Department of Pathology and McGowan Institute for Regenerative Medicine, University of Pittsburgh and Pittsburgh VAMC, Pittsburgh, PA 15261, USA.
Cell Transplant. 2012;21(5):919-31. doi: 10.3727/096368911X623817. Epub 2012 Jan 10.
In skin, the regeneration of the ontogenically distinct mesenchymal and epithelial compartments must proceed in a coordinated manner orchestrated by extracellular signaling networks. We have recently found that the switch from regeneration to remodeling during repair is modulated by chemokines that bind CXCR3 receptor. If this signaling is disrupted wounds continue to be active, resulting in a chronic hypercellular and hypertrophic state characterized by an immature matrix composition. As healing is masterminded in large part by fibroblasts and their synthesis of the extracellular matrix, the question arose as to whether this ongoing scarring can be modulated by transplanted fibroblasts. We examined wounds in the CXCR3-/- mouse scarring model. These wounds exhibited a significant delay in healing in all areas compared to young and aged wild-type mice. Full-thickness wounds were transplanted with fibroblasts derived from newborn CXCR3-/- or wild-type mice. The transplanted fibroblasts were labeled with fluorescent dye (CM-DiI) and suspended in hyaluronic acid gel; by 30 days, these transplanted cells comprised some 30% of the dermal stromal cells regardless of the host or source of transplanted cells. Wild-type fibroblasts transplanted into CXCR3-/- mice wounds reversed the delay and dysfunction previously seen in CXCR3-/- wounds; this correction was not noted with transplanted CXCR3-/- fibroblasts. Additionally, transplant of CXCR3-/- cells into wounds in wild-type animals did not adversely affect those wounds. The transplanted fibroblasts exhibited strong survival and migration patterns and led to an increase in tensile strength. Expression of matrix proteins and collagen in CXCR3-/- wounds transplanted with wild-type fibroblasts resembled normal wild-type healing, and the wound matrix in wild-type mice transplanted with CXCR3-/- cells also presented a mature matrix. These suggest that the major determinant of healing versus scarring lies with the nature of the matrix. These findings have intriguing implications for rational cellular interventions aimed at promoting wound healing via cell therapy.
在皮肤中，胚胎发生上不同的间充质和上皮隔室的再生必须以细胞外信号网络协调的方式进行。我们最近发现，修复过程中从再生到重塑的转变受趋化因子的调节，这些趋化因子与 CXCR3 受体结合。如果这种信号被破坏，伤口会继续活跃，导致以不成熟基质组分为特征的慢性细胞过度和肥大状态。由于愈合在很大程度上由成纤维细胞及其细胞外基质的合成来控制，因此出现了这样一个问题，即这种持续的瘢痕形成是否可以通过移植的成纤维细胞来调节。我们检查了 CXCR3-/-小鼠瘢痕形成模型中的伤口。与年轻和老年野生型小鼠相比，所有区域的这些伤口的愈合均明显延迟。将来自新生 CXCR3-/-或野生型小鼠的成纤维细胞移植到全层伤口中。移植的成纤维细胞用荧光染料（CM-DiI）标记，并悬浮在透明质酸凝胶中；30 天后，这些移植的细胞占真皮基质细胞的约 30%，无论宿主或移植细胞的来源如何。野生型成纤维细胞移植到 CXCR3-/-小鼠的伤口中逆转了以前在 CXCR3-/-伤口中观察到的延迟和功能障碍；在移植的 CXCR3-/-成纤维细胞中未观察到这种纠正。此外，将 CXCR3-/-细胞移植到野生型动物的伤口中不会对这些伤口造成不利影响。移植的成纤维细胞表现出强烈的存活和迁移模式，并导致拉伸强度增加。在移植了野生型成纤维细胞的 CXCR3-/-伤口中，基质蛋白和胶原蛋白的表达类似于正常的野生型愈合，而在移植了 CXCR3-/-细胞的野生型小鼠的伤口基质中也呈现出成熟的基质。这些表明，愈合与瘢痕形成的主要决定因素在于基质的性质。这些发现为通过细胞治疗促进伤口愈合的合理细胞干预提供了有趣的启示。
