Reversing Epidermal Stem Cell Aging: Role of Bmi-1 and the Stem Cell Niche

逆转表皮干细胞衰老：Bmi-1 和干细胞生态位的作用

• 批准号: 7990454
• 负责人: RUBY GHADIALLY
• 金额: $ 20.01万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-10 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7990454
• 关键词: Abbreviations; Age; Aging; B-Cell Lymphomas; B-Lymphocytes; Biological Assay; Cell Aging; Cell Cycle; Cells; Contusions; DNA Methylation; Decubitus ulcer; Dermal; Elderly; Environment; Environmental Risk Factor; Epidermis; Epigenetic Process; Fibroblasts; Frequencies; Gene Expression; Goals; Healed; Homeostasis; Impaired wound healing; Individual; Infectious Skin Diseases; Intrinsic factor; Knockout Mice; Knowledge; Lead; Leg Ulcer; Maintenance; Methods; Moloney Leukemia Virus; Morbidity - disease rate; Mus; Muscle satellite cell; Phenotype; Polycomb; Predisposition; Premature aging syndrome; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Rodent; Role; Skeletal Muscle; Skin; Skin Tissue; Stem cells; Suppressor Genes; Surgical wound; Tissue Engineering; Transcript; Transplantation; Wound Healing; age related; aged; cell age; healing; improved; in vivo; keratinocyte; member; mortality; normal aging; overexpression; premature; prevent; progenitor; public health relevance; self-renewal; senescence; stem cell differentiation; stem cell division; stem cell niche

DESCRIPTION (provided by applicant): Impaired wound healing, susceptibility to skin breakdown and skin fragility lead to skin infections and considerable morbidity and mortality in the US. Our recent study shows that while no significant difference in epidermal stem cell frequency could be detected with aging, the proliferative capacity of individual epidermal stem cells was reduced. Also, transit amplifying cell frequency was greater in the aged, cell cycle duration was increased, and premature progenitor differentiation was observed. Our HYPOTHESIS is that Bmi-1 has a key role in the altered differentiation, proliferation, and symmetric divisions of aged EpiSCs and that intrinsic (Bmi-1) and/or extrinsic (niche) alterations can partially or completely restore the alterations in Bmi-1 expression, differentiation, proliferation, and symmetric division. The long-term goal of this project is to understand the mechanisms that underlie the alterations in epidermal stem cells and their niche with aging. This knowledge will be used to improve wound healing in the aged and for tissue engineering applications. SPECIFIC AIMS: In this proposal we will study the roles of both intrinsic (Bmi-1/p16) and extrinsic/environmental influences on epidermal stem cell aging. In Aim 1 we will optimize and complete our assay of the differences between aged and young EpiSCs and then investigate whether the epidermal stem cells of Bmi-1 knockout mice show a premature aging skin phenotype, (premature differentiation, decreased proliferation, extended cell cycle, increased symmetric division and increased p16 expression). We will then overexpress Bmi-1 in aged epidermal stem cells to determine whether the aging phenotype can be rejuvenated with Bmi-1 overexpression. In Aim 2 we will determine the effects of extrinsic factors, both local and systemic, on the aging of epidermal stem cells, and whether the premature differentiation, decreased proliferative capacity, increased cell cycle, increased symmetric division and decreased Bmi-1 can be reversed with a young local and/or systemic environment. These studies will be performed in a transplantation assay that allows us to look at the effects of local and systemic factors on individual progenitor cells. SIGNIFICANCE: Modifying age-related functional changes in EpiSCs through alteration of Bmi-1/p16 status could be used for retention of proliferative potential and suppression of terminal differentiation. Also better understanding environmental influences on EpiSCs would determine potential therapies to improve aged epidermal function. Great benefits for the elderly would include preventing skin breakdown/fragility (e.g. bedsores, bruising, tearing) and improved treatment of wounds (leg ulcers and slow healing surgical wounds). PUBLIC HEALTH RELEVANCE: Impaired wound healing, susceptibility to skin breakdown and skin fragility lead to skin infections and considerable morbidity and mortality in the US. In this proposal we will study the roles of both intrinsic (Bmi- 1/p16) and environmental influences on epidermal stem cell aging. Modifying age-related functional changes in EpiSCs through alteration of Bmi-1/p16 status could be used for retention of proliferative potential and suppression of terminal differentiation. Also better understanding environmental influences on EpiSCs would determine potential therapies to improve aged epidermal function. Benefits for the elderly would include preventing skin breakdown/fragility (e.g. bedsores, bruising, tearing) and improved treatment of wounds (leg ulcers and surgical wounds).

描述（由申请方提供）：在美国，伤口愈合受损、皮肤破裂易感性和皮肤脆弱性导致皮肤感染以及相当高的发病率和死亡率。我们最近的研究表明，虽然没有显着差异，表皮干细胞的频率可以检测到与老化，个别表皮干细胞的增殖能力降低。此外，过境放大细胞的频率更大的老年人，细胞周期持续时间增加，并观察到过早的祖细胞分化。 我们的假设是Bmi-1在老年EpiSC的分化、增殖和对称分裂的改变中起关键作用，并且内在（Bmi-1）和/或外在（生态位）改变可以部分或完全恢复Bmi-1表达、分化、增殖和对称分裂的改变。 该项目的长期目标是了解表皮干细胞及其生态位随衰老发生变化的机制。这些知识将用于改善老年人的伤口愈合和组织工程应用。 具体目标：在这个建议中，我们将研究内在（Bmi-1/p16）和外在/环境对表皮干细胞衰老的影响。在目标1中，我们将优化并完成我们对老年和年轻EpiSC之间差异的测定，然后研究Bmi-1敲除小鼠的表皮干细胞是否显示出过早衰老的皮肤表型（过早分化，增殖减少，细胞周期延长，对称分裂增加和p16表达增加）。然后，我们将在衰老的表皮干细胞中过表达Bmi-1，以确定衰老表型是否可以通过Bmi-1过表达而恢复活力。在目标2中，我们将确定外部因素，局部和全身，对表皮干细胞老化的影响，以及是否过早分化，增殖能力下降，细胞周期增加，对称分裂增加和Bmi-1减少可以逆转年轻的局部和/或全身环境。这些研究将在移植试验中进行，使我们能够观察局部和全身因素对个体祖细胞的影响。 重要性：通过改变Bmi-1/p16状态来改变EpiSC中与年龄相关的功能变化可用于保留增殖潜力和抑制终末分化。此外，更好地了解环境对EpiSC的影响将确定改善老年表皮功能的潜在疗法。对老年人的巨大益处包括防止皮肤破裂/脆弱（例如褥疮、瘀伤、撕裂）和改善伤口治疗（腿部溃疡和愈合缓慢的手术伤口）。 公共卫生相关性：在美国，伤口愈合受损、皮肤破裂易感性和皮肤脆弱性导致皮肤感染以及相当高的发病率和死亡率。在这项提案中，我们将研究内在（Bmi- 1/p16）和环境对表皮干细胞衰老的影响。通过改变Bmi-1/p16状态来改变EpiSC中与年龄相关的功能变化可用于保留增殖潜力和抑制终末分化。此外，更好地了解环境对EpiSC的影响将确定改善老年表皮功能的潜在疗法。对老年人的好处包括防止皮肤破裂/脆弱（例如褥疮、瘀伤、撕裂）和改善伤口治疗（腿部溃疡和手术伤口）。