; resistance mechanism; response; response to injury; stem; stem cells; therapeutic development; therapeutic evaluation; therapy resistant; tool; transcriptomics; tumor; young adult

PROJECT SUMMARY / ABSTRACT Acute leukemias represent the most frequent group of cancer (~30%) in children and young adults. The advancement of experimental therapeutics for high risk leukemias has been limited by the inadequacy of immortalized cell lines and the cumbersome nature and limited throughput of in vivo xenograft models. In this context, the lack of robust systems for in vitro culture of primary leukemia samples is a significant barrier for the development of effective genetic and chemical screens in pediatric leukemia. In vitro systems, including engineered tissues and organ-on-a-chip systems, are gaining increased interest in the stem cell and cancer fields as human-specific platforms for the study of disease and therapeutic testing. In vitro models of the bone marrow (BM) have yet to gain momentum, largely due to their reduced throughput, technical barriers in biological research, and the heterogeneity of starting stromal cell populations. Further, there have been only few attempts to culture primary donor-derived malignant blood cells in engineered systems, which enable patient-specific studies of disease. In this proposed project, I will (Aim 1) engineer a human, induced pluripotent stem cell (iPSC)- derived bone marrow tissue model, comprised of osteoblasts, mesenchymal stromal cells, and endothelial cells within a bone scaffold, for maintenance of acute lymphoblastic leukemia (ALL) phenotype in vitro. I will then use this model to (Aim 2) study how the secretome of malignant ALL blasts, or the ALL blasts themselves, interact with both healthy hematopoietic stem and progenitor cells (HSPCs) and healthy stroma in the engineered model. I hypothesize that an engineered human BM microenvironment, capable of supporting HSPCs in vitro, will maintain the phenotype of ALL blasts closer to unmanipulated samples than monolayer cultures or patient derived xenograft models, further enabling studies of direct and indirect lymphoblast interactions with the healthy bone marrow. It has been well established that acute leukemias alter their microenvironmental niche, and in many cases, use the stroma to protect malignant clones during treatment; I hypothesize that this model system will be better able to predict therapeutic responses, identifying potential mechanisms of resistance in ALL. Our lab brings strong expertise in engineering human tissues, iPSC technologies, and therapeutic testing, and with support of experts in hematopoiesis, cancer, and sequencing, I believe that the proposed project will successfully establish a novel tool for studying the human bone marrow during malignant leukemic transformation and resistance to therapy.

项目摘要 /摘要 急性白血病是儿童和年轻人中最常见的癌症组（约30％）。这 实验性治疗剂对高风险白血病的进步受到了不足的限制 永生的细胞系和繁琐的体内异​​种移植模型的吞吐量有限。在这个 上下文，缺乏用于原发性白血病样品体外培养的健壮系统是该系统的重要障碍 开发小儿白血病中有效的遗传和化学筛选。体外系统，包括 工程组织和芯片系统的组织正在增加对干细胞和癌症的兴趣 领域是研究疾病和治疗测试的人类特异性平台。骨骼的体外模型 骨髓（BM）尚未获得动力，这主要是由于它们的吞吐量减少，生物学的技术障碍 研究和开始基质细胞群的异质性。此外，只有很少的尝试 在工程系统中培养主要供体衍生的恶性血细胞，这使患者特定 疾病研究。在这个拟议的项目中，我将（AIM 1）设计人类诱导的多能干细胞（IPSC） - 衍生的骨髓组织模型，由成骨细胞，间质基质细胞和内皮细胞组成 在骨支架内，用于维持体外急性淋巴细胞白血病（所有）表型。然后我会使用 该模型（目标2）研究恶性的分泌剂如何所有爆炸或所有爆炸本身如何相互作用 在工程模型中，具有健康的造血干细胞和祖细胞（HSPC）和健康基质。 我假设一个工程设计的人类BM微环境能够在体外支持HSPC，将会 比单层培养物或患者保持所有爆炸的表型，更接近未经操纵的样品 衍生的异种移植模型，进一步研究了与健康的直接和间接淋巴细胞相互作用的研究 骨髓。已经有很好的确定，急性白血病改变了其微环境的利基市场，在 许多情况下，使用基质在治疗过程中保护恶性克隆；我假设这个模型系统 将能够更好地预测治疗反应，从而确定抗药性的潜在机制。我们的 实验室在工程人体组织，IPSC技术和治疗测试方面具有强大的专业知识，并具有 我相信拟议项目将成功地支持造血，癌症和测序的专家 建立一种新的工具，用于研究在恶性白血病转化期间人类骨髓和 抵抗治疗。