Bone marrow-derived fibroblasts in skin wound healing

骨髓来源的成纤维细胞在皮肤伤口愈合中的作用

• 批准号: 7047196
• 负责人: Omaida C Velazquez
• 金额: $ 29.05万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-15 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7047196
• 关键词: Adenoviridae; RNA interference; angiogenesis; bone marrow; bone marrow transplantation; cell differentiation; cell migration; cell population study; cell proliferation; diabetes mellitus; fibroblasts; green fluorescent proteins; human tissue; laboratory mouse; platelet derived growth factor; skin; stem cells; transfection /expression vector; wound healing

DESCRIPTION (provided by applicant): Bone marrow-derived fibroblasts in skin wound healing. Nearly 25% of all diabetic patients, with foot ulcers, will inevitably progress to major limb amputation. Diabetic wound healing deficiencies are associated with impaired tissue level neovascularization, impaired keratinocyte function, reduced tensile strength, and higher infection rates. While these generalized poor wound healing defects of patients with diabetes mellitus are well established, the specific tissue level mechanisms responsible for these wound-healing deficiencies remain poorly understood. A complex cellular cascade mediates normal cutaneous wound healing, where all skin cells cooperate to repair and rebuild the dermis and epidermis. But in patients with chronic wounds, these signals for cell recruitment, proliferation, and differentiation in the wound bed are disrupted. Overall, we aim to develop new strategies for treating chronic leg wounds by primarily identifying specific molecules, that when expressed by cells within the wound itself, will promote healing of chronic wounds as well as fully restore skin architecture and function. Because fibroblasts are the critical cell type for early and late wound healing, we hypothesize that, during normal wound healing, fibroblast precursor cells are recruited from both, the resident resting pool in the skin and the bone marrow-derived stem cell populations, which then subsequently migrate into the wound bed and differentiate into mature fibroblasts. To distinguish between these two cellular populations we have developed in vivo bone marrow transplantation models, using normal and diabetic mice, and novel in vitro three-dimensional reconstructions of human dermis, vascularized dermis, and skin, in which fibroblasts can interact with other key cell types involved in wound healing. In these in vivo wound-healing models and in vitro reconstructions we will determine the extent to which bone marrow-derived fibroblasts influence wound- healing processes including contraction of collagen, stimulation of vessel formation, re-epithelialization and keratinocyte growth and differentiation. With the use of viral vector delivery of agonists and inhibitors, we will test the hypothesis that growth factors, specifically PDGF-B (platelet-derived growth factor) are critical for the activation of bone marrow-derived fibroblasts to invade into collagen, proliferate, migrate to the wound, survive, and differentiate into long-term cellular components of the healed skin wound.

描述（由申请人提供）：皮肤伤口愈合中的骨髓衍生的成纤维细胞。在所有患有步道溃疡的糖尿病患者中，近25％将不可避免地发展为主要肢体截肢。糖尿病伤口愈合缺陷与组织水平新生血管形成受损，角质形成症功能受损，拉伸强度降低和更高的感染率有关。尽管糖尿病患者的这些普遍的不良伤口愈合缺陷已经确定，但负责这些伤口治疗缺陷的特定组织水平机制仍然鲜为人知。复杂的细胞级联反应介导正常的皮肤伤口愈合，所有皮肤细胞都配合修复和重建真皮和表皮。但是，在患有慢性伤口的患者中，这些用于募集细胞，增殖和伤口床分化的信号被中断。总体而言，我们旨在通过主要识别特定分子来制定新的策略来治疗慢性腿部伤口，而当伤口本身中的细胞表达时，将促进慢性伤口的愈合以及完全恢复皮肤的建筑和功能。由于成纤维细胞是早期和晚期伤口愈合的关键细胞类型，因此我们假设在正常的伤口愈合过程中，从两者中募集了成纤维细胞前体细胞，居民在皮肤中的居民静止池和骨髓衍生的干细胞群体，然后随后将其迁移到伤口床中并分化为成熟的纤维纤维细胞。为了区分这两个细胞群体，我们使用正常和糖尿病小鼠在体内骨髓移植模型中开发了体内骨髓移植模型，以及新型的人真皮真皮，血管化真皮和皮肤的体外三维重建，其中成纤维细胞可以与其他关键细胞相互作用。在这些体内伤口愈合模型和体外重建中，我们将确定骨髓衍生的成纤维细胞影响伤口愈合过程，包括胶原蛋白的收缩，血管形成的刺激，再上皮层化和角质形成细胞的生长和差异。通过使用激动剂和抑制剂的病毒载体递送，我们将检验以下假设：生长因子，特别是PDGF-B（血小板衍生的生长因子）对于激活骨髓衍生的成纤维细胞以侵入胶原蛋白，扩散，迁移到伤口中，并分化为长期的细胞组成部分，并分化了愈合的组成症状，使其侵入胶原蛋白蛋白。