Abstract
In the early to mid-gestation fetus, skin wounds heal with no scar formation and perfect restoration of dermal architecture. This phenomenon is intrinsic to fetal skin. The intrinsic phenotypic properties of the fetal fibroblast are believed to be “the effector of scarless repair”. We sought to prepare dermal matrices with high similarity to the mid-gestation fetal dermis using the technology of “self-assembly” with fetal dermal cells of 18, 20, and 22 wk gestation. Comparison of these dermal constructs to those prepared with neonatal dermal cells, adult skin, neonatal foreskin, and mid-gestation fetal skin demonstrates that these fetal dermal matrices bear marked morphological and biochemical resemblance to the mid-gestation fetal dermis. In order to shed further light on the genes involved in scarless wound healing, we conducted a differential gene array analysis of the neonatal and fetal dermal matrices. Using a gene chip (GLYCOv4 gene chip) of approximately 1,260 human genes, we observed differential expression of 67 genes. A number of fibrotic genes were observed to be downregulated and anti-fibrotic genes upregulated.
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Abdel-Malak N. A.; Srikant C. B.; Kristof A. S.; Magder S. A.; Di Batista J. A.; Hussain S. N. Angiopoietin-1 promotes endothelial cell proliferation and migration through AP-1 dependent autocrine production of IL-8. Blood 111: 4145–4154; 2008.
Beanes S. R.; Dang C.; Soo C.; Wang Y.; Urata M.; Ting K.; Fonkalsrud E. W.; Benhaim P.; Hedrick M. H.; Atkinson J. B.; Lorenz H. P. Down regulation of decorin, a transforming growth factor modulator, is associated with scarless fetal wound healing. J. Pediatr. Surg. 36: 1666–1671; 2001.
Benjamini Y.; Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Statist. Soc. B 57: 289–300; 1995.
Bolstad B. M.; Irizarry R. A.; Astrand M.; Speed T. P. A comparison of normalization methods for high density oligonucleotide array data based on bias and variance. Bioinformatics 19: 185–193; 2003.
Brown S.; Worsfold M.; Sharp C. Microplate assay for the measurement of hydroxyproline in acid-hydrolyzed tissue samples. Biotechniques 30: 38–42; 2001.
Buchanan E. P.; Longaker M. P.; Lorenz H. P. Fetal skin wound healing. Adv. Clin. Chem. 48: 138–161; 2009.
Bussolino F.; Di Renzo M. F.; Ziche M.; Bocchietto E.; Olivero M.; Naldini L.; Gaudino G.; Tamagnone L.; Coffer A.; Comoglio P. M. Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth. J. Cell Biol. 119: 629–641; 1992.
Calabro A.; Benavides M.; Tammi M.; Hascall V. C.; Midura R. J. Microanalysis of enzyme digests of hyaluronan and chondroitin/dermatan sulfate by fluorophore assisted carbohydrate electrophoresis (FACE). Glycobiology 10: 273–281; 2001.
Calabro A.; Hascall V. C.; Midura R. J. Adaptation of FACE methodology for microanalysis of total hyaluronan in chondroitin sulfate composition from cartilage. Glycobiology 10: 283–293; 2000.
Danielson K. G.; Baribault H.; Holmes D. F.; Graham H.; Kadler K. E. Targeted disruption of decorin leads to abnormal collagen fibril morphology and skin fragility. J. Cell Biol. 136: 729–743; 1997.
De Cat B.; David G. Developmental roles of the glypicans. Cell Develop. Biol. 12: 117–125; 2001.
Ellis I.; Banyard J.; Schor S. L. Differential response of fetal and adult fibroblasts to cytokines: cell migration and hyaluronan synthesis. Development 124: 1593–1600; 1997.
Fosang A. J.; Hey N. J.; Carney S. L.; Hardingham T. E. An ELISA plate-based assay for hyaluronan using biotinylated proteoglycan G1 domain. Matrix 10: 306–313; 1990.
Hantash B. M.; Longmei Z.; Knowles J. A.; Lorenz H. P. Adult and fetal wound healing. Front. Biosci. 13: 51–61; 2008.
Irizarry R. A.; Bolstad B. M.; Collin F.; Cope L. M.; Hobbs B.; Speed T. P. Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res. 31: e15; 2003.
Kinsella M. G.; Bressler S. L.; Wight T. N. The regulated synthesis of decorin, versican and biglycan: extracellular matrix proteoglycans that influence cellular phenotype. Crit. Rev. Eukaryot. Gene Expr. 14: 203–234; 2004.
Larson B. J.; Longaker M. T.; Lorenz H. P. Scarless fetal wound healing: a basic science review. Plast. Reconstr. Surg. 126: 1172–1180; 2010.
Lorenz H. P.; Lin R. Y.; Longaker M. T.; Whitby D. J.; Adzick N. S. The fetal fibroblast: the effector cell of scarless fetal skin repair. Plast. Reconstr. Surg. 96: 1260–1261; 1995.
Moulin V.; Tam B. Y.; Castilloux G.; Auger F. A.; O’Connor-Mccourt A.; Germain L. Fetal and adult human skin fibroblasts display intrinsic differences in contractile capacity. J. Cell. Physiol. 188: 211–222; 2001.
Nedeau A. E. A CXCl5 and bFGF dependent effect of PDGF-B activated fibroblasts in promoting trafficking and differentiation of bone marrow derived mesenchymal stem cells. Exp. Cell Res. 314: 2176–2186; 2008.
Pouyani T.; Ronfard V.; Scott P. G.; Dodd C. M.; Ahmed A.; Gallo R.; Parenteau N. De novo synthesis of human dermis in vitro in the absence of a three-dimensional scaffold. In Vitro Cell Dev. Biol.-Anim. 45: 430–441; 2009.
Ramelet A. A.; Hirt-Burri N.; Raffoul W.; Scaletta C.; Pioletti D. P.; Offord E.; Mansourian R.; Applegate L. Chronic wound healing by fetal cell therapy may be explained by differential gene profiling observed in fetal versus old skin cells. Exp. Gerontol. 44: 208–218; 2009.
Rho S. S.; Choi H. J.; Min J. K.; Lee H. W.; Park H.; Park H.; Kim Y. N.; Kwon Y. G. CLEC14A is specifically expressed in endothelial cells and mediates cell to cell adhesion. Biochem. Biophys. Res. Commun. 404: 103–108; 2011.
Russell K. S.; Stern D. F.; Polverini P. J.; Bender J. R. Neuregulin activation of ErbB receptors in vascular endothelium leads to angionenesis. Am. J. Physiol. Heart Circ. Physiol. 227: H2205–H2211; 1999.
Smyth, G. K. Linear models and empirical Bayes methods for assessing Bayes methods for assessing differential expression in microarray experiments. Stat. Appl. Genet. Molec. Biol. 3(1); 2004. doi:10.2202/1544-6115.1027.
Soo C.; Hu F. Y.; Zhang X.; Wang Y.; Beanses H. R.; Lorenz H. P.; Hedrick M. H.; Mackool R. J.; Plaas A.; Kim S. J.; Longaker M. T.; Freymiller E.; Ting K. Differential expression of fibromodulin, a TGF-β modulator, in fetal skin development and scarless repair. Am. J. Path. 157: 423–433; 2000.
Sorrell M. J.; Carrino D. A.; Baber M. A.; Caplan A. I. Versican in human fetal skin development. Anat. Embryol. 199: 45–56; 1999.
Sureshbabu A.; Okajima H.; Yamanaka D.; Shastri S.; Tonner E.; Rae C.; Szymanowska M.; Shand J. H.; Takahashi S.; Beattie J.; Allan G. J.; Flint D. J. IGFBP-5 induces epithelial and fibroblast responses consistent with the fibrotic response. Biochem. Soc. Trans. 37: 882–885; 2009.
Svenson L.; Aszodi A.; Reinholdt F. P.; Fassler R.; Heinegard D.; Oldberg A. Fibromodulin null mice have abnormal collagen fibrils, tissue organization, and altered lumican deposition in tendon. J. Biol. Chem. 247: 9636–9647; 1999.
Tonnesen M. C.; Feng X.; Clark R. A. Angiogenesis in wound healing. J. Invest. Dermatol. 5: 40–46; 2000.
Uutela M.; Wirzenius M.; Paavonen K.; Rajantie I.; He Y.; Karpanen T.; Lohela M.; Wiig H.; Salven P.; Pajusola K.; Eriksson U.; Alitalo K. PDGFD induces macrophage recruitment, increased interstitial pressure and blood vessel maturation during angiogenesis. Blood 104: 3198–3204; 2004.
Werner S.; Peters K. G.; Longaker M. T.; Fuller-Pace F.; Banda M. J.; Williams L. T. Large induction of keratinocyte growth factor expression in the dermis during wound healing. Proc. Natl. Acad. Sci. 89: 6896–6900; 1992.
Wight T. N. Versican: a versatile extracellular matrix proteoglycan in cell biology. Curr. Opin. Cell Biol. 14: 617–623; 2002.
Zimmermann D. R.; Dours-Zimmermann M. T.; Schubert M.; Bruckner-Tuderman L. Versican is expressed in the proliferating zone in the epidermis and in association with the elastic network of the dermis. J. Cell Biol. 124: 817–825; 1994.
Acknowledgments
We thank Maria Ericsson and Louise Trakimas (Harvard Medical School) for their valuable assistance with transmission electron microscopy. We are grateful to Gilberto Hernandez (Scripps Research Institute) for his assistance with RNA analysis. This research was supported by a grant from the Charles H. Hood Foundation to TP.
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Editor: Tetsuji Okamoto
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Pouyani, T., Papp, S. & Schaffer, L. Tissue-engineered fetal dermal matrices. In Vitro Cell.Dev.Biol.-Animal 48, 493–506 (2012). https://doi.org/10.1007/s11626-012-9541-9
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DOI: https://doi.org/10.1007/s11626-012-9541-9