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Gap junction intercellular communication mediates the competitive cell proliferation disadvantage of irradiated mouse
1Institute of Toxicology and Environmental Health, Department of Obstetrics and Gynecology, University of California, Davis, California 95616-8615, USA.
Abstract:
Gap junction intercellular communication (GJIC) is thought to play a role in the growth modulation that occurs within cell populations. An example of heterologous growth inhibition (competitive cell proliferation disadvantage) occurs within mouse aggregation chimeras comprised of irradiated and nonirradiated cleavage-stage embryos. The goal of this investigation was to test the hypothesis that GJIC participates in the competitive cell proliferation disadvantage that is expressed by the irradiated embryo in aggregation chimeras. Specifically, we tested the capacity of the GJIC inhibitor 18 alpha-glycyrrhetinic acid (AGA) to inhibit competitive cell proliferation disadvantage in heterologous aggregation chimeras that were comprised of one embryo that was irradiated with 1.0 Gy of (137)Cs gamma rays and then paired with one nonirradiated embryo. We found that AGA successfully inhibited fluorescent dye transfer between irradiated and nonirradiated embryos in heterologous chimeras. Chronic exposure to AGA prevented competitive cell proliferation disadvantage in these radiation chimeras, while exposure to AGA for the first 15 h of culture (prior to gap junction development) did not prevent competitive cell proliferation disadvantage. An unexpected observation was the apparent lack of any effect of inhibiting GJIC by exposure to AGA on blastocyst formation and cell number allocation in the two principal stem cell lineages of the preimplantation mammalian embryo, trophectoderm and inner cell mass.
Insights
Gap junction intercellular communication (GJIC) mediates competitive cell proliferation disadvantage in irradiated mouse embryos. Inhibiting GJIC with 18 alpha-glycyrrhetinic acid (AGA) prevented this growth disadvantage, highlighting GJIC
Area of Science:
- Developmental biology
- Cell biology
- Radiation biology
Background:
- Gap junction intercellular communication (GJIC) is crucial for regulating cell population growth.
- Irradiated mouse embryos exhibit a competitive proliferation disadvantage when aggregated with non-irradiated embryos.
Purpose of the Study:
- To investigate the role of GJIC in the competitive proliferation disadvantage observed in irradiated mouse embryos.
- To test if inhibiting GJIC with 18 alpha-glycyrrhetinic acid (AGA) can prevent this growth disadvantage.
Main Methods:
- Mouse aggregation chimeras were created using irradiated (1.0 Gy gamma rays) and non-irradiated embryos.
- The GJIC inhibitor AGA was administered to assess its effect on dye transfer and embryo development.
- Embryos were cultured, and GJIC inhibition was monitored via fluorescent dye transfer.
Main Results:
- AGA effectively inhibited fluorescent dye transfer between irradiated and non-irradiated embryos.
- Chronic AGA exposure prevented the competitive cell proliferation disadvantage in radiation chimeras.
- Early AGA exposure (15 h) did not prevent the proliferation disadvantage, suggesting a role for GJIC post-development.
- AGA did not affect blastocyst formation or cell allocation in trophectoderm and inner cell mass.
Conclusions:
- GJIC plays a significant role in mediating the competitive cell proliferation disadvantage of irradiated embryos.
- Targeting GJIC with inhibitors like AGA offers a potential strategy to mitigate radiation-induced growth defects.
- Inhibition of GJIC does not appear to disrupt early embryonic stem cell lineage allocation.