MT1-MMP Regulates Mesenchymal Stem Cell Fate Decisions

MT1-MMP 调节间充质干细胞的命运决定

• 批准号: 8759604
• 负责人: STEPHEN J WEISS
• 金额: $ 34.21万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8759604
• 关键词: 3-Dimensional; Actomyosin; Adipocytes; Affect; Aging; Architecture; Bone Marrow; Cartilage; Cell Lineage; Cell Nucleus; Cell Shape; Cell physiology; Cells; Chondrocytes; Chromatin; Commit; Competence; Complex; Cues; Cytoplasmic Protein; Cytoskeletal Modeling; Cytoskeleton; Development; Disease; Employee Strikes; Experimental Animal Model; Extracellular Matrix; Growth and Development function; Health; Hematopoiesis; Hereditary Disease; In Vitro; Integrins; Knockout Mice; Lamin Type A; Life; Link; MMP14 gene; Matrix Metalloproteinases; Mechanics; Membrane; Mesenchymal; Mesenchymal Stem Cells; Metabolism; Molecular; Nuclear; Nuclear Lamin; Nuclear Matrix; Nuclear Matrix-Associated Proteins; Nuclear Translocation; Osteoblasts; Outcome; Pathway interactions; Play; Protein Family; Regulation; Research Design; Role; Series; Signal Transduction; Stem cells; Stromal Cells; System; Transcription Coactivator; Transcriptional Regulation; Transgenic Mice; bone; cell type; in vivo; member; novel; postnatal; programs; response; rho; stem; stem cell differentiation; stem cell fate

DESCRIPTION (provided by applicant): From development through postnatal life, a subset of mesenchymal stromal/stem cells (MSCs) found in the bone marrow compartment, display an ability to differentiate into osteoblasts or adipocytes. While altering MSC shape, extracellular matrix (ECM) rigidity or ECM dimensionality in vitro have all been shown to modulate differentiation, the existence - or identity - of MSC-intrinsic effectors capable of regulating thee environmental cues has remained unclear. Recently, we identified the membrane- anchored matrix metalloproteinase, MT1-MMP, as an MSC-intrinsic regulator of stem cell lineage commitment and differentiation - in vitro as well as in vivo (Dev Cell, 25:402-416, 2013). These studies demonstrated that MT1-MMP-dependent remodeling of the ECM initiated a ?1 integrin-Rho/ROCK signaling cascade that controlled the activity of the key MSC transcriptional activators, YAP and TAZ. However, the molecular mechanisms underlying the changes in MSC transcriptional programs remained unexplored. In new studies, we find that MT1-MMP plays a heretofore unexpected role in modulating MSC nuclear architecture, chromatin organization and transcriptional competence. We further establish that the MT1-MMP-dependent transduction of ECM-directed signals to the nucleus requires functional interactions between the cytoskeleton, actomyosin-generated mechanical tension and Klarsicht, ANC-1, Syne homology (KASH) domain-containing cytoplasmic proteins that transmit signals to the lamin A-rich nuclear scaffold via members of the SUN protein family (i.e., the so-called linker of nucleoskeleton and cytoskeleton; LINC complex). These preliminary findings outline a novel MSC mechanotransduction program that links the 3-D ECM to the nuclear compartment and governs MSC lineage commitment and differentiation. Thus, we propose to i) characterize the dynamics of cytoskeletal and nuclear architecture reorganization on MSC transcriptional activity during MT1-MMP- dependent lineage commitment and differentiation, ii) define the role of MT1-MMP-dependent remodeling of the 3-D pericellular ECM as the upstream regulator of MSC nuclear architecture and function via the nesprin-SUN signaling axis and iii) identify the LINC complex/lamin A-YAP/TAZ axis as the dominant mechanotransduction system responsible for linking ECM-derived cues to the nuclear compartment during MSC lineage commitment and differentiation. As virtually all stem cells reside within a dynamically remodeled ECM, we posit that the molecular mechanisms outlined in this proposal will have broad implications for understanding the regulation of stem cell function and lineage commitment in growth and development as well as during aging and in genetic disorders affecting the nuclear scaffolding.

描述（由申请人提供）：从发育到出生后，在骨髓室中发现的间充质基质/干细胞（MSC）子集表现出分化为成骨细胞或脂肪细胞的能力。虽然在体外改变 MSC 形状、细胞外基质 (ECM) 刚性或 ECM 维度都已被证明可以调节分化，但能够调节环境线索的 MSC 内在效应器的存在或身份仍不清楚。最近，我们在体外和体内鉴定出膜锚定基质金属蛋白酶 MT1-MMP 作为干细胞谱系定型和分化的 MSC 内在调节因子（Dev Cell，25：402-416，2013）。这些研究表明，ECM 的 MT1-MMP 依赖性重塑启动了 α1 整合素-Rho/ROCK 信号级联，控制关键 MSC 转录激活因子 YAP 和 TAZ 的活性。然而，MSC 转录程序变化背后的分子机制仍有待探索。在新的研究中，我们发现 MT1-MMP 在调节 MSC 核结构、染色质组织和转录能力方面发挥着迄今为止意想不到的作用。我们进一步确定，ECM 定向信号的 MT1-MMP 依赖性转导需要细胞骨架、肌动球蛋白产生的机械张力和含有 Klarsicht、ANC-1、Syne 同源 (KASH) 结构域的细胞质蛋白之间的功能性相互作用，这些蛋白通过 SUN 蛋白家族的成员将信号传递到富含核纤层蛋白 A 的核支架 （即所谓的核骨架和细胞骨架的连接体；LINC复合物）。这些初步研究结果概述了一种新颖的 MSC 机械转导程序，该程序将 3-D ECM 连接到核区室并控制 MSC 谱系定向和分化。因此，我们建议 i) 表征 MT1-MMP 依赖性谱系定型和分化期间细胞骨架和核结构重组对 MSC 转录活性的动态，ii) 定义 3-D 细胞周 ECM 的 MT1-MMP 依赖性重塑作为 MSC 核结构和功能通过 nesprin-SUN 信号轴的上游调节器的作用，以及 iii) 确定 LINC 复合体/核纤层蛋白 A-YAP/TAZ 轴作为主要的机械转导系统，负责在 MSC 谱系定型和分化过程中将 ECM 衍生信号与核区室连接起来。由于几乎所有干细胞都存在于动态重塑的 ECM 中，因此我们认为该提案中概述的分子机制将对理解干细胞功能的调节和生长和发育以及衰老过程中和影响核支架的遗传性疾病中的谱系承诺具有广泛的影响。