Bone Marrow Niche dysfunction in sickle cell disease

镰状细胞病的骨髓生态位功能障碍

• 批准号: 9927706
• 负责人: Nadia Carlesso
• 金额: $ 34.6万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9927706
• 关键词: Abnormal Hemoglobins; Acute; Acute Pain; Affect; African American; Age; Allogenic; American; Anemia; Animal Model; Aspirate substance; Autologous; Biological Assay; Biology; Birth; Blood flow; Bone Marrow; Bone Marrow Diseases; Bone Marrow Transplantation; Bone marrow biopsy; Bone remodeling; CD34 gene; Cell physiology; Cells; Cessation of life; Chronic; Cities; Clinical Trials; Coagulation Process; Complex; Development; Disease; Disease-Free Survival; Dissection; Endothelial Cells; Endothelium; Engineering; Engraftment; Enrollment; Erythrocytes; Event; Evolution; Exposure to; Fetal Hemoglobin; Flow Cytometry; Frequencies; Functional disorder; Gene-Modified; Genes; Globin; Hematological Disease; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hemoglobin; Hemolysis; Hispanics; Human; Immune; Immunohistochemistry; Impairment; In Vitro; Incidence; Individual; Infection; Inflammation; Inflammatory; Inherited; Injury; Institution; Intervention; Kidney Failure; Lead; Life Expectancy; Mesenchymal; Mus; Mutation; Myelogenous; NF-kappa B; Natural regeneration; Organ; Organ failure; Outcome; Oxidative Stress; Pain; Pain management; Pathway interactions; Patients; Phase I Clinical Trials; Prevention; Process; Production; Property; Pulmonary Hypertension; Quality of life; Recurrence; Reperfusion Injury; Resolution; Retinal Diseases; Risk; Safety; Sampling; Serum; Siblings; Sickle Cell; Sickle Cell Anemia; Signal Transduction; Specimen; Stress; Stroke; Supportive care; TLR4 gene; Testing; Therapeutic; Therapeutic Intervention; Time; Translations; Transplant Recipients; Transplantation; Up-Regulation; acute chest syndrome; aged; base; chronic pain; comorbidity; curative treatments; cytokine; disease phenotype; experience; fitness; gene correction; gene therapy; graft failure; hematopoietic cell transplantation; hematopoietic stem cell self-renewal; improved; in vivo; insight; nano-string; novel; peripheral blood; polymerization; premature; preservation; programs; reconstitution; sickle vasoocclusion; stem cells; success; transcriptome sequencing

SUMMARY/ABSTRACT Background. Sickle cell disease (SCD) is caused by a single mutation of the -globin gene and is the most common form of inherited blood disorder. In the US, approximately 100,000 of Americans are affected. Patients with SCD suffer from repeated red cell sickling and vaso-occlusion episodes, which, since early age, lead to acute and chronic pain, stroke, anemia, infections, organ failure and premature death. Vaso-occlusion episodes cause ischemia-reperfusion injury, activation of endothelial cells, immune cells and the coagulation cascade. These processes lead to a state of chronic inflammation in SCD, associated with increased pro- inflammatory cytokines, TLR4 activation and oxidative stress in all organs, including the bone marrow (BM). To date, little is known about how inflammation impacts the BM microenvironment and HSC functions in SCD patients. Notably, few and limited studies have been conducted on human samples. Preliminary results. Our previous studies using different animal models have shown that TLR4 activation and upregulation of miR155 and NF-kB signaling during inflammation results in the remodeling of the BM niche, myeloid lineage skewing and loss of hematopoietic stem cell self-renewal. Preliminary results that we obtained in SCD patient samples enrolled in a HSC transplantation (HSCT) clinical trial at City of Hope demonstrated a decrease in frequency and number of CD34+ progenitor cells, decreased ability to generate colonies and increased miR155 and NF-kB signaling in SCD BM-derived mesenchymal cells (MSC). Hypothesis. We hypothesize that SCD-induced chronic inflammation remodels the BM niche and impairs HSC function in SCD patients, and that these changes impact the engraftment of donor HSC during transplant. Aims and Strategy. This study will be conducted on BM specimens of SCD patients (n=21) prior HSCT and at day +15, +30 and +1yr after HSCT. Characterization of the cellular components and inflammatory pathways will be carried on BM biopsies and aspirates by using complementary approaches such as multiparametric flow cytometry analysis, immunohistochemistry and nanostring assays; CD34+ cells will be isolated at baseline, used for RNA-seq and tested for colony-forming assay and ability to engraft NSG mice in vivo; BM and peripheral blood serum will be probed for inflammatory cytokines; MSC will be BM derived in vitro and analyzed characterization and persistence of the inflammatory signature. Results will be correlated with HSCT outcomes. Aged matched healthy donors will be used as controls. Relevance. This study represents a unique opportunity to better understand the biology of SCD in human specimens. Important, the dissection of the mechanisms involved in BM niche dysfunction and inflammatory state in severe SCD should offer avenues for therapeutic intervention to improve engraftment and hematopoietic reconstitution in patients with SCD.

摘要/文摘