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

描述（由申请人提供）：慢性伤口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%的病例仍然对治疗有抵抗力。因此，了解伤口如何愈合将有助于开发新的治疗方法。在不同的方法中，基于干细胞的治疗已经从动物模型和人类研究的初步发现中显示出巨大的潜力。然而，干细胞促进皮肤伤口愈合的潜在机制尚未明确阐明。我们实验室的主要重点是研究一种名为Kruppel样因子4（KLF 4）的核蛋白在组织干细胞中的表达和功能。KLF 4是一种转录因子，在分化的上皮细胞（包括皮肤的上皮细胞）中高度表达。事实上，KLF 4是建立皮肤屏障功能所必需的。KLF 4在干细胞生物学中也具有重要功能，包括胚胎干细胞的自我更新，以及用其他三种蛋白质Oct 4、c-myc和Sox 2从分化良好的成纤维细胞诱导诱导多能干细胞。该提案的重点是测试KLF 4表达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，我们已经发现，使用转基因小鼠模型，KLF 4在小鼠表皮干细胞中表达。我们的初步数据还表明，表达KLF 4的多能细胞，可能是毛囊干细胞，在伤口愈合过程中从其原始位置向伤口迁移，表明这些细胞在皮肤伤口愈合中具有重要功能。在目的1中，我们将验证KLF 4基因在小鼠表皮干细胞中的表达。目的2：研究表达KLF 4的表皮干细胞在小鼠皮肤创伤愈合中的作用。目的3：研究表达KLF 4的骨髓源性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诱导型KLF 4基因敲除小鼠模型。总而言之，拟议的研究不仅将提供有关表达KLF 4的干细胞在小鼠皮肤伤口愈合中发挥作用的机制的新信息，而且可能有助于开发选择性调节表达KLF 4的干细胞功能以促进皮肤的新策略伤口愈合。

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.