P38alpha-selective mitogen-activated protein kinase inhibitor for improvement of cultured human islet recovery
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Sustained Administration of β-cell Mitogens to Intact Mouse Islets Ex Vivo Using Biodegradable Poly(lactic-co-glycolic acid) Microspheres
Published on: November 5, 2016
Keiko Omori1, Ivan Todorov, Jonathan Shintaku
1Southern California Islet Cell Resources Center, Department of Diabetes, Endocrinology and Metabolism, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
Objectives:
We investigated whether the recovery of cultured human islets is improved through the addition of a p38alpha-selective mitogen-activated protein kinase inhibitor, SD-282, to clinically used serum-free culture medium.
Methods:
Immediately after isolation, islets were cultured for 24 hours in medium alone (control) or medium containing dimethyl sulfoxide, 0.1 microM SD-282, or 0.3 microM SD-282. Cytokine expression, apoptotic beta-cell percentage, and islet function were assessed postculture.
Results:
Expression of p38 and phosphorylated p38 in islets increased during culture. Interleukin 6 mRNA expression in cultured islets, as well as IL-6, IL-8, and granulocyte-macrophage colony-stimulating factor released into the medium, was significantly reduced by adding SD-282. The apoptotic beta-cell percentage was significantly lower in islets cultured with 0.1 microM SD-282, but not 0.3 microM, as compared with the control. Stimulation indices measured in vitro were higher but without significance (P = 0.06); the function of transplanted islets in diabetic NOD-scid mice was also better in 0.1-microM SD-282 group as compared with control.
Conclusions:
Better islet function was obtained by adding 0.1 microM SD-282 to the serum-free culture medium. This improvement was associated with suppression of cytokine production and prevention of beta-cell apoptosis. However, this beneficial effect was diminished at a higher concentration.
Insights
Adding SD-282, a p38alpha-selective mitogen-activated protein kinase inhibitor, to serum-free culture medium improved human islet recovery. This enhancement involved reduced cytokine production and beta-cell apoptosis, with optimal results at 0.1 microM.
Area of Science:
- Islet biology and transplantation research.
- Molecular mechanisms of cell survival and function.
Background:
- Human islet culture is crucial for transplantation but faces challenges in maintaining cell viability and function.
- Mitogen-activated protein kinase (MAPK) pathways, including p38alpha, are implicated in cellular stress responses and apoptosis.
Purpose of the Study:
- To evaluate the efficacy of SD-282, a p38alpha-selective MAPK inhibitor, in improving the recovery and function of cultured human islets.
- To assess the impact of SD-282 on cytokine expression and beta-cell apoptosis during islet culture.
Main Methods:
- Human islets were cultured for 24 hours in serum-free medium with or without varying concentrations of SD-282 (0.1 microM or 0.3 microM).
- Assessed outcomes included cytokine expression (mRNA and protein), percentage of apoptotic beta-cells, and in vitro/in vivo islet function post-culture.
Main Results:
- SD-282 significantly reduced the expression of pro-inflammatory cytokines (IL-6, IL-8, GM-CSF) in cultured islets.
- A lower percentage of apoptotic beta-cells was observed with 0.1 microM SD-282 compared to controls.
- Islet function, both in vitro and after transplantation in diabetic mice, showed improvement with 0.1 microM SD-282, though not statistically significant for in vitro measures.
Conclusions:
- Supplementing serum-free culture medium with 0.1 microM SD-282 enhances human islet function.
- The beneficial effects are linked to the suppression of cytokine production and prevention of beta-cell apoptosis.
- Higher concentrations of SD-282 diminished the observed positive effects.
