Histochemistry and Cell Biology

, Volume 151, Issue 3, pp 229–238 | Cite as

Wound healing mechanism in Mongolian gerbil skin

  • Min-Jung Lee
  • Dong‑Joon Lee
  • Han-Sung JungEmail author
Original Paper


The skin wound healing ability of animals differs depending on the environment. The gerbil wound model showed a different wound healing mechanism than was known thus far. Many other wound healing mechanisms have been found to involve transforming growth factor-beta 1 (TGF-β1). However, in the wound healing of gerbil skin, the expression of TGF-β1 seems to be not enough compared to mouse. In this study, we compared the wound healing process of gerbil and mouse back skin. At 3 days after wounding, the TGF-β1 level was downregulated in gerbil skin wound healing compared mouse. In addition, gerbils have fewer integrin signals related to the regulation of TGF-β activation and signaling. Despite lacking these factors, the wound healing results in the gerbil are similar to those for skin wound healing in mice. In contrast, in gerbil skin wound healing, the basal skin layer showed hyperplasia in re-epithelialization, more production of hair follicles, and low probability of collagen infiltration at the late stages of wound healing. These data suggest that different wound healing mechanisms are present in the mammals.


Gerbil Mouse Skin wound TGF-β1 Integrin 



This research was financially supported by grants from the National Research Foundation of Korea (NRF) Grant funded by the Korean Government (MSIP) (NRF-2017M3A9B3061833).

Supplementary material

418_2018_1752_MOESM1_ESM.tif (7.6 mb)
Supplementary Fig. 1 Cell proliferation analysis during wound healing. (A–F) The expression pattern of cell proliferation at the wound areas determined by immunohistochemical staining with anti-Ki-67 antibody in the gerbil (A: 1 day, B: 3 days, and C: 7 days) and the mouse (D: 1 day, E: 3 days, and F: 7 days). At 3 days after wounding, cell proliferation was increased in wounded dermis of the gerbil compared with that in the mouse. The indicated boxed areas are images of increased cell proliferation. The arrow delineates the wound edge. (G) Real-time PCR analysis of MKI67 expression at the wound sites of the gerbil and mouse at 1 and 3 days after wound. The data are expressed as the mean ± s.e.m.; *P<0.05


  1. Abbas L, Rivolta MN (2015) Aminoglycoside ototoxicity and hair cell ablation in the adult gerbil: a simple model to study hair cell loss and regeneration. Hear Res 325:12–26CrossRefGoogle Scholar
  2. Aluwihare P, Mu Z, Zhao Z, Yu D, Weinreb PH, Horan GS et al (2009) Mice that lack activity of αvβ6- and αvβ8-integrins reproduce the abnormalities of Tgfb1- and Tgfb3-null mice. J Cell Sci 122:227–232CrossRefGoogle Scholar
  3. Anders S, Pyl PT, Huber W (2015) HTSeq-A Python framework to work with high-throughput sequencing data. Bioinformatics 31:166–169CrossRefGoogle Scholar
  4. Banh A, Deschamps PA, Gauldie J, Overbeek PA, Sivak JG, West-Mays JA (2006) Lens specific expression of TGF-beta induces anterior subcapsular cataract formation in the absence of Smad3. Invest Ophthalmol Vis Sci 47:3450–3460CrossRefGoogle Scholar
  5. Beckett AC, Piazuelo MB, Noto JM, Peek RM Jr, Washington MK, Algood HM et al (2016) Dietary composition influences incidence of helicobacter pylori-induced iron deficiency anemia and gastric ulceration. Infect Immun 84:3338–3349CrossRefGoogle Scholar
  6. Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc B 57:289–300Google Scholar
  7. Brown RL, Ormsby I, Doetschman TC, Greenhalgh DG (1995) Wound healing in the transforming growth factor-β1-deficient mouse. Wound Rep Reg 3:25–36CrossRefGoogle Scholar
  8. Chevret P, Denys C, Jaeger JJ, Michaux J, Catzeflis FM (1993) Molecular evidence that the spiny mouse (Acomys) is more closely related to gerbils (Gerbillinae) than to true mice (Murinae). Proc Natl Acad Sci USA 90:3433–3436CrossRefGoogle Scholar
  9. Crowe MJ, Doetschman T, Greenhalgh DG (2000) Delayed wound healing in immunodeficient TGF-β1 knockout mice. J Invest Dermatol 115:3–11CrossRefGoogle Scholar
  10. Desmoulie`re A, Geinoz A, Gabbiani F, Gabbiani G (1993) Transforming growth factorβ1 induces a-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol 122:103–111CrossRefGoogle Scholar
  11. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S et al (2013) STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29:15–21CrossRefGoogle Scholar
  12. Fisher RA (1922) On the interpretation of χ2 from contingency tables, and the calculation of P. J R Stat Soc 85:87–94CrossRefGoogle Scholar
  13. Grabherr MG, Haas BJ, Yassour M, Levin JZ, Thompson DA, Amit I et al (2011) Full-length transcriptome assembly from RNA-Seq data without a reference genome. Nat Biotechnol 29:644–652CrossRefGoogle Scholar
  14. Gurtner GC, Werner S, Barrandon Y, Longaker MT (2008) Wound repair and regeneration. Nature 453:314–321CrossRefGoogle Scholar
  15. Haas BJ, Papanicolaou A, Yassour M, Grabherr M, Blood PD, Bowden J et al (2013) De novo transcript sequence reconstruction from RNA-seq using the trinity platform for reference generation and analysis. Nat Protoc 8:1494–1512CrossRefGoogle Scholar
  16. Hosoya A, Lee JM, Cho SW, Kim JY, Shinozaki N, Shibahara T et al (2008) Morphological evidence of basal keratinocyte migration during the re-epithelialization process. Histochem Cell Biol 130:1165–1175CrossRefGoogle Scholar
  17. Huang X, Madan A (1999) CAP3: A DNA sequence assembly program. Genome Res 9:868–877CrossRefGoogle Scholar
  18. Jansa SA, Weksler M (2004) Phylogeny of muroid rodents: relationships within and among major lineages as determined by IRBP gene sequences. Mol Phylogenet Evol 31:256–276CrossRefGoogle Scholar
  19. Lazzari V, Tafforeau P, Michaux J (2011) When homologous cusps display non-homologous wear facets: An occlusal reorganization ensures functional continuity during dental evolution of Murinae (Rodentia, Mammalia). Arch Oral Biol 56:194–204CrossRefGoogle Scholar
  20. Lee MJ, Byun MR, Furutani-Seiki M, Hong JH, Jung HS (2014) YAP and TAZ regulate skin wound healing. J Invest Dermatol 134:518–525CrossRefGoogle Scholar
  21. Lee MJ, Shin JO, Jung HS (2013) Thy-1 knockdown retards wound repair in mouse skin. J Dermatol Sci 69:95–104CrossRefGoogle Scholar
  22. Legate KR, Wickström SA, Fässler R (2009) Genetic and cell biological analysis of integrin outside-in signaling. Genes Dev 23:397–418CrossRefGoogle Scholar
  23. Letterio JJ, Roberts AB (1996) Transforming growth factor-beta-1-deficient mice: identification of isoform-specific activities in vivo. J Leukoc Biol 59:769–774CrossRefGoogle Scholar
  24. Li B, Dewey CN (2011) RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinform 12:323CrossRefGoogle Scholar
  25. Li L, Tang Q, Jung HS (2016a) The grooved rodent incisor recapitulates rudimentary teeth characteristics of ancestral mammals. J Dent Res 95:923–930CrossRefGoogle Scholar
  26. Li L, Tang Q, Nakamura T, Suh JG, Ohshima H, Jung HS (2016b) Fine tuning of Rac1 and RhoA alters cuspal shapes by remolding the cellular geometry. Sci Rep 28:1–12Google Scholar
  27. Li L, Tang Q, Kwon HE, Wu Z, Kim EJ, Jung HS (2018) An explanation for how FGFs predict species-specific tooth Cusp patterns. J Dent Res 97:828–834CrossRefGoogle Scholar
  28. Majesky MW, Lindner V, Twardzik DR, Schwartz SM, Reidy MA (1991) Production of transforming growth factor beta I during repair of arterial injury. J Clin Invest 88:904–910CrossRefGoogle Scholar
  29. Margadant C, Sonnenberg A (2010) Integrin-TGF-beta crosstalk in fibrosis, cancer and wound healing. EMBO Rep 11:97–105CrossRefGoogle Scholar
  30. Martin JA, Wang Z (2011) Next-generation transcriptome assembly. Nat Rev Genet 12:671–682CrossRefGoogle Scholar
  31. Pechkovsky DV, Scaffidi AK, Hackett TL, Ballard J, Shaheen F, Thompson PJ et al (2008) TGF-β1 induces αvβ3 integrin expression in human lung fibroblasts via a β3 integrin-, c-Src-, and p38 MAPK-dependent pathway. J Biol Chem 283:12898–12908CrossRefGoogle Scholar
  32. Pertea G, Huang X, Liang F, Antonescu V, Sultana R, Karamycheva S et al (2003) TIGR Gene Indices clustering tools (TGICL): a software system for fast clustering of large EST datasets. Bioinformatics 19:651–652CrossRefGoogle Scholar
  33. Peters T, Sindrilaru A, Hinz B, Hinrichs R, Menke A, Al-Azzeh EA et al (2005) Wound healing defect of CD18_/_ mice due to a decrease in TGF-b1 and myofibroblast differentiation. EMBO J 24:3400–3410CrossRefGoogle Scholar
  34. Reynolds LE, Conti FJ, Silva R, Robinson SD, Iyer V, Rudling R et al (2008) α3β1 integrin-controlled Smad7 regulates reepithelialization during wound healing in mice. J Clin Invest 118:965–974Google Scholar
  35. Sabol F, Dancakova L, Gal P, Vasilenko T, Novotny M, Smetana K et al (2012) Immunohistological changes in skin wounds during the early periods of healing in a rat model. Vet Med 2:77–82CrossRefGoogle Scholar
  36. Seifert AW, Kiama SG, Seifert MG, Goheen JR, Palmer TM, Maden M (2012) Skin shedding and tissue regeneration in African spiny mice (Acomys). Nature 489:561–565CrossRefGoogle Scholar
  37. Sun J, Nishiyama T, Shimizu K, Kadota K (2013) TCC: an R package for comparing tag count data with robust normalization strategies. Bioinformatics 14:214–219Google Scholar
  38. Tolnai S, Beutelmann R, Klump GM (2017) Effect of preceding stimulation on sound localization and its representation in the auditory midbrain. Eur J Neurosci 45:460–471CrossRefGoogle Scholar
  39. Trapnell C, Williams BA, Pertea G, Mortazavi A, Kwan G, van Baren MJ et al (2010) Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol 28:511–515CrossRefGoogle Scholar
  40. Wang XJ, Han G, Owens P, Siddiqui Y, Li AG (2006) Role of TGFb-mediated inflammation in cutaneous wound healing. J Investig Dermatol Symp Proc 11:112–117CrossRefGoogle Scholar
  41. Winograd-Katz SE, Fässler R, Geiger B, Legate KR (2014) The integrin adhesome: from genes and proteins to human disease. Nat Rev Mol Cell Biol 15:273–288CrossRefGoogle Scholar
  42. Yang Y, Smith SA (2013) Optimizing de novo assembly of short-read RNA-seq data for phylogenomics. BMC Genom 14:328CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division in Anatomy and Developmental Biology, Department of Oral Biology, Oral Science Research Center, BK21 PLUS ProjectYonsei University College of DentistrySeoulSouth Korea

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