Normalization of Sickle Cell Disease bone marrow niche defects by RBC transfusion

通过红细胞输注使镰状细胞病骨髓生态位缺陷正常化

• 批准号: 10494383
• 负责人: JOHN P MANIS
• 金额: $ 85.85万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10494383
• 关键词: Adopted; Affect; Aspirate substance; Autologous; Biopsy; Blood; Blood Transfusion; Blood Vessels; Bone Marrow; Bone Marrow Diseases; Bone Marrow Transplantation; CXCL12 gene; Cell physiology; Cells; Clinical Trials; Collaborations; Data; Defect; Discontinuous Capillary; Disease; Endothelium; Engraftment; Ensure; Erythrocyte Transfusion; Erythrocytes; Erythroid Cells; Event; Exudate; Functional disorder; Growth; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Homeostasis; Homing; Homologous Transplantation; Hour; Hypoxia; Impairment; Inflammation Mediators; Inflammatory; Intervention; Investigation; Link; Mesenchymal; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Mus; Myeloid Cells; Oxygen; Pathologic; Patients; Pharmacology; Phenotype; Physiological; Population; Preparation; Protein Array; Recovery; Regimen; Resolution; Role; Sickle Cell Anemia; Speed; Stress; Structural defect; Testing; Therapeutic Intervention; Time; Transfusion; Translating; Transplantation; Vascular Endothelial Growth Factors; arteriole; burden of illness; cell type; chemokine; curative treatments; endothelial dysfunction; gene correction; hematopoietic engraftment; improved; insight; mortality; neovascular; novel; novel strategies; quantitative imaging; reconstitution; sickling; stem cells; transcriptome

Project Summary To date, the only curative option for Sickle Cell Disease (SCD) is transplantation of allogeneic HSC. Recently, clinical trials utilizing gene corrected autologous HSC have been initiated and hold much promise. However significant limitations and challenges remain for HSC transplantation in SCD patients. In humanized SCD mice we showed for the first time the pathologic impact of SCD on bone marrow (BM) vascular and perivascular niches that are deemed critical to HSC transplantation and steady state hematopoiesis. Specifically, the studies uncovered a disorganized and structurally abnormal BM neovascular network of increased numbers of highly tortuous arterioles occupying the majority of the BM cavity, as well as fragmented sinusoidal vessels filled with aggregates of erythroid and myeloid cells. Additionally, the number of CXCL12 producing perivascular mesenchymal niche cells, was reduced thus further supporting a defective hematopoietic niche in SCD mice. Further investigations provided a model of SCD BM, where slow RBC flow and vaso-occlusion further diminish local oxygen availability in the physiologically hypoxic BM cavity. These events trigger an angiogenic milieu conducive to aberrant vessel growth. Remarkably, the distorted neovascular network was completely reversed by a 6 weeks of blood transfusion highlighting the plasticity of the vascular niche. Additional, unpublished preliminary data indicate that long-term (16 weeks) HSC reconstitution when transplanted into SCD mice is significantly compromised. Collectively, these studies have led us to hypothesize that impaired engraftment of HSPCs into SCD BM is caused by structural and functional abnormalities of the hematopoietic vascular and/or mesenchymal niche; and that correction of key vascular niche cell defects will improve HSPC engraftment. Stem cell mobilization may also be affected by the BM niche and we will seek to understand how stem cells egress from the BM to the blood in SCD. Thus three aims are proposed to test these hypotheses: 1. to define the SCD niche defects at the molecular and cellular level in humanized SCD mouse 2. to determine which niche defects are normalized by blood transfusion and define the BM niche defects in patients; and 3. to ascertain the link between BM niche defects and impaired HSCP engraftment. Collectively, these investigations will help optimize approaches towards efficient and long-term hematopoietic engraftment in the context of curative therapies.

项目摘要 迄今为止，镰状细胞疾病（SCD）的唯一治愈方法是同种异体HSC的移植。最近， 利用基因校正的自体HSC的临床试验已经启动并具有很大的希望。然而 SCD患者的HSC移植仍然存在重大局限性和挑战。在人源化的SCD小鼠中 我们首次展示了SCD对骨髓（BM）血管和血管周围的病理影响 被认为对HSC移植和稳态造血至关重要的生物。具体来说， 研究发现了一个混乱且结构异常的BM新生血管网络，数量增加 高度曲折的小动脉占据了大多数BM腔，以及碎片的正弦血管 充满了红细胞和髓样细胞的聚集体。此外，生产的CXCL12的数量 血管周间充质细胞降低，从而进一步支持有缺陷的造血生态裂市场 SCD小鼠。进一步的研究提供了SCD BM的模型，其中慢速RBC流量和血管封闭 进一步降低生理缺氧BM腔中的局部氧气可用性。这些事件触发了 血管生成环境有利于异常血管生长。值得注意的是，扭曲的新血管网络是 6周的输血完全逆转，突出了血管生态位的可塑性。 其他未发表的初步数据表明，长期（16周）HSC重建 移植到SCD小鼠中受到显着损害。总的来说，这些研究使我们假设 HSPC进入SCD BM的疾病受损是由结构和功能异常引起的 造血血管和/或间充质的生态位；关键血管小众细胞缺陷的纠正将 改善HSPC植入。干细胞动员也可能受到BM利基市场的影响，我们将寻求 了解干细胞如何从BM出口到SCD中的血液。因此提出了三个目标来测试 这些假设：1。定义人源化SCD中分子和细胞水平的SCD小众缺陷 鼠标2。确定哪些利基缺陷通过输血标准化并定义BM小众 患者缺陷；和3。确定BM利基缺陷与HSCP植入受损之间的联系。 总的来说，这些调查将有助于优化有效和长期造血的方法 在治疗疗法的背景下植入。