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: 10682593
• 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/10682593
• 关键词: Adopted; Affect; Autologous; Biopsy; Blood; Blood Transfusion; Blood Vessels; Bone Marrow; Bone Marrow Aspiration; Bone Marrow Diseases; Bone Marrow Transplantation; 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; Phenotype; Physiological; Population; Protein Array; Recovery; Regimen; Resolution; Role; Sickle Cell Anemia; Speed; Stress; Stromal Cell-Derived Factor 1; Structural defect; Testing; Therapeutic Intervention; Time; Transfusion; Translating; Transplantation; Vascular Endothelial Growth Factors; angiogenesis; arteriole; burden of illness; cell type; chemokine; comparison control; curative treatments; endothelial dysfunction; gene correction; hematopoietic engraftment; improved; insight; mortality; neovascular; novel; novel strategies; pharmacologic; 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.

项目概要 迄今为止，镰状细胞病 (SCD) 的唯一治疗选择是同种异体 HSC 移植。最近， 利用基因校正的自体 HSC 进行的临床试验已经启动，并且前景广阔。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 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态位。具体来说， 研究发现，骨髓新生血管网络杂乱且结构异常，其数量增加 高度曲折的小动脉占据了大部分骨髓腔，以及破碎的正弦血管 充满红细胞和骨髓细胞的聚集体。此外，生产CXCL12的数量 血管周围间充质生态位细胞减少，从而进一步支持有缺陷的造血生态位 SCD小鼠。进一步的研究提供了 SCD BM 模型，其中红细胞流动缓慢和血管闭塞 进一步减少生理性缺氧的骨髓腔中局部氧气的可用性。这些事件会触发 血管生成环境有利于异常血管生长。值得注意的是，扭曲的新生血管网络 6周的输血完全逆转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 小鼠体内后会受到显着损害。总的来说，这些研究使我们假设 HSPCs 植入 SCD BM 的受损是由结构和功能异常引起的 造血血管和/或间充质生态位；纠正关键的血管生态位细胞缺陷将 改善 HSPC 植入。干细胞动员也可能受到骨髓生态位的影响，我们将寻求 了解 SCD 中干细胞如何从 BM 进入血液。因此提出了三个目标来测试 这些假设： 1. 在人源化 SCD 的分子和细胞水平上定义 SCD 生态位缺陷 小鼠 2. 确定哪些生态位缺陷可通过输血恢复正常并定义 BM 生态位 患者的缺陷； 3. 确定 BM 生态位缺陷与 HSCP 植入受损之间的联系。 总的来说，这些研究将有助于优化实现高效、长期造血的方法 在治疗性疗法的背景下进行植入。