Repair and regeneration of tracheal surface epithelium and submucosal glands in a mouse model of hypoxic-ischemic injury

Authors

  • AHMED E. HEGAB,

    1. Department of Pediatrics, Mattel Children's Hospital
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  • DEREK W. NICKERSON,

    1. Department of Pediatrics, Mattel Children's Hospital
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  • VI LUAN HA,

    1. Department of Pediatrics, Mattel Children's Hospital
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  • DAPHNE O. DARMAWAN,

    1. Department of Pediatrics, Mattel Children's Hospital
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  • BRIGITTE N. GOMPERTS

    Corresponding author
    1. Department of Pediatrics, Mattel Children's Hospital
    2. Department of Medicine, Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA
    3. Broad Stem Cell Research Center at UCLA, and
    4. Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, California, USA
      Brigitte N. Gomperts, David Geffen School of Medicine at UCLA, Department of Pediatrics, 10833 Le Conte Avenue, A2-410MDCC, Los Angeles, CA 90095, USA. Email: bgomperts@mednet.ucla.edu
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Brigitte N. Gomperts, David Geffen School of Medicine at UCLA, Department of Pediatrics, 10833 Le Conte Avenue, A2-410MDCC, Los Angeles, CA 90095, USA. Email: bgomperts@mednet.ucla.edu

ABSTRACT

Background and objective:  The heterotopic syngeneic tracheal transplant mouse model is an acute hypoxic-ischemic injury model that undergoes complete repair and regeneration. We hypothesized that the repair and regeneration process of the surface epithelium and submucosal glands would occur in a reproducible pattern that could be followed by the expression of specific markers of epithelial cell types.

Methods:  We used the syngeneic heterotopic tracheal transplant model to develop a temporal and spatial map of cellular repair and regeneration by examining the tracheal grafts at post-transplant days 1, 3, 5, 7, 10 and 14. We used pulsed BrdU and immunofluorescent staining to identify and follow proliferating and repairing cell populations.

Results:  We confirmed the reproducibility of the injury and repair in the model and we found a distinct sequence of reappearance of the various stem/progenitor and differentiated cell populations of the tracheal surface epithelium and submucosal glands. In the initial phase, the basal and duct cells that survived the injury proliferated to re-epithelialize the basement membrane with K5 and K14 expressing cells. Then these cells proliferated further and differentiated to restore the function of the epithelium. During this repair process, TROP-2 marked all repairing submucosal gland tubules and ducts. Non-CCSP-expressing serous cells were found to differentiate 4–5 days before Clara, mucus and ciliated cells.

Conclusions:  Improving our understanding of the reparative process of the airway epithelium will allow us to identify cell-specific mechanisms of repair that could be used as novel therapeutic approaches for abnormal repair leading to airway diseases.

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