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. 2023 Jul;19(5):1370-1383.
doi: 10.1007/s12015-023-10522-4. Epub 2023 Mar 4.

Human Amniotic Mesenchymal Stem Cells Alleviate aGVHD after allo-HSCT by Regulating Interactions between Gut Microbiota and Intestinal Immunity

Xiaoyin Bu #  1   2 , Junhui Wang #  1 , Zhao Yin #  1 , Weifeng Pan  1 , Liping Liu  1 , Hua Jin  1 , Qifa Liu  1 , Lei Zheng  3 , Haitao Sun  4 , Ya Gao  5 , Baohong Ping  6   7
Affiliations

Human Amniotic Mesenchymal Stem Cells Alleviate aGVHD after allo-HSCT by Regulating Interactions between Gut Microbiota and Intestinal Immunity

Xiaoyin Bu et al. Stem Cell Rev Rep. 2023 Jul.

Abstract

Acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation poses one of the most vexing challenges. Gut microbiota dysbiosis can proceed aGVHD and mesenchymal stem cells (MSCs) have promising therapeutic potential for aGVHD. However, whether hAMSCs affect the gut microbiota during aGVHD mitigation remains unknown VSports手机版. Accordingly, we sought to define the effects and underlying mechanisms of human amniotic membrane-derived MSCs (hAMSCs) regulating the gut microbiota and intestinal immunity in aGVHD. By establishing humanized aGVHD mouse models and hAMSCs treatment, we found that hAMSCs significantly ameliorated aGVHD symptoms, reversed the immune imbalance of T cell subsets and cytokines, and restored intestinal barrier. Moreover, the diversity and composition of gut microbiota were improved upon treatment with hAMSCs. Spearman's correlation analysis showed that there was a correlation between the gut microbiota and tight junction proteins, immune cells as well as cytokines. Our research suggested that hAMSCs alleviated aGVHD by promoting gut microbiota normalization and regulating the interactions between the gut microbiota and intestinal barrier, immunity. .

Keywords: Acute graft-versus-host disease; Amniotic mesenchymal stem cells; Gut microbiota; Intestinal barrier; Intestinal immunity. V体育安卓版.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Phenotypic and functional characterization of hAMSCs. (A) Representative micrographs of hAMSCs from passage 0 to 3 (no staining, 100 ×). (B) Multilineage differentiation ability of hAMSCs. Adipogenic differentiation of hAMSCs (left) were stained with Oil Red-O, and osteoblastic differentiation of hAMSCs (right) were stained with Alizarin Red (staining, 100 ×). (C) Flow cytometric analysis indicating hAMSCs positive for CD90, CD105 and CD73 while negative for CD34, CD45, CD11b and HLA-DR
Fig. 2
Fig. 2
hAMSCs alleviated aGVHD in NPG mice. (A) A schematic diagram illustrating administration schedule of hAMSCs in aGVHD mouse models. (B) Changes of body weight in different groups (n = 10). (C) aGVHD clinical score (based on weight loss, hunched posture, ruffled fur, skin lesions, reduced mobility and diarrhea) in different groups (n = 10). (D) Survival among different groups (n = 10). (E) Representative microscopic pictures of H&E staining (400 ×) and histology score (based on the tissues structure destruction and lymphocyte infiltration) (n = 4). (F) Representative microscopic pictures of immunohistochemistry (400 ×) and the proportion of CD45 positive area (n = 4). Values were presented as mean ± SD
Fig. 3
Fig. 3
hAMSCs inhibited donor T cell expansion while enhanced Tregs generation or expansion in vivo. (A) Flow cytometry analysis of CD3 + CD4 + T cells(n = 6), (B) Flow cytometry analysis of CD3 + CD8 + T cells(n = 6), (C) Flow cytometry analysis of CD4 + CD25 + Foxp3 + Tregs (n = 6). Values were presented as mean ± SD
Fig. 4
Fig. 4
hAMSCs downregulated pro-inflammatory cytokines IL-17A, IFN-γ, TNF, IL-6, IL-2 and upregulated anti-inflammatory cytokines IL-10 and IL-4 in vivo (n = 5). Values were presented as mean ± SD
Fig. 5
Fig. 5
hAMSCs ameliorated intestinal barrier dysfunction in aGVHD mice. (A) GFP-labeled hAMSCs infiltrated into the intestines. (B) Representative microscopic pictures of H&E staining of intestines (400 ×) and histology score (based on the tissues structure destruction and lymphocyte infiltration) (n = 4). (C) Representative microscopic pictures of immunohistochemistry (400 ×) of intestines and the proportion of CD45 positive area (n = 4). (D) Representative microscopic pictures of immunohistochemistry (400 ×) of intestines and the proportion of ZO-1 positive area (n = 4). (E) mRNA expression levels of ZO-1 and Occludin (n = 3). (F) Plasma levels of D-LA and DAO (n = 4). Values were presented as mean ± SD
Fig. 6
Fig. 6
Gut microbiota alternations in aGVHD mice. (A) comparison of α-diversity. (B) comparison of β-diversity. (C) Venn diagram of OTUs. (D) Relative bacterial abundance at the phylum level. (E) Heatmap of species abundance at the genus level. (F) Relative abundances of Odoribacter at the genus level. (G) Relative abundances of Ruminococcus_1 at the genus level. (H) Cladogram based on LEfSe analysis. (I) LDA score computed from features differentially abundant between aGVHD and hAMSCs groups. (A-I) n = 3 mice per group. Values were presented as mean ± SD
Fig. 7
Fig. 7
Correlation analysis between gut microbiota and intestinal immunity. Spearman’s correlation analysis was conducted between the relative abundance of 15 different gut microbiota (at the genus level) and the mRNA expression level of TJs, the percentage of immune cells as well as the concentration of cytokines in the intestines among the two groups. Spearman r values range from -0.5 (blue) to 0.5 (red)
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