REGULATION OF BONE MARROW MESENCHYMAL STEM CELLS BY VCAM1

摘要 造血干细胞(HSCs)是一种罕见的细胞，存在于维持它们的骨髓(BM)中 由内皮细胞、基质细胞和其他造血细胞所处的特殊微环境(称为生态位) 合成调节HSC功能的重要生态位因子。间充质干细胞(MSCs)是必不可少的 BM利基市场的组成部分。这些罕见的非造血血管周围基质细胞的特征是 独特的自我更新和分化为骨骼、软骨和脂肪的能力，确保骨骼的正常发育 和维护。骨髓间充质干细胞形成专门的利基细胞，通过分泌高水平的利基细胞来调节HSC的功能 CXC-趋化因子配体12(CXCL12)、干细胞因子(SCF)和血管细胞黏附等因子 分子-1(VCAM1)。VCAM1在血管内皮细胞和间质细胞上经典地表达，在那里它扮演着一个 一种黏附分子，优先与造血干细胞和祖细胞上的α4β1整合素结合。删除中的Vcam1 内皮细胞和造血细胞诱导造血干细胞和祖细胞(HSPC)外周动员 在不影响内皮细胞(EC)动态平衡的情况下释放血液。然而，虽然内皮细胞衍生的贡献 VCAM1到BM的动态平衡已被广泛研究，MSC来源的VCAM1在HSC和HSC中的特异性作用 关于骨髓间充质干细胞的维持和多血统能力，目前尚不清楚。我们的支持数据表明，MSCs BM是Vcam1的主要来源，提示VCAM1对维持、生存和功能至关重要 骨髓间充质干细胞。由于MSCs是HSC功能的重要调节者，对骨骼和骨髓基质是必不可少的 形成和维持，关键是要了解MSC衍生的Vcam1缺失影响的程度 间充质干细胞与造血动态平衡。根据我们的支持数据，我假设MSC衍生的VCAM1 表达对骨髓间充质干细胞的维持和定位功能至关重要。这个项目的总体目标是 阐明VCAM1促进MSC存活和调节HSPC功能的机制。总而言之， 我们的提议将为VCAM1作为一种新的MSCs调节因子提供机制证据。虽然关键是 骨髓间充质干细胞维持和分化的调控因子已被广泛研究，但骨髓间充质干细胞的维持和分化调控机制仍处于研究阶段 在很大程度上仍然不为人知。我们的研究不仅有助于我们对MSCs的理解，还将有助于我们了解MSCs的机制 包括造血干细胞的维持，以最终帮助改善血液系统疾病的治疗。

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.