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Invest Ophthalmol Vis Sci. 2017 Nov 1;58(13):5654-5665. doi: 10.1167/iovs.17-22071.

Manipulation of Panx1 Activity Increases the Engraftment of Transplanted Lacrimal Gland Epithelial Progenitor Cells.

Author information

1
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, United States.
2
Advirna LLC, Cambridge, Massachusetts, United States.
3
Department of Comprehensive Care, Tufts University School of Dental Medicine, Boston, Massachusetts, United States.
4
Department of Ophthalmology, Tufts University School of Medicine, Boston, Massachusetts, United States.
5
Bascom Palmer Eye Institute Department of Ophthalmology, University of Miami School of Medicine, Miami, Florida, United States.
6
Department of Cell Biology, University of Miami School of Medicine, Miami, Florida, United States.

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.

PMID:
29098296
PMCID:
PMC5678547
DOI:
10.1167/iovs.17-22071
[Indexed for MEDLINE]
Free PMC Article

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