Low-Dose Pesticide Mixture Induces Accelerated Mesenchymal Stem Cell Aging In Vitro

Abstract

The general population is chronically exposed to multiple environmental contaminants such as pesticides. We have previously demonstrated that human mesenchymal stem cells (MSCs) exposed in vitro to low doses of a mixture of seven common pesticides showed a permanent phenotype modification with a specific induction of an oxidative stress‐related senescence. Pesticide mixture also induced a shift in MSC differentiation toward adipogenesis. Thus, we hypothesized that common combination of pesticides may induce a premature cellular aging of adult MSCs. Our goal was to evaluate if the prolonged exposure to pesticide mixture could accelerate aging‐related markers and in particular deteriorate the immunosuppressive properties of MSCs. MSCs exposed to pesticide mixture, under long‐term culture and obtained from aging donor, were compared by bulk RNA sequencing analysis. Aging, senescence, and immunomodulatory markers were compared. The protein expression of cellular aging‐associated metabolic markers and immune function of MSCs were analyzed. Functional analysis of the secretome impacts on immunomodulatory properties of MSCs was realized after 21 days' exposure to pesticide mixture. The RNA sequencing analysis of MSCs exposed to pesticide showed some similarities with cells from prolonged culture, but also with the MSCs of an aged donor. Changes in the metabolic markers MDH1, GOT and SIRT3, as well as an alteration in the modulation of active T cells and modifications in cytokine production are all associated with cellular aging. A modified functional profile was found with similarities to aging process. stem cells 2019;37:1083–1094

Antioxidants inhibit cell senescence and preserve stemness of adipose tissue-derived stem cells by reducing ROS generation during long-term in vitro expansion

“…Increasing evidences suggest that oxidative stress may induce stem cells into premature senescence, causing a series of cellular changes including cell morphological alterations, low cell proliferation, telomere shortening, and reduced genomic stability [37]. In particular, oxidative stress induced by excessive ROS production is the most important factor in stem cell senescence and injuries [38].…”

Senescent mesenchymal stem/stromal cells and restoring their cellular functions

“…And these genes were mainly involved in metabolic functions and cell adhesion. Additionally, 394, 1073, and 2077 genes were significantly up-regulated in BM-MSCs from pesticide exposed, P14 MSCs, and MSCs from aged donor, compared with control MSCs (P3), respectively[ 51 ]. And 218, 1077, and 1571 genes were down-regulated in BM-MSCs from pesticide exposed, P14 MSCs, and MSCs from aged donor, compared with P3 MSCs, respectively.…”

“…And 218, 1077, and 1571 genes were down-regulated in BM-MSCs from pesticide exposed, P14 MSCs, and MSCs from aged donor, compared with P3 MSCs, respectively. Insulin-like growth factor-1 ( Igf-1 ), prolactin , leptin , and Cox-2 were identified as key genes of the predicted protein–protein interactions[ 51 ]. In murine BM-MSCs that were freshly sorted by fluorescence-activated cell sorting, 927 differentially expressed genes were obtained in aged BM-MSCs.…”

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“…These findings suggested to the authors that pesticides may induce premature aging , and so the team compared MSCs obtained from young donors exposed to pesticides with MSCs isolated from untreated older donors as well as in vitro‐aged MSCs. Reporting in Stem Cells , Leveque et al used RNA sequencing to establish that young donor MSCs exposed to pesticides for 21 days acquired a profile similar to that derived from MSCs in prolonged in vitro culture (14 passages) or MSCs from an aged donor (72 years old). RNA alterations included the increased expression of genes associated with the proinflammatory senescence‐associated secretory phenotype and aging, alongside the modulation of genes related to cellular metabolism.…”

“…Stem cells derived from these donors may present with lower therapeutic potential, thereby requiring the application of stem cells from younger and/or healthier donors, even if this may provoke immunogenic problems, for optimal therapeutic outcomes. In our first Featured Article this month from Stem Cells , Leveque et al report that a combination of seven pesticides commonly encountered at low doses in food samples can induce signs of premature aging in mesenchymal stem cells (MSCs), including metabolic alterations and a notable decrease in immunomodulatory capacity . In a Related Article in Stem Cells Translational Medicine , Mancini et al establish that MSCs derived from elderly atherosclerotic patients also exhibit reduced immunomodulatory capabilities and secrete high levels of pro‐inflammatory cytokines, thereby impeding any proposed therapeutic application .…”