Cholesterol Sensitivity and Mechanisms of MSC Responses to 3D Substrate Rigidity
胆固醇敏感性和 MSC 对 3D 基质刚性的响应机制
基本信息
- 批准号:9040162
- 负责人:
- 金额:$ 33.85万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-04-01 至 2019-03-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAdherenceAdhesionsAdhesivesAdoptedAdultAffectAtomic Force MicroscopyAttentionBehaviorBiologicalBiological AssayBone MarrowBrainCaveolaeCell AdhesionCell Differentiation processCell FractionationCell ShapeCell membraneCellsCellular MorphologyCharacteristicsCholesterolCholesterol HomeostasisCytoskeletal ModelingElectron MicroscopyEndocytosisEventF-ActinFlow CytometryFluorescence PolarizationFocal AdhesionsFutureGelatinGene ExpressionGoalsHealthHomeostasisHumanHyaluronanHydrogelsImmunofluorescence ImmunologicIntegrinsKnowledgeLigandsMechanicsMediatingMembraneMembrane FluidityMembrane MicrodomainsMesenchymal Stem CellsMorphologyNeuronsOsteoblastsOsteocalcinOsteogenesisOutcomePathway interactionsPharmaceutical PreparationsPhenotypePopulationPropertyProteinsReverse Transcriptase Polymerase Chain ReactionRoleRuptureSeedsShapesSignal PathwaySignal TransductionSmall Interfering RNASucroseSupplementationSuspension substanceSuspensionsSystemTestingTimeTissue EngineeringTissuesWestern Blottingbasecaveolin 1cell behaviorchemical propertydesignethylene dimethacrylatein vivoinhibitor/antagonistknock-downosteogenicphysical propertyregenerative therapyresponsescaffoldsoft tissuestem cell differentiationtissue regeneration
项目摘要
ABSTRACT
We propose a mechanistic study of the biological responses of adult human bone marrow-derived
mesenchymal stem cells (MSCs) to 3D substrate rigidity using hydrogel scaffolds of photocrosslink-controllable
stiffness. Specifically, our focus is on the role of membrane cholesterol and caveolae subdomains, and focal
adhesion signaling in these responses. The responses of MSCs to substrate rigidity, particularly in a 3D
context, represent an important regulatory mechanism of their biological activities, of particular relevance to
their application in tissue engineering and regeneration. We postulate here that these responses involve
integrin-mediated focal adhesion signaling, and are potentially sensitive to cellular cholesterol homeostasis.
We therefore propose to analyze the effects of the cholesterol/Caveolin-1 (Cav-1)/caveolae membrane system,
which is known to regulate focal adhesion signaling, on MSC substrate rigidity responses, with special
attention to differentiation. Information on the effects of this system on MSC behavior may be important in a
wider context, if it is affected in vivo by cholesterol-modifying drugs, which are widely clinically prescribed and
thus may influence outcomes of regenerative therapies.
We hypothesize that elevated cell membrane levels of cholesterol/Cav-1/caveolae decrease MSC
sensitivity to substrate stiffness through increasing integrin endocytosis and decreasing focal
adhesion signaling. To test our hypothesis, we propose three specific aims in which we will use cholesterol
depletion, cholesterol supplementation, Cav-1 knockdown, and pharmacological inhibitors, to study the roles of
MSC membrane cholesterol, Cav-1, caveolae, and focal adhesion signaling in MSC rigidity sensing in our 3D
experimental platform. AIM 1: Test the effects of perturbations in cholesterol/Cav-1/caveolae homeostasis on
MSC membrane properties and adhesive characteristics. This will verify that manipulation of cholesterol/Cav-
1/caveolae impacts aspects of the MSC cell membrane important to substrate sensing, including integrin
expression, activation and internalization, and the strength of cell adhesion to defined substrates. AIM 2: Test
the responses of MSCs with and without perturbations in cellular cholesterol/Cav-1/caveolae homeostasis to
varied stiffness in a 3D context. This will determine how MSCs respond to varied substrate rigidity in 3D, in
terms of their morphology, substrate adhesion, cytoskeletal organization, and differentiation, and if
manipulation of cholesterol/Cav-1/caveolae affects these responses. AIM 3: Test the activity of integrin-
activated focal adhesion signaling pathways in MSCs within soft and stiff 3D substrates, and the regulatory
effects of cholesterol/Cav-1/caveolae on focal adhesion signaling and downstream differentiation as influenced
by soft and stiff 3D scaffolds. This will determine if focal adhesion signaling is involved in MSC substrate
rigidity responses, and if such involvement is affected by cholesterol/Cav-1/caveolae.
摘要
项目成果
期刊论文数量(0)
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Regenerative Enhancement of Aged Chondrocytes via Cytoskeletal Modulation
通过细胞骨架调节增强老化软骨细胞的再生
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- 资助金额:
$ 33.85万 - 项目类别:
Cholesterol Sensitivity and Mechanisms of MSC Responses to 3D Substrate Rigidity
胆固醇敏感性和 MSC 对 3D 基质刚性的响应机制
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