Literature Analysis: SDF-1 as a Novel Therapeutic Target for Diabetes by Inhibiting Islet β Cell Dedifferentiation

1. Research Overview

In November 2021, the research teams led by Professor Jingna Lin and Professor Chunjun Li from the Department of Endocrinology, Nankai University People's Hospital, published an online article entitled "SDF-1 inhibits the dedifferentiation of islet β cells in hyperglycaemia by up-regulating FoxO1 via binding to CXCR4" in the Journal of Cellular and Molecular Medicine. This study focuses on the effect of Stromal Cell-Derived Factor-1 (SDF-1) on islet β cell dedifferentiation, providing a novel therapeutic target for diabetes. Notably, the 4-Color Multiplex Fluorescence IHC Staining Kit (Catalog No.: abs50012) from the Absin product line of ANT BIO PTE. LTD. was a key technical tool employed in this research.

2. Background of Diabetes and Islet β Cell Dedifferentiation

The occurrence of diabetes is closely associated with low insulin levels. Insulin, secreted by islet β cells, is the only hormone in the body that can lower blood glucose. In diabetic patients, islet β cells undergo dedifferentiation, reverting to a precursor state and thus losing the ability to secrete insulin. Previous studies have documented that SDF-1 can regulate the differentiation and function of immune cells and is implicated in both type 1 and type 2 diabetes. Based on this, the research team designed and conducted a series of experiments to explore the role of SDF-1 in islet β cell dedifferentiation.

3. Key Research Findings

3.1 Confirmation of the Association Between SDF-1 and Islet β Cell Dedifferentiation

In preliminary studies, the research team primarily used fluorescence single/double staining and Western blot (WB) techniques. First, they identified the markers of islet dedifferentiation (SOX9 and NGN3). Subsequent double staining with SDF-1 showed a high overlap of fluorescence images (Figure 1), confirming that SDF-1 is indeed associated with islet β cell dedifferentiation. WB results further revealed that increased SDF-1 expression inhibits islet β cell dedifferentiation (Figure 2), while inhibiting SDF-1 expression exacerbates dedifferentiation (Figure 3).

3.2 Exploration of the SDF-1/CXCR4/AKT/FOXO1 Signaling Pathway

After confirming that SDF-1 affects islet β cell dedifferentiation, the research team searched the STRING database and found an interaction between SDF-1 and FOXO1. They then further explored whether SDF-1 exerts its effects through the SDF-1/CXCR4/AKT/FOXO1 pathway. WB detection showed that FOXO1 content in samples from diabetic patients and mice was significantly lower than that in normal samples. Subsequently, they detected changes in the contents of CXCR4, AKT, and FOXO1 in Min6 cells (a dedifferentiation cell model) when SDF-1 expression was decreased or increased. When SDF-1 expression was decreased, the content of CXCR4 (the receptor of SDF-1) increased, while the contents of p-AKT and FOXO1 decreased (Figure 4). When SDF-1 expression was increased, the expression levels of all three proteins increased (Figure 5). These results indicate that SDF-1 inhibits islet β cell dedifferentiation by up-regulating FOXO1 expression.

3.3 Effect of the SDF-1/CXCR4 Complex on Islet β Cell Dedifferentiation

To further investigate whether the complex formed by SDF-1 and its receptor CXCR4 exerts effects, the research team used multiplex fluorescence immunohistochemistry technology (employing ANT BIO PTE. LTD.'s abs50012 kit) to perform multi-labeling of three indicators—insulin (Insulin, used to mark the islet range), SDF-1, and CXCR4—in human and mouse samples. The results showed that although there was a significant difference in SDF-1 expression between diabetic and non-diabetic islets, there was no significant difference in CXCR4 expression, a phenomenon also reflected in WB results (Figure 6).

3.4 Role of DPP-IV in Regulating SDF-1/CXCR4 Binding

The research team previously found that DPP-IV expression is enhanced in the islets of diabetic mice compared with non-diabetic mice, suggesting that DPP-IV may act on SDF-1, preventing it from activating CXCR4. Therefore, the team continuously treated Min6 cells with different concentrations of DPP-IV for 48 hours. The results showed that DPP-IV treatment did not affect the expression of SDF-1 and CXCR4, but significantly reduced FOXO1 expression. Further WB detection of other dedifferentiation-related indicators showed that the expression of SOX9 and NGN3 was up-regulated, while the expression of p-AKT and FOXO1 was down-regulated, with no significant changes in SDF-1 and CXCR4 expression. To further study the relationship between SDF-1 and CXCR4, the research team conducted a Co-IP experiment, which showed that DPP-IV intervention reduced the binding amount between them (Figure 7). In summary, the results indicate that DPP-IV does not change the overall expression of SDF-1 and CXCR4, but reduces their binding amount, thereby affecting the downstream p-AKT and FOXO1 pathways, decreasing their expression, and ultimately leading to increased islet β cell dedifferentiation. A subsequent glucose intervention experiment further verified that the binding of SDF-1 and CXCR4 can increase FOXO1 expression.

4. Research Conclusion

This study shows that compared with normal organisms, the binding amount of SDF-1 and its receptor CXCR4 in hyperglycemic organisms is reduced, followed by a decrease in AKT phosphorylation, and ultimately a decrease in the expression of FOXO1, which can reduce islet β cell dedifferentiation (Figure 8). The research results also provide a new target for the treatment of diabetes.

5. Research Images

Figure 1. Double staining results of SDF-1 with islet dedifferentiation markers (SOX9 and NGN3), showing high overlap of fluorescence images.

Figure 2. WB results showing that increased SDF-1 expression inhibits islet β cell dedifferentiation.

Figure 3. WB results showing that inhibiting SDF-1 expression exacerbates islet β cell dedifferentiation.

Figure 4. WB results showing changes in CXCR4, p-AKT, and FOXO1 contents when SDF-1 expression is decreased.

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8. Disclaimer

This article is AI-compiled and interpreted based on the original work in document 1225.docx (Absin Multicolor Literature Interpretation: SDF-1, a Novel Therapeutic Target for Diabetes). All intellectual property (e.g., images, data) of the original publication shall belong to the journal Journal of Cellular and Molecular Medicine and the research teams led by Professor Jingna Lin and Professor Chunjun Li. For any infringement, please contact us promptly and we will take immediate action.

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