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: 7580904
• 负责人: Omaida C Velazquez
• 金额: $ 26.93万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 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/7580904
• 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

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.

骨髓源性成纤维细胞在皮肤创伤愈合中的作用。 近25%的糖尿病患者，足部溃疡，将不可避免地进展到主要截肢。 糖尿病伤口愈合缺陷与受损的组织水平新血管形成、受损的组织水平新血管形成、受损的组织水平新血管形成和受损的组织水平新血管形成相关。 角质形成细胞功能、降低的抗张强度和更高的感染率。虽然这些穷人 糖尿病患者的伤口愈合缺陷已得到充分证实， 造成这些伤口愈合缺陷的机制仍然知之甚少。一个复杂的细胞 级联介导正常的皮肤伤口愈合，其中所有皮肤细胞合作修复和重建伤口。 真皮和表皮。但在慢性伤口的患者中，这些细胞募集，增殖， 和伤口床中的分化被破坏。总的来说，我们的目标是开发新的治疗策略， 慢性腿部伤口，主要是通过识别特定的分子，当表达的细胞内， 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。 因为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，在伤口愈合期间， 正常的伤口愈合，成纤维细胞前体细胞从皮肤中的驻留休息池中招募 以及骨髓来源的干细胞群，其随后迁移到伤口床中 并分化成成熟的成纤维细胞。为了区分这两种细胞群， 开发了体内骨髓移植模型，使用正常和糖尿病小鼠， 人真皮、血管化真皮和皮肤的三维重建，其中成纤维细胞可以 与伤口愈合中涉及的其他关键细胞类型相互作用。在这些体内伤口愈合模型中， 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的收缩、血管形成的刺激、上皮再生和 角质形成细胞生长和分化。随着激动剂和抑制剂的病毒载体递送的使用，我们将 测试生长因子，特别是PDGF-B（血小板衍生生长因子）对血小板生长至关重要的假设。 激活骨髓来源的成纤维细胞以侵入胶原、增殖、迁移到伤口， 存活并分化成愈合的皮肤伤口的长期细胞成分。