Skin Stem Cells: Purification and Characterization
皮肤干细胞:纯化和表征
基本信息
- 批准号:7730441
- 负责人:
- 金额:$ 38.03万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-02-26 至 2014-04-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAdvanced Malignant NeoplasmAgeAgingAging-Related ProcessBasal CellBehaviorBiologicalBiological AssayBlindnessBody SurfaceBurn injuryCancerousCell Culture TechniquesCell CycleCell LineageCell SurvivalCell physiologyCellsCharacteristicsClinicalCorneaCultured CellsDataEmbryoEmbryonic DevelopmentEngineeringEpidermisEpithelialEpitheliumExhibitsFundingGene ExpressionGenesGeneticGrantGrowthHairHair follicle structureHomeostasisHumanIn Situ HybridizationIn VitroInjuryLabelLacZ GenesLearningMaintenanceMeasuresModelingMolecularMonitorMorphogenesisMusNatural regenerationNeonatalNormal tissue morphologyOperative Surgical ProceduresPathway interactionsPhysiologic pulsePhysiologicalPopulationProductionPropertyRegenerative MedicineRelative (related person)ResearchResting PhaseRodentSebaceous GlandsSkinSkin TransplantationSkin graftStagingStem Cell DevelopmentStem cellsStratum BasaleTestingTimeTissuesUndifferentiatedValidationWound Healingadult stem cellage relatedbasecancer therapyclinical applicationcomparativeepidermis cellgene therapyin vitro Assayin vivoinsightkeratinocytemouse genomeprogenitorprogramspublic health relevanceregenerativeregenerative therapyrepairedresponse to injuryself-renewalsmall hairpin RNAstem cell nichestem cell populationstemnesstissue regenerationtranscription factor
项目摘要
DESCRIPTION (provided by applicant): Stem cells (SCs) are natural units of tissue repair and homeostasis. Their versatility holds promise for tissue regeneration, particularly for less controversial adult SCs. Adult epithelial SCs of the skin reside within the innermost (basal) layer of the interfollicular epidermis (IFE) as well as the bulge, a niche located within the hair follicle (HF). Basal IFE SCs function in normal homeostasis to form the stratified epithelial barrier of terminally differentiated cells that are constantly shed from the body surface. HF-SCs function in homeostasis to fuel hair growth and the cyclical bouts of regeneration and degeneration of the HF. During injury, HF-SCs participate with basal IFE SCs to repair damaged epidermis and sebaceous glands. Both basal IFE SCs and HF-SCs can be cultured and propagated long-term outside their native niches under conditions where their stemlike features are retained. This remarkable feature of keratinocyte SCs renders them fundamentally important to a range of clinical applications and issues, ranging from gene therapy to burn operations, hair replacement and treatment of blindness arising from corneal degeneration. In the past grant period, we developed a strategy for marking & purifying the slow-cycling populations of adult murine SCs from their natural niches. In the last period, we focused on HF label retaining cells (LRCs), showing that they possess properties of SCs and undergo self-renewal, replenish HFs during cycling, and repair both sebaceous glands and IFE in response to injury/loss of their resident progenitors. We showed that HF-SCs express a group of transcription factors-- Sox9, Lhx2, NFATc1 & Tcf3/4--which basal IFE SCs do not, and we used these markers to trace the origins of HF-SCs to embryogenesis. We also showed that Sox9 not only marks these early SCs but also is essential for their maintenance as HF-SCs both in vivo and in vitro. We also showed that in contrast to adult HF-SCs, which only transiently repair epidermal wounds, neonatal HF-SCs provide robust and long-term wound repair. This is particularly intriguing in that during aging, the resting phase of HFs increases, and the IFE becomes thinner and loses proliferative potential. Our newfound ability to track and monitor SCs over time now affords a segue into exploring the molecular basis for the age-related decline in SC potential. In addition, our findings raise the following key questions: (1). What are the molecular differences between neonatal and adult HF-SCs and how can they explain mechanistically the biological differences in HF-SCs that occur during aging? (2) Are the adult SCs within the IFE basal layer also slow-cycling as postulated 3 decades ago, or are these cells a reflection of the aging process? What are the molecular characteristics of basal IFE cells and what are their embryonic origins? How do basal IFE SCs differ from HF-SCs and are these differences reflected in different potentials for tissue regeneration and long-term self-renewal? (3) Are the differences that define basal IFE and HF-SCs intrinsic or extrinsic? Both neonatal SC populations can be cultured and propagated in vitro--do they maintain their molecular and tissue regenerative differences in vitro or do the cultured cells converge upon a common program of gene expression and tissue regenerative potential? (4) Of the 1% of the mouse genome whose expression is preferentially up/downregulated in HF-SCs or basal IFE SCs in vivo and in vitro, which are the genes that are functionally important to these features of SCs? What genes regulate self-renewal and/or long term potential? What maintains SCs in their undifferentiated state? Can we exploit the information gained by optimizing the ability of skin epithelial SCs to be maintained long term in culture without losing features of their stemness? By addressing these issues, we expect to uncover new insights into understanding how skin SCs possess and maintain their proliferative/tissue regenerative potential and are kept in an undifferentiated state until mobilized to generate tissue. This research is prerequisite to ascertaining the potential of skin SCs for regenerative therapies that go beyond burn treatments. PUBLIC HEALTH RELEVANCE: Stem cells are natural units of tissue repair and homeostasis, and their versatility holds promise for tissue regeneration. This research focuses on deciphering the properties of embryonic and adult skin stem cells that exist within the basal layer of the epidermis and the bulge of the hair follicle. We will focus on delineating the intrinsic mechanisms that render skin SCs their ability to self-renew in vitro and in vivo and to select one of three differentiation pathways: epidermis, hair follicle and sebaceous gland. This study is a fundamental prerequisite to ascertaining the potential of skin stem cells for regenerative therapies that go beyond burn treatments.
描述(由申请人提供):干细胞(SC)是组织修复和体内平衡的天然单位。它们的多功能性为组织再生带来了希望,特别是对于争议较少的成人干细胞。皮肤的成体上皮 SC 位于毛囊间表皮 (IFE) 的最内(基底)层以及位于毛囊 (HF) 内的凸起处。基础 IFE SC 在正常稳态中发挥作用,形成终末分化细胞的分层上皮屏障,这些细胞不断从体表脱落。 HF-SCs 在体内平衡中发挥作用,促进毛发生长以及 HF 再生和退化的周期性发作。损伤期间,HF-SC 与基础 IFE SC 一起修复受损的表皮和皮脂腺。基础 IFE SC 和 HF-SC 都可以在保留其茎状特征的条件下在其原生生态位之外长期培养和繁殖。角质形成细胞 SC 的这一显着特征使其对于一系列临床应用和问题至关重要,从基因治疗到烧伤手术、毛发替换和角膜变性引起的失明治疗。在过去的资助期内,我们制定了一项策略,用于标记和纯化成年小鼠 SC 的自然生态位中的慢循环种群。在上一期中,我们重点研究了 HF 标记保留细胞(LRC),表明它们具有 SC 的特性并进行自我更新,在循环过程中补充 HF,并修复皮脂腺和 IFE 以应对其居民的损伤/损失祖先。我们发现 HF-SC 表达一组转录因子——Sox9、Lhx2、NFATc1 和 Tcf3/4——而基础 IFE SC 则不表达,并且我们使用这些标记来追踪 HF-SC 到胚胎发生的起源。我们还表明,Sox9 不仅标记这些早期 SC,而且对于它们在体内和体外维持为 HF-SC 至关重要。我们还表明,与仅短暂修复表皮伤口的成人 HF-SC 相比,新生儿 HF-SC 提供强大且长期的伤口修复。这是特别有趣的,因为在衰老过程中,HF 的静息期增加,IFE 变得更薄并失去增殖潜力。我们新发现的随着时间的推移跟踪和监测 SC 的能力现在可以继续探索与年龄相关的 SC 潜力下降的分子基础。此外,我们的研究结果提出了以下关键问题:(1)。新生儿和成人 HF-SC 之间的分子差异是什么?它们如何从机制上解释衰老过程中发生的 HF-SC 的生物学差异? (2) IFE基底层内的成体SC是否也像30年前假设的那样缓慢循环,或者这些细胞是衰老过程的反映?基础 IFE 细胞的分子特征是什么?它们的胚胎起源是什么?基础 IFE SC 与 HF-SC 有何不同?这些差异是否反映在组织再生和长期自我更新的不同潜力上? (3) 定义基础 IFE 和 HF-SC 的差异是内在的还是外在的?两种新生儿 SC 群体都可以在体外培养和繁殖——它们在体外是否保持其分子和组织再生差异,或者培养的细胞是否会趋于基因表达和组织再生潜力的共同程序? (4) 在体内和体外 HF-SC 或基础 IFE SC 中表达优先上调/下调的 1% 小鼠基因组中,哪些基因对 SC 的这些特征具有重要的功能?哪些基因调节自我更新和/或长期潜力?是什么使 SC 保持未分化状态?我们能否利用通过优化皮肤上皮干细胞在培养物中长期维持的能力而获得的信息而不失去其干性特征?通过解决这些问题,我们希望能够揭示新的见解,以了解皮肤干细胞如何拥有和维持其增殖/组织再生潜力,并保持未分化状态直至动员生成组织。这项研究是确定皮肤干细胞在烧伤治疗之外的再生疗法中的潜力的先决条件。公共健康相关性:干细胞是组织修复和体内平衡的天然单位,其多功能性为组织再生带来了希望。这项研究的重点是破译存在于表皮基底层和毛囊凸起内的胚胎和成人皮肤干细胞的特性。我们将重点描述使皮肤 SC 具有体外和体内自我更新能力的内在机制,并选择三种分化途径之一:表皮、毛囊和皮脂腺。这项研究是确定皮肤干细胞在烧伤治疗之外的再生疗法中的潜力的基本先决条件。
项目成果
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ELAINE FUCHS其他文献
ELAINE FUCHS的其他文献
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{{ truncateString('ELAINE FUCHS', 18)}}的其他基金
Cell adhesion and cytoskeletal dynamics in skin
皮肤中的细胞粘附和细胞骨架动力学
- 批准号:
7929089 - 财政年份:2009
- 资助金额:
$ 38.03万 - 项目类别:
Skin Stem Cells: Purification and Characterization
皮肤干细胞:纯化和表征
- 批准号:
6861129 - 财政年份:2004
- 资助金额:
$ 38.03万 - 项目类别:
Skin Stem Cells: Purification and Characterization
皮肤干细胞:纯化和表征
- 批准号:
9257282 - 财政年份:2004
- 资助金额:
$ 38.03万 - 项目类别:
Skin Stem Cells: Purification and Characterization
皮肤干细胞:纯化和表征
- 批准号:
10407470 - 财政年份:2004
- 资助金额:
$ 38.03万 - 项目类别:
Skin Stem Cells: Purification and Characterization
皮肤干细胞:纯化和表征
- 批准号:
8257868 - 财政年份:2004
- 资助金额:
$ 38.03万 - 项目类别:
Skin Stem Cells: Purification and Characterization
皮肤干细胞:纯化和表征
- 批准号:
7348400 - 财政年份:2004
- 资助金额:
$ 38.03万 - 项目类别:
Skin Stem Cells: Purification and Characterization
皮肤干细胞:纯化和表征
- 批准号:
8067023 - 财政年份:2004
- 资助金额:
$ 38.03万 - 项目类别:
Skin Stem Cells: Purification and Characterization
皮肤干细胞:纯化和表征
- 批准号:
8257868 - 财政年份:2004
- 资助金额:
$ 38.03万 - 项目类别:
Skin Stem Cells: Purification and Characterization
皮肤干细胞:纯化和表征
- 批准号:
7876797 - 财政年份:2004
- 资助金额:
$ 38.03万 - 项目类别:
Skin Stem Cells: Purification and Characterization
皮肤干细胞:纯化和表征
- 批准号:
8628335 - 财政年份:2004
- 资助金额:
$ 38.03万 - 项目类别:
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