FETAL WOUND HEALING--ROLE OF THE EXTRACELLULAR MATRIX

最近的临床和实验证据表明，胎儿 对手术损伤的反应方式与 成人：胎儿愈合迅速，没有疤痕和炎症， 成人的伤口。 这些差异背后的机制 是未知的。 我们已经建立了无瘢痕修复模型， 长妊娠胎羊模型和成年无胸腺小鼠模型 人胚胎皮肤修复 我们认为无疤痕的胎儿修复 似乎是胎儿组织固有的，而不是继发于外源性的 胎儿环境因素（例如，羊水暴露）。 我们 假设无瘢痕胎儿修复是一种独特的 胎儿成纤维细胞产生的细胞外基质（ECM）， 结合缺乏成人样炎症反应， 损伤 我们的一般策略是描绘关键的ECM（胶原蛋白） 和蛋白聚糖）和细胞（成纤维细胞、肌成纤维细胞、炎性 细胞）成分，使用这些成分将胎儿愈合与成人愈合区分开来。 建立了胎儿修复模型。 这项建议的第一个目的是 使用已建立的形态学技术研究ECM （蛋白聚糖）和细胞（肌成纤维细胞，炎症细胞）成分 区分羊的胎儿和成人修复，特别是在 子宫内从无疤痕的胎儿伤口愈合到“成人”的转变 愈合并形成疤痕。 相关研究将确定相对 胎儿/成人ECM和胎儿/成人细胞在愈合中的贡献 成年绵羊皮肤移植到胎羊上的界面，因为 瘢痕形成只发生在成人皮肤的这个成人-胎儿组织上 接口. 第二个目标是定义生物化学（胶原蛋白）， 类型、糖胺聚糖谱）和生物力学（伤口破裂 强度）之间的差异胎儿和成年羊伤口修复。 的 第三个目标是表征无瘢痕人类胎儿皮肤的独特模型 使用人类胎儿皮肤移植进行愈合， 移植到成年无胸腺小鼠上。 实验计划， 阐明物种特异性ECM的作用，成年小鼠与胎儿人 成纤维细胞，炎性细胞，生长因子谱，分化， 在这个无疤痕的人类胎儿伤口模型中， 治愈 我们的长期目标是将这些知识应用于临床 避免瘢痕形成（瘢痕疙瘩、腹膜内粘连、狭窄等） 通过改变成人伤口的ECM和细胞反应， 以更像胎儿的方式发生。

Recent clinical and experimental evidence suggests that the fetus responds to surgical injury in a fashion fundamentally different from the adult: the fetus heals rapidly without the scarring and inflammation that accompany adult wounds. The mechanisms that underlie these differences are unknown. We have established scarless repair models in both the long-gestation fetal sheep model and in an adult athymic mouse model of human fetal skin repair. We determined that scarless fetal repair appears to be intrinsic to fetal tissue and is not secondary to extrinsic fetal environmental factors (e.g., amniotic fluid exposure). We hypothesize that scarless fetal repair is a consequence of a unique extracellular matrix (ECM) produced by the fetal fibroblast in conjunction with the absence of an adult-like inflammatory response to injury. Our general strategy is to delineate the crucial ECM (collagen and proteoglycan) and cellular (fibroblast, myofibroblast, inflammatory cell) components that differentiate fetal from adult healing using these established fetal repair models. The first aim of this proposal is to use established morphologic techniques to investigate the ECM (proteoglycan) and cellular (myofibroblast, inflammatory cell) components that distinguish fetal from adult repair in sheep, particularly during the in utero transition from scarless fetal wound healing to "adult" healing with scar formation. Related studies will determine the relative contributions of fetal/adult ECM and fetal/adult cells at the healing interface of adult sheep skin transplanted onto fetal lambs, since scarring occurs only within the adult skin at this adult-fetal tissue interface. The second objective is to define the biochemical (collagen types, glycosaminoglycan profile) and biomechanical (wound breaking strength) differences between fetal and adult sheep wound repair. The third aim is to characterize a unique model of scarless human fetal skin healing using human fetal skin grafts that are wounded after transplantation onto adult athymic mice. Experiments are planned to elucidate the role of species-specific ECM, adult mouse vs. fetal human fibroblasts, inflammatory cells, growth factor profile, differentiation, and the air-tissue interface in this model of scarless human fetal wound healing. Our long-term objective is to apply this knowledge clinically to avoid scarring (keloids, intra-peritoneal adhesions, strictures, etc.) by altering the ECM and cellular response of adult wounds so that healing occurs in a more fetal-like manner.