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Siglec‑15 dysregulation and its therapeutic implications in new‑onset type 1 diabetes 

  • Authors:
    • Heming Guo
    • Yunwen Tao
    • Sicheng Li
    • Ying Gu
    • Yiting Huang
    • Chen Fang
    • Ji Hu
  • View Affiliations / Copyright

    Affiliations: Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China, Department of Clinical Nutrition, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
    Copyright: © Guo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 135
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    Published online on: March 20, 2026
       https://doi.org/10.3892/ijmm.2026.5806
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Abstract

Type 1 diabetes (T1D) is a T cell‑mediated autoimmune disorder characterized by the destruction of insulin‑producing β‑cells. Sialic acid‑binding Ig‑like lectin 15 (Siglec‑15) could inhibit T‑cell activation and suppress immune responses. However, the association between Siglec‑15 expression levels and T1D is largely unknown. Serum concentrations of soluble Siglec‑15 were quantified in a cohort comprising 34 individuals newly diagnosed with T1D and 21 healthy control subjects. A murine mesenchymal stem cell (MSC) line, C3H10 T1/2, was genetically engineered to stably express SIGLEC15 through lentiviral transduction. Non‑obese diabetic (NOD) mice were administered treatments with Siglec15‑expressing MSCs, control MSCs, or phosphate‑buffered saline. The present study evaluated diabetes incidence, blood glucose concentrations, the severity of insulitis and the composition of immune cell populations in the pancreatic lymph nodes and spleens. In the present study, measurement of human serum specimens by ELISA revealed a positive association between new‑onset T1D and soluble Siglec‑15 levels. In NOD mice, treatment with Siglec15‑MSCs resulted in a significant reduction in diabetes incidence, preservation of insulin‑positive islets and mitigation of insulitis. Flow cytometric analysis demonstrated an increase in CD4+effector memory T cells within the pancreatic‑draining lymph nodes of mice treated with Siglec15‑MSCs, while no significant alterations were observed in splenic T cell populations or the frequencies of regulatory T cells. The findings of this study underscore the potential of Siglec‑15‑overexpressing MSCs as a promising cell‑based therapeutic approach for T1D, primarily through the localized modulation of memory T cells within the pancreatic lymph nodes.
View Figures

Figure 1

Comparison of serum levels of
Siglec15 between new-onset T1D patients and healthy control group.
New-onset T1D, n=34; healthy control, n=21. Data are shown as the
means. P-value was determined by unpaired Student's t-test.
Siglec15, sialic acid-binding Ig-like lectin 15; T1D, type 1
diabetes.

Figure 2

Ectopic expression of Siglec15 in
C3H10 cells. (A) Representative microscopy images of Control-MSCs
and Siglec15-MSCs are shown. Scale bar, 50 µm (left), 100
µm (right). (B) Reverse transcription-quantitative PCR
quantified the relative expression of Siglec15 in Siglec-15-MSCs
compared with Control-MSCs. Data are shown as the means ± SEM.
P-value was determined by one-way ANOVA with post hoc multiple
comparisons. SEM, standard error of the mean.
***P<0.001; ns, not significant. (C) Comparative
immunofluorescence analysis of Siglec15 expression in Siglec15-MSCs
vs. Control-MSCs. Siglec15, sialic acid-binding Ig-like lectin 15;
MSCs, mesenchymal stem cells. Scale bar, 100 µm (left), 50
µm (right).

Figure 3

Experimental design showing
intravenous injection and subsequent euthanasia in NOD mice. NOD,
non-obese diabetic; PLNs, pancreatic lymph nodes.

Figure 4

Effect of Siglec 15-MSCs treatment on
T1D incidence. (A) Diabetes-free rate at week 8 post-injection.
Mice with blood glucose levels greater than 13.9 mmol/l were
regarded as diabetic. (B) The mean blood glucose level in each
group. Blood glucose levels were measured with a simple glucose
meter. Those exceeding the upper limit of measurement with a simple
blood glucose meter were regarded as having a blood glucose level
of 33.3 mmol/l. PBS, n=6; Control-MSCs, n=6; Siglec15-MSCs, n=6.
Data are shown as the means ± SEM. The log-rank test was used to
compare diabetes-free rates (Fig.
4A). Blood glucose levels were analyzed by mixed ANOVA followed
by Sidak's test (Fig. 4B).
*P<0.05; **P<0.01;
***P<0.001. Siglec15, sialic acid-binding Ig-like
lectin 15; MSCs, mesenchymal stem cells; T1D, type 1 diabetes.

Figure 5

Morphological changes following
Siglec-15-MSCs treatment. (A) Cohorts of mice were sacrificed week
8 post-treatment, pancreatic sections were subjected to hematoxylin
and eosin staining and grading for insulitis severity. Examples of
islets with different insulitis grades are shown. Scale bar, 50
µm. (B) The percentage of medium and large islet areas was
quantified and is shown according to insulitis grade. Fisher's
exact test to compare the relative frequencies of islets with
insulitis grades ≤2 and ≥3 between the groups. Siglec15, sialic
acid-binding Ig-like lectin 15; MSCs, mesenchymal stem cells.

Figure 6

Effect of Siglec15-MSCs treatment on
insulin positive islet. (A) Immunofluorescence staining of
pancreatic sections for insulin (red), glucagon (green) and nuclei
(blue), assessed for insulitis and insulin-positive islets. Scale
bar, 20 µm. (B) Analysis of insulitis severity, showing the
percentage of islets at each grade. Fisher's exact test was used to
compare the frequency of low-grade (≤III) vs. high-grade (≥IV)
insulitis between the Siglec15-MSCs and Control-MSCs groups.
Siglec15, sialic acid-binding Ig-like lectin 15; MSCs, mesenchymal
stem cells.

Figure 7

Effect of Siglec15-MSCs treatment on
Tregs and memory T-cells. (A) Percentages of Tregs in pancreatic
draining lymph nodes (upper panel) and the spleen (lower panel)
across the three groups. (B) Comparison of memory T-cell subset
percentages in pancreatic draining lymph nodes across the three
groups. (C) Comparison of memory T-cell subset percentages in the
spleen across the three groups. PBS, n=4; Control-MSCs, n=4;
Siglec15-MSCs, n=4. Data are shown as the means ± SEM. Statistical
analyses were performed using one-way ANOVA and post hoc multiple
comparisons. *P<0.05; **P<0.01;
***P<0.001. Siglec15, sialic acid-binding Ig-like
lectin 15; Tregs, regulatory T cells; MSCs, mesenchymal stem cells;
TEM. effector memory T cell; Foxp3, forkhead box protein P3.
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Copy and paste a formatted citation
Spandidos Publications style
Guo H, Tao Y, Li S, Gu Y, Huang Y, Fang C and Hu J: Siglec‑15 dysregulation and its therapeutic implications in new‑onset type 1 diabetes&nbsp;. Int J Mol Med 57: 135, 2026.
APA
Guo, H., Tao, Y., Li, S., Gu, Y., Huang, Y., Fang, C., & Hu, J. (2026). Siglec‑15 dysregulation and its therapeutic implications in new‑onset type 1 diabetes&nbsp;. International Journal of Molecular Medicine, 57, 135. https://doi.org/10.3892/ijmm.2026.5806
MLA
Guo, H., Tao, Y., Li, S., Gu, Y., Huang, Y., Fang, C., Hu, J."Siglec‑15 dysregulation and its therapeutic implications in new‑onset type 1 diabetes&nbsp;". International Journal of Molecular Medicine 57.5 (2026): 135.
Chicago
Guo, H., Tao, Y., Li, S., Gu, Y., Huang, Y., Fang, C., Hu, J."Siglec‑15 dysregulation and its therapeutic implications in new‑onset type 1 diabetes&nbsp;". International Journal of Molecular Medicine 57, no. 5 (2026): 135. https://doi.org/10.3892/ijmm.2026.5806
Copy and paste a formatted citation
x
Spandidos Publications style
Guo H, Tao Y, Li S, Gu Y, Huang Y, Fang C and Hu J: Siglec‑15 dysregulation and its therapeutic implications in new‑onset type 1 diabetes&nbsp;. Int J Mol Med 57: 135, 2026.
APA
Guo, H., Tao, Y., Li, S., Gu, Y., Huang, Y., Fang, C., & Hu, J. (2026). Siglec‑15 dysregulation and its therapeutic implications in new‑onset type 1 diabetes&nbsp;. International Journal of Molecular Medicine, 57, 135. https://doi.org/10.3892/ijmm.2026.5806
MLA
Guo, H., Tao, Y., Li, S., Gu, Y., Huang, Y., Fang, C., Hu, J."Siglec‑15 dysregulation and its therapeutic implications in new‑onset type 1 diabetes&nbsp;". International Journal of Molecular Medicine 57.5 (2026): 135.
Chicago
Guo, H., Tao, Y., Li, S., Gu, Y., Huang, Y., Fang, C., Hu, J."Siglec‑15 dysregulation and its therapeutic implications in new‑onset type 1 diabetes&nbsp;". International Journal of Molecular Medicine 57, no. 5 (2026): 135. https://doi.org/10.3892/ijmm.2026.5806
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