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. 2018 Sep;27(9):1390-1400.
doi: 10.1177/0963689718782442. Epub 2018 Jul 6.

The Therapeutic Effects of Adipose-Derived Stem Cells and Recombinant Peptide Pieces on Mouse Model of DSS Colitis

Reiko Iwazawa  1 , Sayako Kozakai  1 , Tsukasa Kitahashi  1 , Kentaro Nakamura  1 , Ken-Ichiro Hata  1
Affiliations

The Therapeutic Effects of Adipose-Derived Stem Cells and Recombinant Peptide Pieces on Mouse Model of DSS Colitis

Reiko Iwazawa et al. Cell Transplant. 2018 Sep.

Abstract

Cell therapies using adipose-derived stem cells (ADSCs) have been used to treat inflammatory bowel disease (IBD) in human and dog. We previously reported the CellSaic technique, which uses a recombinant scaffold to enhance the efficacy of cell therapy. To examine whether this technique can be applied to cell therapy for colitis, we evaluated the efficacy of CellSaic in colitis mouse models. Colitis mouse models were developed by administering dextran sulfate sodium (DSS) to C57BL/6 mice for 7 days. Then CellSaic comprising human/canine ADSCs (1.2 × 106 cells) or human/canine ADSCs only (1.2 × 106 cells) were administered to the mice. The body weights were measured, and the colon length measurements and histological evaluations were conducted at 7 days after administration. After in vitro culture of human ADSC (hADSC) CellSaic and hADSC spheroids in medium containing TNFα, the levels of the anti-inflammatory protein TSG-6 in each supernatant were measured. Furthermore, we conducted tumorigenicity and general toxicity tests of canine ADSC (cADSC) CellSaic in NOG mice for 8 weeks. In the colitis mouse models, the ADSC CellSaic group presented recovery of body weight and colon length compared with the ADSC-only group. Histological analysis showed that ADSC CellSaic decreased the number of inflammatory cells and repaired ulceration. In vitro, hADSC CellSaic secreted 3.1-fold more TSG-6 than the hADSCs. In addition, tumorigenicity and general toxicity of cADSC CellSaic were not observed. This study suggests that human and canine ADSC CellSaic has a therapeutic effect of colitis in human and dogs.

Keywords: adipose-derived stem cells; dextran sulfate sodium-induced colitis mouse; inflammatory bowel disease; veterinary therapy.

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Conflict of interest statement

Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Fig. 1.
Fig. 1.
Experimental design of this study. We conducted an efficacy test and safety test of ADSC CellSaic. (A) Efficacy test: therapeutic effects of hADSC/cADSC CellSaic, evaluated in DSS-induced mouse model, compared with hADSC/cADSC suspension; Body weight was measured. Seven days after administration, mice were sacrificed, colon length was measured, and histological evaluation was conducted. (B) Safety test: Tumorigenicity and toxicity tests were conducted. cADSC CellSaic evaluated in NOG mouse. Volume of nodules, body weight, and food consumption were measured until 8 weeks. Four and 8 weeks after administration, urinalysis, hematology test, body chemistry test, necropsy organ weight measurement, and histopathological examination were conducted.
Fig. 2.
Fig. 2.
hADSC CellSaic attenuates recovery of body weight and colon length. (A) Percentage of body weight changes. Non-DSS group [no treatment with DSS, n = 5 (gray square)], DSS group [no cell transplantation into DSS mice, n = 5 (green cross)], hADSC suspension i.p. group [1.2 × 106 hADSCs in suspension intraperitoneally administered to DSS mice, n = 5 (blue triangle)], hADSC CellSaic i.p. group [CellSaics of 1.2 × 106 hADSCs and 1 mg u-pieces, intraperitoneally administered to DSS mice, n = 5 (red circle)]. *p < 0.05. The hADSC CellSaic i.p. group and hADSC suspension i.p. group were each compared with the DSS group by one-way analysis of variance with Dunnett’s test. (B) Colon length on day 14. The value of 75% – median (blue box), median – the value of 25% (red box), value of average (green cross). Non-DSS group [no treatment with DSS, n = 5], DSS group [no cell transplantation into DSS mice, n = 5], hADSC suspension i.p. group [1.2 × 106 hADSCs in suspension intraperitoneally administered to DSS mice, n = 5], hADSC CellSaic i.p. group [CellSaics of 1.2 × 106 hADSCs and 1 mg u-pieces, intraperitoneally administered to DSS mice, n = 5]. *p < 0.05. hADSC CellSaic group and hADSC suspension group compared with the DSS group. (C) The images of colon tissues. Representative images of colon tissue in each group were shown.
Fig. 3.
Fig. 3.
ADSC CellSaic decreased inflammatory cells and repaired ulceration in histological analysis. Histopathological comparison of colitis in lower colon at day 14. There was no ulceration and no infiltration in the non-DSS group. In the DSS group and hADSC suspension group, ulceration and infiltration are more severe than in the hADSC CellSaic group. The arrows indicate ulceration and infiltration. Scale Bar is 100 µm. (A) Histopathological comparison of colitis in the rectum at day 14. There was no edema in the non-DSS group. In the DSS group and hADSC suspension group, edema was more severe than in the hADSC CellSaic group. The arrows indicate edema. Scale bar is 100 µm. (B) Histological evaluation of the colon at day 14. The value of 75% – median (blue box), median – the value of 25% (red box), the value of average (green cross). Non-DSS group [no treatment with DSS, n = 5], DSS group [no cell transplantation into DSS mice, n = 5], hADSC suspension i.p. group [1.2 × 106 hADSCs in suspension intraperitoneally administered to DSS mice, n = 5], hADSC CellSaic i.p. group [CellSaics of 1.2 × 106 hADSCs and 1 mg u-pieces, intraperitoneally administered to DSS mice, n = 5]. *p < 0.05. hADSC CellSaic group compared with DSS group and hADSC suspension group.
Fig. 4.
Fig. 4.
cADSC CellSaic also attenuates recovery of body weight and colon length. (A) Percentage of body weight changes. Non-DSS group [no treatment with DSS, n = 5 (gray square)], DSS group [no cell transplantation into DSS mice, n = 5 (green cross)], cADSC suspension i.v. group [1.2 × 106 cADSCs in suspension intravenously administered to DSS mice, n = 4 (close blue triangle solid line)], cADSC in suspension clinical dose i.v. group [4 × 104 cADSCs in suspension intravenously administered to DSS mice, n = 5 (open blue triangle dotted line)], cADSC CellSaic group [CellSaics of 1.2 × 106 cADSC and 0.25 mg u-pieces, intraperitoneally administered to DSS mice, n = 4 (red circle)]. *p < 0.05. The cADSC CellSaic i.p. group, cADSC suspension i.v. group, and cADSC suspension clinical dose i.v. group were each compared with the DSS group by one-way analysis of variance with Dunnett’s test. (B) Colon length of day 14. The value of 75% – median (blue box), median – the value of 25% (red box), value of average (green cross). Non-DSS group [no treatment with DSS, n = 5], DSS group [no cell transplantation into DSS mice, n = 5], cADSC suspension i.v. group [1.2 × 106 cADSCs in suspension intravenously administered to DSS mice, n = 4], cADSCs in suspension clinical dose i.v. group [4 × 104 cADSCs in suspension intravenously administered to DSS mice, n = 5], cADSC CellSaic group [CellSaics of 1.2 × 106 cells cADSCs and 0.25 mg u-pieces, intraperitoneally administered to DSS mice, n = 4]. *p < 0.05. **p < 0.01. cADSC CellSaic group compared with DSS group, cADSC suspension i.v. group, and cADSC suspension clinical dose i.v. group. (C) The images of colon tissues. Representative images of colon tissue in each group were shown.
Fig. 5.
Fig. 5.
Comparison of TSG-6 levels in vitro. TSG-6 level in the supernatants collected from hADSC spheroids and hADSC CellSaic, after incubation with or without TNFα for 48 h, as measured by ELISA. ***p < 0.005.
Fig. 6.
Fig. 6.
Volume of nodules in tumorigenicity test. (A) Volume of nodules in male mice. Control (saline) group; circle, Control (culture media) group: square, CellSaic group; triangle. CellSaic group was significantly different from the control (saline) group (##: p < 0.01 by Steel–Dwass test) and control (culture media) group (++: p < 0.01 by Steel–Dwass test). (B) Volume of nodules in female mice. Control (saline) group; circle, Control (culture media) group: square, CellSaic group; triangle.
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