hPMSCs-Derived Exosomal miRNA-21 Protects Against Aging-Related Oxidative Damage of CD4+ T Cells by Targeting the PTEN/PI3K-Nrf2 Axis

Abstract

Mesenchymal stem cells (MSCs)-derived exosomes were considered a novel therapeutic approach in many aging-related diseases. This study aimed to clarify the protective effects of human placenta MSCs-derived exosomes (hPMSC-Exo) in aging-related CD4+ T cell senescence and identified the underlying mechanisms using a D-gal induced mouse aging model. Senescent T cells were detected SA-β-gal stain. The degree of DNA damage was evaluated by detecting the level of 8-OH-dG. The superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) activities were measured. The expression of aging-related proteins and senescence-associated secretory phenotype (SASP) were detected by Western blot and RT-PCR. We found that hPMSC-Exo treatment markedly decreased oxidative stress damage (ROS and 8-OH-dG), SA-β-gal positive cell number, aging-related protein expression (p53 and γ-H2AX), and SASP expression (IL-6 and OPN) in senescent CD4+ T cells. Additionally, hPMSC-Exo containing miR-21 effectively downregulated the expression of PTEN, increased p-PI3K and p-AKT expression, and Nrf2 nuclear translocation and the expression of downstream target genes (NQO1 and HO-1) in senescent CD4+ T cells. Furthermore, in vitro studies uncovered that hPMSC-Exo attenuated CD4+ T cell senescence by improving the PTEN/PI3K-Nrf2 axis by using the PTEN inhibitor bpV (HOpic). We also validated that PTEN was a target of miR-21 by using a luciferase reporter assay. Collectively, the obtained results suggested that hPMSC-Exo attenuates CD4+ T cells senescence via carrying miRNA-21 and activating PTEN/PI3K-Nrf2 axis mediated exogenous antioxidant defenses.

How Can We Improve the Vaccination Response in Older People? Part II: Targeting Immunosenescence of Adaptive Immunity Cells

“…The blockade of TNF-α, or its receptor, postpones CD28 down-regulation in replicative senescent T cells [ 143 ]. Alternatively, exosomes derived from placenta mesenchymal stem cells (MSC) containing miR-21 induce loss of expression of senescence markers in CD4 + aged T cells by activating the phosphatase and tensin homolog (PTEN)/PI3K-NFE2-like bZIP transcription factor 2 (Nrf2) signalling axis [ 148 ]. The AMPK agonist metformin could be considered an interesting treatment to reverse T cell immunosenescence, as it reduces inflammation by decreasing Th17 differentiation and increasing Tregs [ 149 ].…”

“…For example, exosomes derived from placental MSCs reduce the expression of senescence markers in aged CD4 + T cells. This outcome relied on the miR-21, a microRNA that activates the PTEN/PI3K-Nrf2 axis, a signalling pathway that has been implicated as an important regulator of the proliferation, differentiation and apoptosis in a variety of cell types [ 148 ]. Thymic negative selection can be restored by the transplantation of these extracellular vesicles from young mice to older animals, leading to moderation of inflammaging [ 168 ].…”

Human PMSCs-derived small extracellular vesicles alleviate neuropathic pain through miR-26a-5p/Wnt5a in SNI mice model

“…sEVs can serve as a means of intercellular communication by facilitating the transfer of various RNA, DNA, cytokines, and growth factors between cells [ 19 ]. Currently, sEVs of MSCs derived from different sources, e.g., human umbilical cord blood, adipose, bone marrow, have been demonstrated its therapeutic potential in wound healing, myocardial injury, spinal cord injury etc.…”

Vitamin E‑coated dialyzer alleviates erythrocyte deformability dysfunction in patients with end‑stage renal disease undergoing hemodialysis

“…Western blot analyses were performed as described previously ( 22 ). Total protein from the RBCs was obtained using a protein extraction kit (cat.…”