Role of Mechanical Loading and Stem Cell Mechanotransduction in Tendon Degeneration
机械负荷和干细胞力转导在肌腱退变中的作用
基本信息
- 批准号:9320001
- 负责人:
- 金额:$ 0.96万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-07-01 至 2017-08-14
- 项目状态:已结题
- 来源:
- 关键词:ActinsAffectBiophysicsCalciumCalcium SignalingCell LineageCell NucleusCellsCollagen FibrilDataDegenerative DisorderDepositionDisciplineFailureFatigueFatty acid glycerol estersFocal AdhesionsGene ExpressionImpairmentIn SituIn VitroLeadLearningMeasuresMechanicsMediatingMentorsMesenchymal Stem CellsMetaplasiaModelingMolecular BiologyMusculoskeletal DiseasesNuclearPathway interactionsPersistent painPhenotypeProcessPropertyResearchResearch PersonnelRoleSignal TransductionStem cellsStimulusStretchingSystemTechniquesTendinopathyTendon structureTherapeuticTissuesTrainingWeight-Bearing stateWorkcartilaginouscell behaviorcell typeexperienceinhibitor/antagonistmechanical forcemechanical loadmechanotransductionnovelpreventresponsestem cell biologystem cell differentiationstem cell fatestem cell nichetissue culturetissue degenerationtransmission process
项目摘要
Abstract
Tendinopathy is a progressive degenerative disease that accounts for 20-30% of all musculoskeletal
disorders and results in impaired tendon function and persistent pain. A primary cause of tendon degeneration
is overuse (i.e., fatigue loading), which produces repeated microscale mechanical damage leading to the
breakdown of load-bearing collagen fibrils. Furthermore, tendon degeneration is characterized by the
accumulation of atypical tissue components (e.g., cartilaginous, fat, and calcium deposits), which additionally
requires the synthetic activity of cells with abnormal (i.e., non-tenogenic) phenotypes. Endogenous tendon
stem cells (TSCs) have the capacity to differentiate into multiple cell types and are hypothesized to undergo
non-tenogenic differentiation in response to fatigue loading. Indeed, elevated or prolonged in vitro stretching of
isolated TSCs has been shown to promote non-tenogenic differentiation. However, it is unknown how TSC fate
is regulated by the specific changes in the native tendon microenvironment observed with fatigue loading. First,
the actual in situ strains that cells experience in fatigue-damaged tissue have not been measured. Second,
prior studies have shown that mechanical stretch can activate all non-tenogenic pathways suggesting that
additional biophysical inputs (e.g., tissue stiffness and organization) are required to direct TSC commitment to
a specific lineage. Finally, the intracellular mechanotransduction mechanisms that modulate TSC differentiation
in response to changes in their mechanical microenvironment are unknown. Identifying how mechanical stimuli
alter TSC fate and lead to tendon degeneration will elucidate the underlying cause of tendinopathy and will
inform the discovery of novel treatments to prevent or reverse the degenerative process.
The objective of this proposal is to determine how non-tenogenic TSC differentiation is
regulated by fatigue-induced changes in the tendon mechanical microenvironment and to identify the
mechanotransduction mechanisms that mediate this response. Specifically, this work aims to 1)
determine how in situ microscale tendon mechanics are altered with fatigue loading, 2) isolate the unique
effects of aberrant mechanical stimuli on TSC differentiation, and 3) identify the key mechanotransduction
mechanisms that mediate TSC differentiation. This will be accomplished by measuring the local strains,
stiffness, and organization of the cellular microenvironment in fatigue-damaged tendon using an ex vivo tissue
culture model. To identify how non-tenogenic TSC differentiation is mediated by altered mechanical stimuli
separate from other influences within the TSC niche (e.g., soluble factors), we will stretch isolated TSCs on
substrates with different stiffness and topographies that match the measured in situ biophysical inputs. Finally,
we will use various inhibitors of cytoskeletal tension and intracellular signaling to investigate the
mechanotransduction mechanisms that convert the altered mechanical stimuli to non-tenogenic TSC
differentiation. The findings of this work will identify the mechanisms by which tendon overuse induces non-
tenogenic TSC differentiation and leads to tendon degeneration. Furthermore, the ex vivo tendon fatigue model
provides a platform to evaluate novel treatments aimed at preventing degeneration and restoring tissue
properties. Finally, this research will provide the applicant with the necessary training to become a successful
independent investigator.
摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Spencer Szczesny', 18)}}的其他基金
Colocalization of gene expression and microscale tissue strains in live tendon explants using barcoded biosensors
使用条形码生物传感器对活体肌腱外植体中的基因表达和微型组织菌株进行共定位
- 批准号:
10558584 - 财政年份:2022
- 资助金额:
$ 0.96万 - 项目类别:
Colocalization of gene expression and microscale tissue strains in live tendon explants using barcoded biosensors
使用条形码生物传感器对活体肌腱外植体中的基因表达和微型组织菌株进行共定位
- 批准号:
10373315 - 财政年份:2022
- 资助金额:
$ 0.96万 - 项目类别:
Studying Mechanotransduction in Late Embryonic Development to Inform Tendon Tissue Engineering
研究胚胎发育晚期的力转导为肌腱组织工程提供信息
- 批准号:
9808374 - 财政年份:2019
- 资助金额:
$ 0.96万 - 项目类别:
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