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

基本信息

批准号：
8034974
负责人：
Omaida C Velazquez
金额：
$ 12.98万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-23 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8034974
关键词：
Acute Adenovirus Vector Agonist Amputation Architecture Area Beds Bone Marrow Bone Marrow Transplantation Cell Differentiation process Cells Chronic Collagen Complement Complex Cutaneous Defect Dermis Development Diabetes Mellitus Diabetic mouse Differentiation and Growth Endothelial Cells Epidermis Fibroblasts Foot Ulcer Goals Growth Factor Healed Human Impaired wound healing In Vitro Infection Invaded Knowledge Label Leg Limb structure Mediating Mesenchymal Stem Cells Modeling Molecular Biology Mus Myofibroblast Patients Platelet-Derived Growth Factor Population Process Proliferating Protein Overexpression Proto-Oncogene Proteins c-sis Recruitment Activity Rest Role Signal Transduction Skin Tensile Strength Testing Tissues Viral Vector Work Wound Healing angiogenesis cell type cytokine diabetic diabetic patient diabetic wound healing healing in vitro Model in vivo inhibitor/antagonist keratinocyte keratinocyte differentiation migration neovascularization novel novel therapeutics precursor cell reconstitution reconstruction repaired research study stem cell population three-dimensional modeling vasculogenesis wound

项目摘要

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 differentiateinto 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 reconstructionswe 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.

骨髓来源的成纤维细胞在皮肤伤口愈合中的作用。近 25% 的糖尿病患者患有足部溃疡，将不可避免地发展到截肢。糖尿病伤口愈合缺陷与组织水平新生血管受损、受损角质形成细胞功能、抗拉强度降低和感染率较高。虽然这些普遍贫困糖尿病患者的伤口愈合缺陷已明确，具体组织水平造成这些伤口愈合缺陷的机制仍然知之甚少。复杂的细胞级联介导正常的皮肤伤口愈合，所有皮肤细胞合作修复和重建伤口真皮和表皮。但在慢性伤口患者中，这些细胞募集、增殖的信号，伤口床的分化被破坏。总体而言，我们的目标是制定新的治疗策略通过主要识别特定分子来识别慢性腿部伤口，当这些分子由腿部内的细胞表达时伤口本身，将促进慢性伤口的愈合以及完全恢复皮肤结构和功能。由于成纤维细胞是早期和晚期伤口愈合的关键细胞类型，我们假设，在正常伤口愈合时，成纤维细胞前体细胞从皮肤中的常驻静息池中招募以及骨髓来源的干细胞群，随后迁移到伤口床并分化为成熟的成纤维细胞。为了区分这两个细胞群，我们有使用正常和糖尿病小鼠开发体内骨髓移植模型，以及新颖的体外人体真皮、血管化真皮和皮肤的三维重建，其中成纤维细胞可以与参与伤口愈合的其他关键细胞类型相互作用。在这些体内伤口愈合模型和体外重建我们将确定骨髓来源的成纤维细胞影响伤口的程度愈合过程包括胶原蛋白收缩、刺激血管形成、上皮细胞再生和角质形成细胞的生长和分化。通过使用病毒载体递送激动剂和抑制剂，我们将检验以下假设：生长因子，特别是 PDGF-B（血小板衍生生长因子）对于激活骨髓来源的成纤维细胞侵入胶原蛋白、增殖、迁移到伤口，存活并分化为愈合皮肤伤口的长期细胞成分。