The Role of Inflammation and Inflammatory Mediators in Hematopoiesis

炎症和炎症介质在造血中的作用

• 批准号: 9251073
• 负责人: Lindsay Nicole Theodore
• 金额: $ 3.66万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9251073
• 关键词: Adult; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Aorta; Biology; Biophysical Process; Biophysics; Birth; Blood; Bone Marrow; CXCL12 gene; CXCR4 Signaling Pathway; CXCR4 gene; Cell Count; Cell Maturation; Cell Proliferation; Cell physiology; Cells; Chemicals; Clinical; Data; Development; Digestion; Dinoprostone; Disease; Dorsal; Embryo; Endopeptidases; Endothelium; Engraftment; Enzymes; Extracellular Matrix; Family; Fertilization; Fetal Liver; Fibronectins; Foundations; Gelatinases; Genes; Genetic; Goals; Gonadal structure; Harvest; Hematologic Neoplasms; Hematological Disease; Hematology; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Immune; Immune response; Immune system; Immunocompromised Host; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Injury; Interferon Type II; Interleukin-1 beta; Investigation; Knockout Mice; Light; Link; MMP2 gene; MMP9 gene; Marrow; Matrix Metalloproteinases; Mediating; Mesonephric structure; Mind; Movement; Myeloid Cells; Outcome; Patients; Phase; Physiological; Play; Process; Production; Protocols documentation; Publications; RUNX1 gene; Regulation; Reporter; Research; Role; Signal Transduction; Signaling Molecule; Site; Stem cell transplant; Stem cells; Stimulus; Study models; TNF gene; Thymus Gland; Tissues; Vertebrates; Work; Zebrafish; Zinc; angiogenesis; base; cell motility; chemokine; cytokine; granulocyte; hematopoietic tissue; improved; induced pluripotent stem cell; inflammatory milieu; macrophage; migration; mutant; neutrophil; novel; oncology; response; self-renewal; standard of care; stem cell differentiation; transcription factor; vertebrate embryos

Abstract: The immune response is intimately linked to the dynamics of hematopoietic stem and progenitor cell (HSPCs) regulation, including their production, migration and lineage commitment. We, and others, recently showed that inflammatory signaling upregulates overall HSPC formation in the developing vertebrate embryos. Further, primitive myeloid cells, which act as the first inflammatory intermediates, appear to play an unexpected role in regulating the specification and production of embryonic HSPCs; however, the cellular interactions and biophysical mechanisms downstream of inflammatory stimulation that modulate HSPC number and function remain unknown. Pro-inflammatory matrix metalloproteinases (MMPs) are a group of extracellular matrix (ECM)-remodeling enzymes expressed in response to immune stimuli. Of the 25 known MMPs, MMP2 and MMP9, which comprise the “gelatinase” family, are tightly associated with inflammation and secreted by adult HSPCs to break down bone marrow endothelium, allow for cell migration, and promote angiogenesis. Additionally, MMP2/9 double knockout mice have dysregulated immune biology, suggesting a potential intersection between inflammatory signaling and MMP-induced niche remodeling that may function to control HSPC emergence, migration and differentiation. HSPCs are born from hemogenic endothelium in the aorta-gonad mesonephros (AGM) region of the embryo, and migrate to/expand in the fetal liver (caudal hematopoietic tissue (CHT) in zebrafish) before colonizing the thymus and marrow. Chemical or genetic inhibition of MMP2, expressed in the endothelial niche during HSPC emergence, retained runx1+ cells in the zebrafish AGM, delaying migration to the CHT; preliminary data indicates this may be due to MMP2-mediated ECM digestion. In contrast, loss of MMP9 did not affect HSPC budding, but instead resulted in aberrant HSPC expansion within the CHT. Our preliminary data suggests that effect is due to MMP9-dependent modulation of SDF1/CXCR4 chemokine signaling, induced downstream of inflammatory stimuli like prostaglandin-E2 (PGE2). Importantly, inhibition of either MMP2 or MMP9 led to abnormal colonization of the thymus, a process dependent on normal HSPC production and function, demonstrating these enzymes are necessary throughout developmental hematopoiesis. Therefore, our central hypothesis is that matrix metalloproteinases, specifically MMP2 and MMP9 regulate the production and migration of HSPCs during developmental hematopoiesis. Our proposed studies will reveal whether MMP2/9 serve as the effector of primitive myeloid cells and inflammatory signaling in controlling HSPCs form and function the hemogenic niche.

抽象的： 免疫响应与造血茎的动态密切相关， 祖细胞（HSPCS）调节，包括其生产，迁移和血统 承诺。我们和其他人最近表明，炎症信号传导上调了总体 发育中的脊椎动物胚胎中的HSPC形成。此外，原始的髓样细胞，该细胞 充当第一个炎症性中间体，似乎在调节 胚胎HSPC的规格和生产；但是，细胞相互作用和 炎症刺激下游的生物物理机制调节HSPC数 功能仍然未知。促炎性基质金属蛋白酶（MMP）是一组 响应免疫刺激的响应的细胞外基质（ECM） - 重塑酶。的 构成“明胶酶”家族的25个已知MMP和MMP9紧密 与炎症相关，成人HSPC分泌以分解骨髓 内皮，允许细胞迁移并促进血管生成。另外，MMP2/9双 敲除小鼠的免疫生物学失调，表明 炎症信号传导和MMP诱导的利基重塑，可以控制HSPC 出现，迁移和差异化。 HSPC是由血液生成的植物诞生的 胚胎的主动脉中肾（AGM）区域，然后迁移到/膨胀在胎儿肝脏中 （斑马鱼中的尾造血组织（CHT））在定居胸腺和骨髓之前。 MMP2的化学或遗传抑制，在HSPC期间内皮细分市场中表达 出现，在斑马鱼AGM中保留Runx1+细胞，延迟迁移到CHT； 初步数据表明这可能是由于MMP2介导的ECM消化。相反，损失 MMP9的of不会影响HSPC的萌芽，而是导致异常HSPC扩展 CHT。我们的初步数据表明效果是由于MMP9依赖的调制引起的 SDF1/CXCR4趋化因子信号传导，诱导的炎症刺激下游 Prostaglandin-E2（PGE2）。重要的是，抑制MMP2或MMP9导致异常 胸腺的定殖，这是一个取决于正常HSPC的产生和功能的过程， 证明这些酶在整个发育性造血作用中都是必要的。 因此，我们的中心假设是基质金属蛋白酶，特别是MMP2和 MMP9调节发育造血期HSPC的生产和迁移。 我们提出的研究将揭示MMP2/9是否用作原始髓样细胞的效应子 控制HSPC中的炎症信号传导形式并发挥了血源性的作用。