Bone marrow-derived fibroblasts in skin wound healing

骨髓源性成纤维细胞在皮肤伤口愈合中的作用。 在所有患有足部溃疡的糖尿病患者中，有近25%的患者不可避免地会进展为大腿截肢。 糖尿病创面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、抗张强度降低和更高的感染率。而这些普遍的穷人 糖尿病患者创面愈合缺陷已确立，特定的组织水平 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 CASCADE介导正常的皮肤伤口愈合，所有皮肤细胞协同修复和重建皮肤创伤 真皮和表皮。但在慢性伤口的患者中，这些细胞募集、增殖的信号， 伤口床中的分化被破坏。总体而言，我们的目标是开发新的治疗策略 慢性腿部创伤主要通过识别特定的分子，当这些分子由细胞表达时， 伤口本身，将促进慢性伤口的愈合，并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 伤口愈合正常，成纤维细胞前体细胞都是从两者中招募来的，驻留在皮肤休息池中 和骨髓来源的干细胞群体，然后迁移到伤口床 分化为成熟的成纤维细胞。为了区分这两个细胞群体，我们有 利用正常和糖尿病小鼠建立了体内骨髓移植模型，并在体外建立了新的模型 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 与其他参与伤口愈合的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对伤口的影响程度- 愈合过程包括胶原的收缩，刺激血管形成，再上皮化和 角质形成细胞的生长和分化。通过使用病毒载体传递激动剂和抑制剂，我们将 检验生长因子，特别是PDGF-B(血小板衍生生长因子)对 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，并分化为愈合的皮肤伤口的长期细胞成分。

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.