Manipulation of panx1 activity increases the engraftment of transplanted lacrimal gland epithelial progenitor cells

Liana V. Basova, Xin Tang, Takeshi Umasume, Anastasia Gromova, Tatiana Zyrianova, Taisia Shmushkovich, Alexey Wolfson, Dillon Hawley, Driss Zoukhri, Valery I. Shestopalov, Helen P. Makarenkova

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

PURPOSE: Sjögren's syndrome is a systemic chronic autoimmune inflammatory disease that primarily targets the salivary and lacrimal glands (LGs). Currently there is no cure; therefore, cell-based regenerative therapy may be a viable option. LG inflammation is facilitated by extracellular ATP and mediated by the Pannexin-1 (Panx1) membrane channel glycoprotein. We propose that suppression of inflammation through manipulation of Panx1 activity can stimulate epithelial cell progenitor (EPCP) engraftment. METHODS: The expression of pannexins in the mouse and human LG was assayed by qRT-PCR and immunostaining. Acute LG inflammation was induced by interleukin-1α (IL1α) injection. Prior to EPCP transplantation, IL1α-injured or chronically inflamed LGs of thrombospondin-1-null mice (TSP-1-/-) were treated with the Panx1-specific blocking peptide (10panx) or the self-deliverable RNAi (sdRNAi). The efficacy of cell engraftment and the area of inflammation were analyzed by microscopy. RESULTS: Panx1 and Panx2 were detected in the mouse and human LGs. Panx1 and proinflammatory factors were upregulated during acute inflammation at days 1 to 3 after the IL1α injection. The analysis of EPCP engraftment demonstrated a significant and reproducible positive correlation between the 10panx peptide or Panx1 sdRNAi treatment and the number of engrafted cells. Similarly, treatment of the LG of the TSP-1-/- mouse (mouse model of chronic LG inflammation) by either Panx1 or Caspase-4 (also known as Casp11) sdRNAi showed a significant decrease in expression of proinflammatory markers and the lymphocyte infiltration. CONCLUSIONS: Our results suggest that blocking Panx1 and/or Casp4 activities is a beneficial strategy to enhance donor cell engraftment and LG regeneration through the reduction of inflammation.

Original languageEnglish (US)
Pages (from-to)5654-5665
Number of pages12
JournalInvestigative Ophthalmology and Visual Science
Volume58
Issue number13
DOIs
StatePublished - Nov 2017

Keywords

  • Epithelial progenitor cells
  • Injury-induced inflammation
  • Lacrimal gland
  • Pannexin-1
  • Regeneration

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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    Basova, L. V., Tang, X., Umasume, T., Gromova, A., Zyrianova, T., Shmushkovich, T., Wolfson, A., Hawley, D., Zoukhri, D., Shestopalov, V. I., & Makarenkova, H. P. (2017). Manipulation of panx1 activity increases the engraftment of transplanted lacrimal gland epithelial progenitor cells. Investigative Ophthalmology and Visual Science, 58(13), 5654-5665. https://doi.org/10.1167/iovs.17-22071