Shields Up: lessons from placental genetics to avoid immune attack on islet transplants

Shields Up: lessons from placental genetics to avoid immune attack on islet transplants

By: Shruthi Kandalai

Islet cell transplantation, or transplanting insulin-producing islet cells from donors into patients, has been proposed as a method to treat T1D without daily insulin injections. However, it remains that immune recognition of transplanted cells as foriegn can limit the activity of transplants. As a result, many patients that undergo transplants are required to take immunosuppressive drugs to prevent transplant cell rejection, which tend to have significant side effects. Helping patients achieve immune tolerance of the grafts may allow transplants to function, without side effects of immunosuppressive drugs. One of the most well-known conditions of immune tolerance relates to pregnancy, where a mother’s immune system tolerates the embryo, while still continuing to fight off other foreign invaders. Understanding how the immune system achieves immune tolerance during pregnancy may shed light on future efforts to create a similar immune tolerance of islet transplants in patients.

A recent paper noted that the DNA of the placenta may have structural differences compared to embryonic DNA. Placental DNA has an unusual amount of torsion on it, leading to the double helix structure breaking into single strands. The DNA base N6-methyladenine was found to help stabilize single-stranded regions in the placenta, and strongly repel SATB1, which organizes chromatin. Overall, the breaking of DNA into single strands may help with immune tolerance, with N6-methyladenine being used to help stabilize these single strands and regulate growth.

MicroRNAs (miRNAs) are involved in multiple stages of placental development, including implantation of the trophectoderm of embryo, differentiation into the placenta (trophoblasts), and vasculogenesis. Understanding how trophoblasts interact with immune cells, migrate and invade tissue, and develop their vasculature, are most relevant to bettering islet transplants. A 2018 review set out to understand how miRNAs played a role in development at each of these placental stages.

  • miRNAs may play some role in trophectoderm implantation, and have been found to play a role in regulating the interaction with maternal immune cells.
    • Two types of miRNAs were found to bind to HLA-G and reduce inhibition of NK cytotoxicity.
    • miRNAs have also been shown to regulate other maternal immune cell types, including macrophages, dendritic cells and T cells.
    • miRNAs were also found to promote antiviral immunity in placental cell lines, with some able to confer this resistance to other cell types. 
  • miRNAs have been found to play a role in trophoblast migration and invasion.
  • miRNAs play a role in placental vascular development.
    • Under hypoxic conditions, miRNAs can remodel maternal spiral arteries, converting maternal blood flow to the placenta and promote vasculogenesis. 
    • Other miRNAs can increase vascular sprouting and target pro-angiogenic factor VEGF, though their role in placental development has not been studied. 

Overall, many miRNAs have been found to play a role in placental development, with some playing multiple roles. Understanding how miRNAs regulate development and interact with maternal cells may provide avenues to prevent transplants from being attacked. However, many miRNAs have also been implicated in the T1D disease process (to the extent that multiple miRNAs have been proposed as biomarkers for the disease). Further studies would need to be done to study if miRNAs could be used to protect islets, and if this may vary based on T1D disease stage.

The takeaway: Avoiding immune cell attacks is important for islet cell transplantation, and better understanding how fetuses do so during pregnancy may better inform future directions. Understanding structural differences in DNA and miRNA expression may both be potential avenues to avoid immune attack and should be studied further in relation to T1D and islet transplants.

Sources:

  • Li, Z., Zhao, S., Nelakanti, R. V., Lin, K., Wu, T. P., Alderman, M. H., . . . Xiao, A. Z. (2020). N6-methyladenine in DNA antagonizes SATB1 in early development. Nature, 583(7817), 625-630.
  • Hayder, H., O’Brien, J., Nadeem, U., & Peng, C. (2018). MicroRNAs: Crucial regulators of placental development. Reproduction, 155(6), R259-R271.
  • Krishnan, P., Syed, F., Kang, N. J., Mirmira, R. G., & Evans-Molina, C. (2019). Profiling of RNAs from Human Islet-Derived Exosomes in a Model of Type 1 Diabetes. International Journal of Molecular Sciences, 20(23), 5903.

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