O3-17. Mesenchymal stromal cells and their effects on the renin-angiotensin system in dextran sodium sulfate colitis

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Hanne Salmenkari [1], Anita Laitinen [2], Mervi Holappa [1], Richard Forsgård [1], Jere Lindén [3], Lauri Pasanen [1], Matti Korhonen [2], Heikki Vapaatalo [1], Riitta Korpela [1], Johanna Nystedt [2].
Affiliates: [1] Medicum, Faculty of Medicine, University of Helsinki, Finland, [2] Advanced Cell Therapy Centre, Finnish Red Cross Blood Service, Finland, [3] Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, University of Helsinki, Finland.

Background
Mesenchymal stromal cells (MSC) could offer a novel cell therapy treatment option in IBD, although their therapeutic efficiency has been inconsistently proven in preclinical and clinical studies. The renin-angiotensin system (RAS) participates in intestinal inflammation locally via classical angiotensin-converting enzyme (ACE)-Angiotensin II-Angiotensin II receptor, type 1 (AGTR1A) axis. We studied the effects of fresh and cryopreserved MSCs on the severity of dextran sodium sulfate (DSS) colitis and the protein and mRNA expression of RAS components.

Methods
Colitis was induced to Balb/c male mice with 3% DSS in drinking water for 6 days followed by a 7-day recovery period. Mice were injected with fresh or cryopreserved human bone marrow-derived MSCs via the tail vein on days three and five of DSS administration (n=10 in each group). The severity of the colitis was measured by bodyweight change and histopathology scores. Protein and mRNA expression of pro-inflammatory cytokines; IL-1β and TNFα; and RAS components; ACE and Agtr1a were measured in colon tissue homogenates.

Results
Minor improvements were seen in pro-inflammatory cytokine IL-1β and TNFα protein and Il-1β mRNA expression in mice treated with fresh MSCs. The cytokine levels were increased in DSS controls and in mice which received cryopreserved MSCs but not in mice which received fresh MSCs. The overall severity of colitis was not ameliorated by the MSC treatments. Protein expression and ectodomain shedding of ACE were downregulated by cryopreserved MSCs. DSS alone reduced Agtr1a gene expression but the reduction was no more significant after MSC treatments.

Conclusions
The therapeutic effects of MSCs were minor in alleviating DSS colitis. Fresh MSCs might have a limited anti-inflammatory effect, although we could not verify any significant differences between fresh and cryopreserved MSCs. MSCs modulate intestinal RAS by reducing the potentially pro-inflammatory ACE tissue expression and possibly reducing the downregulation of Agtr1a expression.