Immunoregulatory Sertoli Cell Allografts Engineered to Express Human Insulin Survive Humoral-Mediated Rejection
Abstract
:1. Introduction
2. Results
2.1. Survival of MSC1-HI Cells Transduced to Express Human Insulin after Exposure to Human Serum Containing Complement
2.2. Survival of MSC1 and MSC1-HI Cells after Transplantation as Allografts in Mice
2.3. Deposition of IgM and IgG on MSC1-HI or MSC1 Cell Grafts
2.4. Deposition of Complement Factors C3, C4, FB and C9 in MSC1 or MSC1-HI Cell Grafts
2.5. Protein Expression of COMP and C1QBP by MSC1 and MSC1-HI Cells
3. Discussion
4. Materials and Methods
4.1. Animals
4.2. SC Transduction
4.3. Cell Preparation and Transplantation
4.4. Human Serum Complement Cytotoxicity Assay
4.5. Immunohistochemical Graft Characterization
4.6. ELISA Quantification of COMP and C1QBP Protein Secretion
4.7. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Antibody | Day 20 Post-Transplantation | Day 50 Post-Transplantation | ||
---|---|---|---|---|
MSC1-HI | MSC1 | MSC1-HI | MSC1 | |
IgG | 39.8 | 37.1 | >200 | 173.3 |
IgM | 0 | 0 | 2.2 | 28.5 |
Complement Factor | Day 20 Post-Transplantation | Day 50 Post-Transplantation | ||
---|---|---|---|---|
MSC1-HI | MSC1 | MSC1-HI | MSC1 | |
C3 | 22.1 | 11.4 | 37.1 | 30.1 |
C4 | 19.6 | 4.938 | 37.4 | 10.8 |
FB | 0.2983 | 2.478 | 0.2 | 4.625 |
C9 | 10.94 | 3.462 | 6.67 | >200 |
Complement Component | Levels in Diabetes | Effects in Diabetes | Ref. |
---|---|---|---|
C1q (CP, activation) | Elevated | Apoptosis of adipocytes, increases infiltration of inflammatory macrophages | [37] |
C3 (AP, amplification) | Elevated | Insulin resistance; increases diabetic neuropathy, nephropathy, retinopathy, microangiopathy, and atherosclerosis; causes chronic fibrinolysis and thrombosis; important in beta cell protective autophagy | [38,39] |
C3a (anaphylatoxin) | Elevated | Increases inflammation and macrophage recruitment, elevates secretion of insulin by beta cells | [40] |
C3aR (receptor) | Elevated | Enhances expression of inflammatory mediators and activation of immune cells | [41] |
C3a desArg (anaphylatoxin) | Elevated | Stimulates uptake of glucose, lipid storage, and triglyceride synthesis in adipose tissue; promotes microvascular complications in metabolic disorders | [42,43] |
Factor D (AP, amplification) | Elevated | Elevated in obesity, leads to increased activation and amplification through the alternative pathway | [37] |
MAC (cytolysis) | Elevated | Promotes endothelial dysfunction and production of ROS; stimulates diabetic complications | [44,45,46] |
MASP-2 (LP, activation) | Elevated | Promotes endothelial dysfunction, ROS production, and diabetic vascular complications | [44,45] |
CD55 (CIP of C3 and C5) | Reduced | Decreases inhibition of C3 and C5 convertases involved in amplification | [47] |
CD59 (CIP of MAC) | Reduced | Decreases inhibition of MAC; maintains stability of lipid rafts, basal insulin secretion, and recycling exocytotic core proteins for insulin release | [44,45,47] |
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Washburn, R.L.; Hibler, T.; Kaur, G.; Sabu-Kurian, A.; Landefeld, A.; Dufour, J.M. Immunoregulatory Sertoli Cell Allografts Engineered to Express Human Insulin Survive Humoral-Mediated Rejection. Int. J. Mol. Sci. 2022, 23, 15894. https://doi.org/10.3390/ijms232415894
Washburn RL, Hibler T, Kaur G, Sabu-Kurian A, Landefeld A, Dufour JM. Immunoregulatory Sertoli Cell Allografts Engineered to Express Human Insulin Survive Humoral-Mediated Rejection. International Journal of Molecular Sciences. 2022; 23(24):15894. https://doi.org/10.3390/ijms232415894
Chicago/Turabian StyleWashburn, Rachel L., Taylor Hibler, Gurvinder Kaur, Anna Sabu-Kurian, Alissa Landefeld, and Jannette M. Dufour. 2022. "Immunoregulatory Sertoli Cell Allografts Engineered to Express Human Insulin Survive Humoral-Mediated Rejection" International Journal of Molecular Sciences 23, no. 24: 15894. https://doi.org/10.3390/ijms232415894