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）：从发育到产后寿命，在骨髓室中发现的间充质基质/干细胞（MSC）的子集，表现出分化为成骨细胞或脂肪细胞的能力。尽管改变了MSC形状，但在体外的细胞外基质（ECM）刚度或ECM尺寸都被证明可以调节分化，但能够调节环境线索的MSC-内膜效应子的存在或身份尚不清楚。最近，我们将膜锚定的基质金属蛋白酶MT1-MMP确定为干细胞谱系识别和分化的MSC - 内膜调节剂 - 体外和体内（Dev Cell，25：402-416，2013，2013）。这些研究表明，ECM的MT1-MMP依赖性重塑启动了A？1整合蛋白RHO/ROCK信号传导级联，该级联控制了关键MSC转录激活剂YAP和TAZ的活性。但是，MSC转录程序变化的基础机制仍未开发。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起着意外的作用。我们进一步确定，ECM定向信号的MT1-MMP依赖性转导向细胞核需要在细胞骨架，肌动蛋白生成的机械张力和Klarsicht，ANC-1，Syne同源性（KASH）域含有核蛋白与核蛋白与核蛋白质的核定型核蛋白A-licamin A-ramiNAMINE A I I I I I克纳蛋白之间的功能相互作用。 （即，核骨骼和细胞骨架的所谓接头；林克复合物）。这些初步发现概述了一种新型的MSC机械转移计划，该计划将3-D ECM与核舱连接起来，并控制MSC的谱系承诺和分化。因此，我们提出i）表征在MT1-MMP依赖性谱系承诺和差异过程中，在MSC转录活性上重组细胞骨架和核结构的动力学，ii）定义MT1-MMP依赖性依赖于MT1-MMP的作用，是3-D-D-D-D-DCELLEAL ECM的NIDENIDE SCEMSTREAM IIDINED SCERIN和MSSC核架构的概述，并通过MSC核架构的概述，并通过nike sectration sectration and ne ne ne ne ne n. LINC复合物/层层A-YAP/TAZ轴是负责将ECM衍生的线索与MSC谱系承诺和分化过程中的核舱连接起来的主要机械转导系统。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以及在衰老和衰老中以及影响核骨架的遗传性疾病中的调节和谱系承诺具有广泛的影响。