REGULATION OF BONE MARROW MESENCHYMAL STEM CELLS BY VCAM1

VCAM1 对骨髓间充质干细胞的调节

• 批准号: 10537391
• 负责人: Anna Marisa Di Staulo
• 金额: $ 4.05万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10537391
• 关键词: Adult; Affect; Aging; Binding; Biological Assay; Blocking Antibodies; Blood; Blood Cells; Blood Vessels; Bone Marrow; Bone Marrow Transplantation; Bone Regeneration; CXC Chemokines; Cartilage; Cell Adhesion Molecules; Cell Count; Cell Cycle; Cell Differentiation process; Cell Lineage; Cell Maintenance; Cell physiology; Cells; Complex; Confocal Microscopy; Data; Disease; Endothelial Cells; Endothelium; Ensure; Exhibits; Fatty acid glycerol esters; Flow Cytometry; Fluorouracil; Frequencies; Genetic Models; Grouping; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Mobilization; Hematopoietic stem cells; Homeostasis; Homing; Human; In Vitro; Integrin alpha4beta1; Integrins; Leukemic Cell; Ligands; Maintenance; Mediating; Mesenchymal Stem Cells; Mus; N-Cadherin; Organism; Pathway interactions; Phenotype; Predisposition; Regenerative capacity; Role; Sampling; Series; Signal Transduction; Skeletal Development; Skeleton; Source; Spatial Distribution; Spleen; Stains; Stem Cell Factor; Sternum; Stress; Stromal Cells; Structure; Tamoxifen; Testing; Transgenic Mice; Vascular Cell Adhesion Molecule-1; X-Ray Computed Tomography; base; bone; bone marrow mesenchymal stem cell; ezrin; genotoxicity; hematopoietic stem cell niche; hematopoietic stem cell quiescence; improved; innate immune function; innovation; irradiation; microCT; mouse model; novel; peripheral blood; progenitor; receptor; regeneration potential; self-renewal; single-cell RNA sequencing; stem cell function; stem cell niche; stem cell survival; stem cells; transcriptome sequencing

ABSTRACT Hematopoietic stem cells (HSCs) are rare cells that reside in the bone marrow (BM) where they are maintained by specialized microenvironments (termed niches) in which endothelial, stromal, and other hematopoietic cells synthesize important niche factors that regulate HSC function. Mesenchymal stem cells (MSCs) are an essential component of the BM niche. These rare non-hematopoietic perivascular stromal cells are characterized by their unique ability to self-renew and differentiate into bone, cartilage, and fat, ensuring proper skeletal development and maintenance. BM MSCs form specialized niches that regulate HSC function by secreting high levels of niche factors such as CXC-chemokine ligand 12 (CXCL12), stem cell factor (SCF), and Vascular Cell Adhesion Molecule-1 (VCAM1). VCAM1 is classically expressed on endothelial and stromal cells where it acts as an adhesion molecule that preferentially binds to α4β1 integrin on HSCs and progenitors. Deletion of Vcam1 in endothelial and hematopoietic cells induces HSC and progenitor cell (HSPC) mobilization into the peripheral blood without affecting endothelial cell (EC) homeostasis. However, while the contribution of endothelial-derived VCAM1 to BM homeostasis has been extensively studied, the specific role of MSC-derived VCAM1 on HSC and on MSC maintenance and multilineage potency remains unknown. Our supporting data indicates that MSCs are the BM’s main source of Vcam1 and suggests that VCAM1 is critical for the maintenance, survival, and function of MSCs. Since MSCs are important regulators of HSC function and essential for skeleton and BM stroma formation and maintenance, it is critical to understand the extent at which MSC-derived Vcam1 deletion impacts MSCs and hematopoietic homeostasis. Based on our supporting data, I hypothesize that MSC-derived VCAM1 expression is critical for MSC maintenance and niche functions. The overall aims of this project are to elucidate the mechanisms by which VCAM1 promotes MSC survival and regulates HSPC function. Altogether, our proposal will provide mechanistic evidence for VCAM1 as a novel regulator of MSCs. While the critical regulators of HSC maintenance and differentiation have been intensively studied, that of BM niche MSCs still remain largely unknown. Our studies will not only aid in our understanding of MSCs but also the mechanisms encompassing HSC maintenance to ultimately help improve treatments for hematopoietic diseases.

抽象的 造血干细胞（HSC）是驻留在骨髓（BM）中的稀有细胞 通过专门的微环境（称为壁ni），其中内皮，基质和其他造血细胞 合成调节HSC功能的重要利基因素。间充质干细胞（MSC）是必不可少的 BM利基市场的组成部分。这些罕见的非脊髓性周围间质细胞的特征是 独特的自我更新和分化为骨骼，软骨和脂肪的能力，以确保适当的骨骼发育 和维护。 BM MSC形成专门的小甲基 诸如CXC-化合物配体12（CXCL12），干细胞因子（SCF）和血管细胞粘附等因素 分子1（VCAM1）。 VCAM1在内皮细胞和基质细胞上经典表达 在HSC和祖细胞上优先与α4β1整合素结合的粘附分子。删除VCAM1在 内皮和造血细胞诱导HSC和祖细胞（HSPC）动员到周围 血液不影响内皮细胞（EC）稳态。但是，虽然内皮衍生的贡献 VCAM1至BM稳态已广泛研究，这是MSC衍生的VCAM1在HSC和 在MSC维护上和多线效力上仍然未知。我们的支持数据表明MSC是 BM的VCAM1的主要来源，并暗示VCAM1对于维护，生存和功能至关重要 MSC。由于MSC是HSC功能的重要调节剂，对于骨骼和BM基质必不可少 形成和维护，了解MSC衍生的VCAM1删除影响的程度至关重要 MSC和造血稳态。根据我们的支持数据，我假设MSC衍生的VCAM1 表达对于MSC维护和利基函数至关重要。该项目的总体目的是 阐明VCAM1促进MSC存活并调节HSPC功能的机制。共， 我们的建议将为VCAM1作为MSC的新调节剂提供机械证据。而关键 HSC维护和差异化的调节剂已被深入研究，BM利基MSC仍然 在很大程度上未知。我们的研究不仅将有助于我们对MSC的理解，还将有助于机制 涵盖HSC维护，最终有助于改善造血疾病的治疗方法。