Open Access Transplanted Fibroblasts Prevents Dysfunctional Repair in a Murine CXCR3-Deficient Scarring Model

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Abstract:

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.

Keywords: Cell therapy; Collagen; Epidermal‚Äźdermal communication; Extracellular matrix; Fibroblast

Document Type: Research Article

DOI: http://dx.doi.org/10.3727/096368911X623817

Affiliations: Department of Pathology and McGowan Institute for Regenerative Medicine, University of Pittsburgh and Pittsburgh VAMC, Pittsburgh, PA, USA

Publication date: May 1, 2012

More about this publication?
  • Cell Transplantation publishes original, peer-reviewed research and review articles on the subject of cell transplantation and its application to human diseases. To ensure high-quality contributions from all areas of transplantation, separate section editors and editorial boards have been established. Articles deal with a wide range of topics including physiological, medical, preclinical, tissue engineering, and device-oriented aspects of transplantation of nervous system, endocrine, growth factor-secreting, bone marrow, epithelial, endothelial, and genetically engineered cells, among others. Basic clinical studies and immunological research papers are also featured. To provide complete coverage of this revolutionary field, Cell Transplantation will report on relevant technological advances, and ethical and regulatory considerations of cell transplants. Cell Transplantation is now an Open Access journal starting with volume 18 in 2009, and therefore there will be an inexpensive publication charge, which is dependent on the number of pages, in addition to the charge for color figures. This will allow work to be disseminated to a wider audience and also entitle the corresponding author to a free PDF, as well as prepublication of an unedited version of the manuscript.
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