Papait, A. | Search bioRxiv

bioRxiv2024

Bisphenol A Disrupts Mitochondrial Functionality Leading to Senescence and Apoptosis in Human Amniotic Mesenchymal Stromal Cells

In todays context, microplastics pollution has become an increasingly pressing issue not only for the environmental fallout but also for the assumed negative effects on human health. It is now well-established that microplastics (>1 mm in size) can enter the human body through ingestion, inhalation, dermal contact and also maternal-fetal transmission. Alarming was the recent findings of microplastics within the human term placenta. Among the degradation by-products of microplastics, Bisphenol A (BPA) has emerged as a hazardous chemical, with potential toxicity at multisystemic level, particularly on the earliest stages of human development. Based on these findings, our study focuses on assessing the impact of BPA on properties and functions of mesenchymal stromal cells isolated from the amniotic membrane (hAMSC) of the human term placenta. The amniotic membrane surrounds the fetus, playing a fundamental protective role toward toxic chemicals and pollutants that the mother may encounter. Our research revealed how exposure to increasing concentrations of BPA compromise mitochondrial functionality in hAMSC, resulting in enhanced production of reactive oxygen species at mitochondrial level (mtROS). This, in turn, leads to the stabilization of p53, which triggers an increased expression of p21 and p27 encoding genes and an imbalance in the genetic expression of Bax and Bcl-2. Additionally, we observed upregulated expression of cytokines and chemokines associated with the senescence-associated secretory phenotype (SASP). The increased oxidative stress, which plays a central role in BPA-mediated toxicity, can trigger the activation of the senescence pathways, or culminate in cell death, due to the overwhelming stress conditions. Therefore, our results provide novel insights into the mechanism of action of BPA and elucidates its impact on the functionality of hAMSC. This underscores the pressing need to reconsider the use of BPA as a plastic additive, mitigating the potential adverse effects on babies.

pharmacology and toxicology↗

bioRxiv2023

Mesenchymal stromal cells affect CD8 naive to memory subsets polarization by down-modulating IL12beta1 and IL2Ralpha signaling pathways

Adaptive immunity is typified by specificity and memory. Immune memory protects from subsequent infection and relies on functional, fully activated, T lymphocytes. Mesenchymal stromal cells (MSC) have been investigated for their potential therapeutic applications in a variety of diseases in which a dysregulated immune response plays a central role in pathogenesis or progression. Notably, for adaptive immunity, MSC can reduce the activation and cytotoxic activity of CD8+ T lymphocytes as well as the polarization of CD4+ T lymphocytes toward inflammatory subsets while favoring polarization toward the T regulatory subset. Although MSC have been widely reported to impact CD4 T cell proliferation and polarization, how MSC affect T-cell commitment toward memory subsets is still not known. Here, we report for the first time that MSC isolated from the amniotic membrane of human term placenta (hAMSC) determine T cell fate. We show that hAMSC influence naive CD8+ T cell activation and differentiation by downregulating mTOR pathway activation and modulating the expression of Tbet and Eomes, master regulators of the commitment of naive CD8+ T cells toward memory precursor effector cells (MPECs). This effect can be partly attribute to the ability of hAMSC to reduce the phosphorylation of STAT4 and STAT5, two transcriptional factors downstream IL-12R{beta}1 and IL-2R receptors. Our results unravel a novel feature of MSC, offering new mechanistic insights into the effects of MSC in the treatment of diseases characterized by an altered activation of memory subsets, such as autoimmune diseases and graft versus host disease.

immunology↗