Division of Plastic and Reconstructive Surgery, Wound Healing Research Group, University of Alberta, Edmonton, Alberta, Canada.
Department of Burn and Reconstructive Surgery, 2nd Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
Wound Repair Regen. 2016 Jan-Feb;24(1):14-25. doi: 10.1111/wrr.12378. Epub 2015 Nov 20.
Hypertrophic scars (HTS) are caused by trauma or burn injuries to the deep dermis and are considered fibrosis in the skin. Monocytes, M1 and M2 macrophages are mononuclear phagocytes. Studies suggest that M2 macrophages are profibrotic and might contribute to HTS formation. Our lab has established a human HTS-like nude mouse model, in which the grafted human skin develops red, raised, and firm scarring, resembling HTS seen in humans. In this study, we observed the natural behavior of mononuclear phagocyte system in this nude mouse model of dermal fibrosis at multiple time points. Thirty athymic nude mice received human skin grafts and an equal number of mice received mouse skin grafts as controls. The grafted skin and blood were harvested at 1, 2, 3, 4, and 8 weeks. Wound area, thickness, collagen morphology and level, the cell number of myofibroblasts, M1- and M2-like macrophages in the grafted skin, as well as monocyte fraction in the blood were investigated at each time points. Xenografted mice developed contracted and thickened scars grossly. The xenografted skin resembled human HTS tissue based on enhanced thickness, fibrotic orientation of collagen bundles, increased collagen level, and infiltration of myofibroblasts. In the blood, monocytes dramatically decreased at 1 week postgrafting and gradually returned to normal in the following 8 weeks. In the xenografted skin, M1-like macrophages were found predominantly at 1-2 weeks postgrafting; whereas, M2-like macrophages were abundant at later time points, 3-4 weeks postgrafting coincident with the development of fibrosis in the human skin tissues. This understanding of the natural behavior of mononuclear phagocytes in vivo in our mouse model provides evidence for the role of M2-like macrophages in fibrosis of human skin and suggests that macrophage depletion in the subacute phases of wound healing might reduce or prevent HTS formation.
增生性瘢痕（HTS）是由真皮深层的创伤或烧伤引起的，被认为是皮肤纤维化。单核细胞、M1 和 M2 巨噬细胞是单核吞噬细胞。研究表明，M2 巨噬细胞具有促纤维化作用，可能有助于 HTS 的形成。我们的实验室建立了一种人类 HTS 样裸鼠模型，在该模型中，移植的人类皮肤会出现红色、隆起和坚硬的瘢痕，类似于人类 HTS。在这项研究中，我们在多个时间点观察了单核吞噬细胞系统在这种真皮纤维化裸鼠模型中的自然行为。30 只无胸腺裸鼠接受了人皮肤移植，作为对照，同样数量的小鼠接受了鼠皮肤移植。在 1、2、3、4 和 8 周时采集移植皮肤和血液。在每个时间点，研究了移植皮肤中的伤口面积、厚度、胶原形态和水平、肌成纤维细胞数量、M1 和 M2 样巨噬细胞以及血液中的单核细胞分数。异种移植小鼠的皮肤出现明显的收缩和增厚。基于增强的厚度、胶原束纤维化方向、胶原水平增加以及肌成纤维细胞浸润，异种移植皮肤类似于人类 HTS 组织。在血液中，单核细胞在移植后 1 周急剧减少，并在随后的 8 周内逐渐恢复正常。在异种移植皮肤中，M1 样巨噬细胞主要在移植后 1-2 周内存在；而 M2 样巨噬细胞在后期大量存在，即在移植后 3-4 周，与人类皮肤组织纤维化的发展相一致。本研究了解了单核吞噬细胞在我们的小鼠模型中的体内自然行为，为 M2 样巨噬细胞在人类皮肤纤维化中的作用提供了证据，并提示在伤口愈合的亚急性期巨噬细胞耗竭可能减少或预防 HTS 的形成。
