Function of KLF4-expressing stem cells in mouse cutaneous wound healing

表达KLF4的干细胞在小鼠皮肤伤口愈合中的功能

• 批准号: 8225255
• 负责人: Walden Ai
• 金额: $ 6.85万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-14 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8225255
• 关键词: Animal Model; Area; Bone Marrow; Bone Marrow Transplantation; Cell Therapy; Cell physiology; Cells; Chronic; Clinical; Cutaneous; Data; Development; Embryo; Epithelial; Epithelial Cells; Fibroblasts; GKLF protein; Gene Expression; Hair follicle structure; Hematopoietic stem cells; Human; Knock-out; Knockout Mice; Laboratories; Mus; Names; Nuclear Protein; Positioning Attribute; Proteins; Publishing; Resistance; Role; Sebaceous Glands; Skin; Stem cells; Tamoxifen; Testing; Therapeutic; Tissues; Transgenic Mice; Wound Healing; base; c-myc Genes; embryonic stem cell; induced pluripotent stem cell; mouse model; novel; novel strategies; promoter; self-renewal; stem; stem cell biology; stem cell therapy; tissue regeneration; transcription factor; wound

DESCRIPTION (provided by applicant): Chronic wounds are still an important clinical concern since up to 50% of all cases that have been present for more than a year remain resistant to treatment. Therefore, understanding how wounds heal will help in the development of new treatments. Among different approaches, stem cell based therapy has shown great potential from preliminary findings in both animal models and human studies. However, the underlying mechanisms through which stem cells contribute to cutaneous wound healing have not been clearly delineated. The major focus of our laboratory is to examine the expression and function of a nuclear protein, named Kruppel-like factor 4 (KLF4), in tissue stem cells. KLF4 is a transcription factor that is highly expressed in differentiated epithelial cells including those of the skin. Indeed, KLF4 is required to establish the barrier function of the skin. KLF4 also has important functions in stem-cell biology, including the self-renewal of embryonic stem cells, and induction of induced pluripotent stem cells from well-differentiated fibroblasts with three other proteins, Oct4, c-myc, and Sox2. This proposal focuses on testing the hypothesis that KLF4- expressing stem cells have a critical function in mouse cutaneous wound healing. In support of this hypothesis, we have found, using transgenic mouse models, that KLF4 is expressed in mouse epidermal stem cells. Our preliminary data also showed that KLF4-expressing pluripotent cells, probably hair follicle stem cells, migrate from its original position toward the wound during wound healing, indicating that these cells have an important function in cutaneous wound healing. In Aim 1, we will validate KLF4 gene expression in mouse epidermal stem cells. In Aim 2, we will study the function of KLF4-expressing epidermal stem cells in mouse skin wound healing. In Aim 3, we will study the function of bone marrow-derived KLF4-expressing stem cells in mouse skin wound healing. We will use a novel inducible KLF4 knockout mouse model. Taken together, the proposed studies will not only provide novel information about the mechanisms by which KLF4-expressing stem cells function in mouse cutaneous wound healing, but may contribute to the development of novel strategies that selectively modulate the function of KLF4-expressing stem cells to promote cutaneous wound healing.

描述(申请人提供)：慢性创面仍然是一个重要的临床问题，因为在所有存在超过一年的病例中，高达50%的病例仍然对治疗产生抗药性。因此，了解伤口是如何愈合的将有助于开发新的治疗方法。在不同的方法中，从动物模型和人体研究的初步发现来看，基于干细胞的治疗显示出巨大的潜力。然而，干细胞促进皮肤创面愈合的潜在机制尚不清楚。我们实验室的主要工作是检测一种名为Kruppel-like factor4(KLF4)的核蛋白在组织干细胞中的表达和功能。KLF4是一种转录因子，在分化的上皮细胞包括皮肤上皮细胞中高表达。事实上，KLF4是建立皮肤屏障功能所必需的。KLF4在干细胞生物学中也具有重要的功能，包括胚胎干细胞的自我更新，以及用另外三种蛋白质Oct4、c-myc和Sox2从分化良好的成纤维细胞诱导出多能干细胞。这项建议侧重于验证KLF4表达的干细胞在小鼠皮肤伤口愈合中具有关键功能的假设。为了支持这一假设，我们利用转基因小鼠模型发现，KLF4在小鼠表皮干细胞中表达。我们的初步数据还显示，在伤口愈合过程中，表达KLF4的多能细胞，可能是毛囊干细胞，从原来的位置向伤口迁移，表明这些细胞在皮肤伤口愈合中具有重要的功能。在目的1，我们将验证KLF4基因在小鼠表皮干细胞中的表达。在目的2中，我们将研究表达KLF4的表皮干细胞在小鼠皮肤创伤愈合中的作用。在目的3中，我们将研究骨髓来源的表达KLF4的干细胞在小鼠皮肤创伤愈合中的作用。我们将使用一种新的可诱导的KLF4基因敲除小鼠模型。综上所述，这些研究不仅将为表达KLF4的干细胞在小鼠皮肤伤口愈合中的作用机制提供新的信息，而且可能有助于开发选择性调节表达KLF4的干细胞的功能以促进皮肤伤口愈合的新策略。