Mesenchymal stem cell transplantation worsens intestinal inflammation and microenvironment in PI3Kγ-knockout mice
Yi Li1, Qian-Qian Chen1, Wen-Ya Zhu2
1Department of Gastroenterology, the First Medical Center, General Hospital of the Chinese People's Liberation Army, No. 28, Fu Xing Road, Hai Dian District, Beijing 100853, China.
Abstract:
Considering the possible interaction between mesenchymal stem cells (MSCs) and PI3Kγ-associated drugs, we evaluated the efficacy and action mechanism of MSCs in the treatment of colitis in PI3Kγ-/- mice. Trinitro-benzene-sulfonic acid enema was used to create a colitis model, and MSCs were transplanted through the caudal vein to treat colitis in wild-type and PI3Kγ-/- mice. We sequenced microbial 16S rRNA genes in the colonic mucosa of PI3Kγ-/- and wild-type mice and quantified colonic IgA, IL-2, IL-10, IL-17A, occludin, and serum IgA. MSC transplantation led to a more serious reduction in the weight of trinitro-benzene-sulfonic acid-administered PI3Kγ-/- mice than that in wild-type mice. The disease activity index, pathological scoring, number of taxa in the colon, Berger-Parker index, I-index, proportion of Proteobacteria, and IgA level in the blood were higher in PI3Kγ-/- mice than in wild-type mice after MSC transplantation. The occludin and IL-10 levels in the colon tissues decreased before and after MSC transplantation in PI3Kγ-/- mice, whereas they were increased in wild-type mice The IL-17 level decreased in both wild-type and PI3Kγ-/- mice, with knockout mice showing a greater decrease. Therefore, MSC transplantation in PI3Kγ-/- mice led to increased numbers of exogenous pathogenic microorganisms and enhanced colitis that was difficult to relieve.
Insights
Mesenchymal stem cell (MSC) transplantation worsened colitis in PI3Kγ knockout mice by increasing pathogenic microbes and reducing protective factors. This suggests PI3Kγ is crucial for MSC therapy efficacy in colitis.
Area of Science:
- Immunology
- Gastroenterology
- Microbiology
Background:
- Mesenchymal stem cells (MSCs) show therapeutic potential for inflammatory conditions like colitis.
- The role of phosphoinositide 3-kinase gamma (PI3Kγ) in MSC-mediated treatment remains unclear.
- Investigating PI3Kγ's interaction with MSCs is crucial for understanding treatment efficacy.
Purpose of the Study:
- To evaluate the efficacy and mechanism of MSCs in treating colitis in PI3Kγ knockout mice.
- To compare MSC treatment outcomes in PI3Kγ-/- mice versus wild-type mice.
- To elucidate the impact of PI3Kγ deficiency on the gut microbiome and immune response during MSC therapy.
Main Methods:
- A colitis model was induced using trinitro-benzene-sulfonic acid enema in wild-type and PI3Kγ-/- mice.
- Mesenchymal stem cells were administered intravenously to treat colitis.
- Colonic microbial 16S rRNA genes, IgA, IL-2, IL-10, IL-17A, occludin, and serum IgA were quantified.
Main Results:
- MSC transplantation exacerbated weight loss and disease severity in PI3Kγ-/- mice compared to wild-type.
- PI3Kγ-/- mice exhibited increased disease activity, pathological scores, gut microbial diversity, and blood IgA post-MSC treatment.
- Colon occludin and IL-10 levels decreased in PI3Kγ-/- mice but increased in wild-type mice after MSC transplantation.
Conclusions:
- Mesenchymal stem cell transplantation in PI3Kγ-/- mice leads to increased pathogenic microorganisms and aggravated colitis.
- PI3Kγ plays a critical role in mediating the therapeutic effects of MSCs in colitis.
- Targeting PI3Kγ may be essential for optimizing MSC-based therapies for inflammatory bowel diseases.
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