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Published on: July 19, 2018
Mesothelial cell transplantation in models of acute inflammation and chronic peritoneal dialysis
Liesbeth H P Hekking1, V Susan Harvey, Carin E G Havenith
1Department of Molecular Cell Biology, VU University Medical Center, Amsterdam, The Netherlands. ehp.hekking.cell@med.vu.nl
Objectives:
Mesothelial cell (MC) injury caused by continuous exposure to unphysiological peritoneal dialysis (PD) fluid and by episodes of peritonitis can eventually lead to peritoneal adhesions and peritoneal fibrosis. In the present study, we evaluated the possibility of using autologous genetically modified MCs for transplantation after the induction of peritoneal injury by acute inflammatory mediators or chronic instillation of PD fluid.
Methods:
Rats were injected intraperitoneally either once with N-formyl-methionyl-leucyl-phenylalanine (fMLP), or thioglycollate, or PD fluid [i.e., Dianeal (Baxter Healthcare, Deerfield, Illinois, USA) or Physioneal (Baxter, Nivelles, Belgium)], or chronically (up to 8 weeks) with Dianeal. From 2 to 48 hours later, animals were injected with syngeneic MCs genetically modified to express the LacZ reporter gene. Rats were sacrificed 2 days later and expression of beta-galactosidase (beta-Gal) was visualized by X-Gal staining of excised tissues. Quantification of the percent area of beta-Gal-positive MCs on part of the parietal peritoneum was performed using computerized image analysis.
Results:
The highest numbers of repopulated genetically modified MCs were observed 8 hours after a single thioglycollate injection, approximately 0.66% of a representative 2-cm2 area selected for study (corresponding to approximately 10% of the peritoneal surface). The number of genetically modified MCs found to repopulate the peritoneal surface following short-term injury varied with inflammatory mediator (thioglycollate > PD fluid > fMLP) and duration of exposure. No obvious differences were observed between the two PD fluids tested. Reimplantation of syngeneic genetically modified MCs was also observed after chronic instillation of PD fluid.
Conclusions:
These data demonstrate that transplanted genetically modified MCs repopulate the denuded areas on the peritoneal surface that were caused by acute or chronic inflammation. This technique opens possibilities of MC transplantation and gene therapy in order to prevent complications relevant to the continuous ambulatory PD setting.
Insights
Transplanted genetically modified mesothelial cells (MCs) can repopulate damaged peritoneal surfaces after inflammation. This cell therapy shows promise for preventing peritoneal dialysis complications.
Area of Science:
- Regenerative Medicine
- Cell Biology
- Nephrology
Background:
- Peritoneal dialysis (PD) fluid and peritonitis can injure mesothelial cells (MCs), leading to peritoneal adhesions and fibrosis.
- Current treatments lack effective strategies to repair MC damage in the peritoneal cavity.
Purpose of the Study:
- To evaluate the potential of autologous genetically modified MC transplantation for repairing peritoneal injury.
- To assess MC repopulation following acute inflammatory mediators or chronic PD fluid exposure.
Main Methods:
- Rats received intraperitoneal injections of inflammatory mediators (fMLP, thioglycollate) or PD fluid, or chronic PD fluid.
- Syngeneic MCs, genetically modified to express LacZ, were injected into rats.
- Beta-galactosidase (beta-Gal) expression was quantified to assess MC repopulation.
Main Results:
- Genetically modified MCs successfully repopulated denuded peritoneal areas, with highest numbers observed 8 hours post-thioglycollate injection.
- MC repopulation varied with inflammatory mediator and exposure duration, with thioglycollate showing the most significant effect.
- Successful repopulation was observed even after chronic PD fluid instillation.
Conclusions:
- Transplanted genetically modified MCs can effectively repopulate peritoneal surfaces damaged by inflammation.
- This approach offers a potential strategy for MC transplantation and gene therapy to prevent PD-related complications.
