Pericellular Proteolysis and the Regulation of Bone/Tendon Stem Cell Fate
Pericellular Proteolysis and the Regulation of Bone/Tendon Stem Cell Fate
批准号:
10677552
负责人:
STEPHEN J WEISS
金额:
$43.5万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-08-05 至 2027-05-31
关键词:
AnatomyAnimal ExperimentsAnimal ModelBone MarrowCaspaseCell LineageCell physiologyCellsChondrogenesisCollagenCollagen Type ICytoskeletonDataFamilyGenetic TranscriptionGrowth and Development functionHematopoietic Stem Cell MobilizationIn VitroLigamentsLightLinkMMP14 geneMatrix MetalloproteinasesMembraneMesenchymalMetalloproteasesModelingMolecularOutcomePathologicPathway interactionsPeriosteumPhenotypePhysiologic OssificationPhysiologicalPlayPopulationProteolysisRegulationReportingRoleRouteSeriesSignal PathwaySignal TransductionStromal CellsStructureTendon structureTissuesTransforming Growth Factor betaTransgenic OrganismsTraumaWorkbonecarboxypeptidase Ccathepsin Kdesignin vivointramembranous bone formationmechanotransductionnovelprogramsproteinase Inreceptorskeletal stem cellstemstem cell differentiationstem cell fatestem cell functionstem cell populationstem cellstrafficking
中文摘要
摘要
骨骼和肌腱都含有干细胞群,嵌入在I型胶原丰富的组织中。骨
骨髓和骨内干细胞通过软骨内成骨生成骨,而骨膜干细胞通过骨膜干细胞生成骨
细胞通过膜内途径形成骨。反过来,肌腱干细胞产生肌腱细胞,这些细胞充斥在
成熟的组织。最近的研究发现,半胱氨酸蛋白酶,组织蛋白酶K(CTSK)是一种独特的
骨膜干细胞的标记,我们已经证实了这一发现,但这也导致了我们到目前为止鉴定出
与肌腱相关的未特化的第二干群。在骨髓来源的MSCs中,我们有
先前发现了对膜锚定的金属蛋白酶MT1-MMPs的一种新的需求
调节机械敏感的YAP/TAZ依赖的途径,通过
细胞周围胶原基质的蛋白水解性重塑。相比之下,MT1-MMPs和MT1-MMPs的相对作用
CTSK在骨膜或肌腱/韧带干细胞中的表达尚不清楚。利用CTSK-Cre转基因株系打靶
骨膜干细胞,我们发现单独靶向MT1-MMP在体内引起深刻的骨质疏松状态,而不是
不仅独立于CTSK运作,而且还将干细胞重定向为异常的过度增殖,
软骨化状态。此外,出人意料的是,CTSK-CRE依赖于MT1-MMP的靶向-而不是CTSK,
通过改变以前未描述的肌腱旁干细胞-肌腱运输路线来破坏肌腱/结构。在……里面
体内,MT1-MMP零的肌腱干细胞致力于高增殖,软骨化表型类似于
肌腱/韧带损伤后观察。基于这些新的数据,我们认为MT1-MMPs控制
这些干细胞群中的每一个都通过调节一条机械转导途径不仅控制
YAP/TAZ连接的共转录程序,但也是典型的转铁蛋白β信号通路通过蛋白分解
辅助转化生长因子β受体,转化生长因子βRIII的脱落。总之,这些发现勾勒出了一种新的MSC模式
MT1-基质金属蛋白酶依赖的胶原酶分解和受体脱落共同在
骨膜组织和肌腱。因此,我们提出了三个目标:i)表征MT1-MMPs在调控中的作用
骨膜干细胞在体外和体内的分化和功能,II)确定CTSK肌腱干细胞的新作用
肌腱功能调控中的细胞及其对MT1-MMP3的调节作用
骨膜/旁干细胞YAP/TAZ的机械转导与转化生长因子β/转化生长因子βRIII依赖的分化
程序。总而言之,这些目标应该会为需要MT1-1的特化干细胞家族带来新的曙光。
基质金属蛋白酶依赖的蛋白分解不仅调节膜内骨形成,还调节肌腱
结构/功能也是如此。
英文摘要
ABSTRACT
Bone as well as tendons each contain stem cell populations embedded in type I collagen-rich tissues. Bone
marrow and endosteal-derived stem cells generate bone via endochondral ossification while periosteal stem
cells form bone via the intramembranous route. In turn, tendon stem cells give rise to tenocytes that populate
the mature tissues. Recent studies have identified the cysteine proteinase, cathepsin K (CTSK), as a unique
marker of periosteal stem cells, a finding we have confirmed, but that also led to our identification of a heretofore
uncharacterized second stem population associated with tendons. In bone marrow-derived MSCs, we have
previously identified a novel requirement for the membrane-anchored metalloproteinase, MT1-MMP, in
regulating a mechanosensitive, YAP/TAZ-dependent pathway that controls stem cell lineage commitment via
the proteolytic remodeling of the pericellular collagen matrix. By contrast, the relative roles of MT1-MMP and
CTSK in periosteal or tendon/ligament stem cells are unknown. Using a Ctsk-Cre transgenic line to target
periosteal stem cells, we find that Mt1-mmp targeting alone elicits a profound osteopenic state in vivo that not
only operates independently of Ctsk, but also redirects the stem cells to an aberrant hyperproliferative,
chondrogenic state. Further, and unexpectedly, Ctsk-Cre–dependent targeting of MT1-MMP - but not Ctsk,
disrupts tendon/ structure by altering a previously undescribed paratenon stem cell-tendon trafficking route. In
vivo, MT1-MMP-null tendon stem cells commit to a hyperproliferative, chondrogenic phenotype similar to that
observed following tendon/ligament trauma. Based on these new data, we propose that MT1-MMP controls
each of these stem cell populations by regulating a mechanotransduction pathway that not only controls
YAP/TAZ-linked co-transcriptional programs, but also canonical TFGβ signaling pathways via the proteolytic
shedding of the accessory TGFβ receptor, TGFβRIII. Together, these findings outline a new model of MSC
function wherein MT1-MMP-dependent collagenolysis and receptor shedding together play a required role in
periosteal tissues and tendons. As such, we propose 3 aims; i) characterize the role of MT1-MMP in regulating
periosteal stem cell differentiation and function in vitro and in vivo, ii) define a novel role for Ctsk+ tendon stem
cells in controlling tendon function and its regulation by MT1-MMP and iii) delineate the impact of MT1-MMP on
periosteal/paratenon stem cell YAP/TAZ mechanotransduction and TGFβ/TGFβRIII- dependent differentiation
programs. Together, these aims should cast new light on a family of specialized stem cells that require MT1-
MMP-dependent proteolysis to not only regulate intramembranous bone formation, but also tendon
structure/function as well.
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