TY - JOUR
T1 - Manipulation of panx1 activity increases the engraftment of transplanted lacrimal gland epithelial progenitor cells
AU - Basova, Liana V.
AU - Tang, Xin
AU - Umasume, Takeshi
AU - Gromova, Anastasia
AU - Zyrianova, Tatiana
AU - Shmushkovich, Taisia
AU - Wolfson, Alexey
AU - Hawley, Dillon
AU - Zoukhri, Driss
AU - Shestopalov, Valery I.
AU - Makarenkova, Helen P.
N1 - Funding Information:
The authors thank Dale W. Laird, University of Western Ontario, Canada, for providing the Panx1 antibody. Supported by National Institutes of Health, National Eye Institute Grants 1R01EY026202 (to HPM), R01-EY12383 (to DZ and HPM), and 2R01EY012383 (to VS) and Small Business Innovation Research (SBIR) Grant 5R44HG006788 from National Human Genome Research Institute (NHGRI) (to AW).
Publisher Copyright:
© 2017 The Authors.
PY - 2017/11
Y1 - 2017/11
N2 - 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.
AB - 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.
KW - Epithelial progenitor cells
KW - Injury-induced inflammation
KW - Lacrimal gland
KW - Pannexin-1
KW - Regeneration
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U2 - 10.1167/iovs.17-22071
DO - 10.1167/iovs.17-22071
M3 - Article
C2 - 29098296
AN - SCOPUS:85033405691
VL - 58
SP - 5654
EP - 5665
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
SN - 0146-0404
IS - 13
ER -