REGULATION OF BONE MARROW MESENCHYMAL STEM CELLS BY VCAM1

VCAM1 对骨髓间充质干细胞的调节

基本信息

项目摘要

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.
摘要 造血干细胞(HSCs)是一种罕见的细胞,存在于骨髓(BM)中, 通过专门的微环境(称为壁龛),其中内皮细胞,基质细胞和其他造血细胞 合成调节HSC功能的重要小生境因子。间充质干细胞(MSC)是一种重要的 BM niche的组成部分。这些罕见的非造血血管周围基质细胞的特征在于它们的 独特的自我更新和分化成骨骼,软骨和脂肪的能力,确保骨骼正常发育 和维护骨髓间充质干细胞形成专门的小生境,通过分泌高水平的小生境来调节HSC的功能。 因子如CXC-趋化因子配体12(CXCL 12)、干细胞因子(SCF)和血管细胞粘附因子(VCAM)。 分子-1(VCAM 1)。VCAM 1典型地表达于内皮细胞和基质细胞上,在这些细胞中,它充当血管内皮细胞和基质细胞的调节剂。 粘附分子,其优先结合HSC和祖细胞上的α4β1整联蛋白。删除Vcam 1, 内皮细胞和造血细胞诱导HSC和祖细胞(HSPC)动员到外周血中, 血液,而不影响内皮细胞(EC)的稳态。然而,虽然内皮源性 VCAM 1对BM的稳态已经被广泛研究,MSC衍生的VCAM 1对HSC和造血干细胞的特异性作用已经被证实。 对MSC维持和多系潜能的影响仍然未知。我们的支持数据表明,MSC是 BM的VCAM 1的主要来源,并表明VCAM 1是维持,生存和功能的关键 的MSC。由于MSC是HSC功能的重要调节者,并且对于骨骼和BM基质是必需的, 因此,了解MSC来源的Vcam 1缺失对MSC的形成和维持的影响程度至关重要。 MSC和造血稳态。基于我们的支持数据,我假设MSC衍生的VCAM 1 表达对于MSC维持和小生境功能是关键的。该项目的总体目标是 阐明VCAM 1促进MSC存活和调节HSPC功能的机制。总的来说, 我们的建议将为VCAM 1作为MSC的新调节剂提供机制证据。虽然关键的 HSC维持和分化的调节因子已被深入研究,BM niche MSC的调节因子仍在研究中。 仍然在很大程度上未知。我们的研究不仅有助于我们理解MSC,而且有助于我们理解其作用机制。 包括HSC维持,以最终帮助改善造血系统疾病的治疗。

项目成果

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Anna Marisa Di Staulo的其他文献

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