Human MSC-Derived Exosomes Reduce Cellular Senescence in Renal Epithelial Cells

Abstract

Cellular senescence of renal tubular cells is associated with chronic diseases and age-related kidney disorders. Therapies to antagonize senescence are, therefore, explored as novel approaches in nephropathy. Exosomes derived from human mesenchymal stroma-/stem-like cells (MSC) entail the transfer of multiple bioactive molecules, exhibiting profound regenerative potential in various tissues, including therapeutic effects in kidney diseases. Here, we first demonstrate that exosomes promote proliferation and reduce senescence in aged MSC cultures. For potential therapeutic perspectives in organ rejuvenation, we used MSC-derived exosomes to antagonize senescence in murine kidney primary tubular epithelial cells (PTEC). Exosome treatment efficiently reduced senescence while diminishing the transcription of senescence markers and senescence-associated secretory phenotype (SASP) factors. Concomitantly, we observed less DNA damage foci and more proliferating cells. These data provide new information regarding the therapeutic property of MSC exosomes in the development of renal senescence, suggesting a contribution to a new chapter of regenerative vehicles in senotherapy.

Mesenchymal Stem Cell Therapy in Kidney Diseases: Potential and Challenges

“…For example, Wang et al 159 showed that MSCs-derived exosomal let-7b-5p ameliorates cisplatin-induced AKI by reducing renal senescence and cell apoptosis. Another study confirmed that treatment with exosomes derived from MSCs efficiently reduced senescence in renal tubular epithelial cells by diminishing the transcription of senescence markers and senescence-associated secretory phenotype factors 80 . In addition, the paracrine effects of MSCs were enhanced after pretreated with metformin and inhibited MSCs senescence by suppressing SA-β-gal activity, p16 Ink4a expression, and p53 and NF-κB activation, thus effectively reducing CKD inflammation and fibrosis 160 .…”

“…Cellular senescence is a specialized cell state of permanent cell cycle arrest caused by the accumulation of cellular damage due to a variety of stressors such as telomere shortening, DNA damage, oxidative stress, and activation of oncoproteins 80 , 149 . Senescent cells are known to be present at increased levels in KD, and accumulation of senescent cells is thought to facilitate renal fibrosis, DN, severe AKI, and decay in renal function 150 , 151 .…”

Extracellular Vesicles as “Very Important Particles” (VIPs) in Aging

“…A recent study showed that human mesenchymal stroma-/stem-like cell exosome treatment reduced renal tubular cell senescence, thereby delaying the development of renal aging [ 123 ]. These studies highlight that mesenchymal stromal cell-derived EVs could act as an innovative therapeutic tool for regenerative medicine in aging-related diseases [ 17 , 124 ]. Therefore, EVs from stem cells can be potentially used as a therapeutic vehicle in senotherapy owing to their regenerative potential.…”

Exosomes based advancements for application in medical aesthetics

“…Cells permanently exit the cell proliferation cycle, and cellular aging has permanent cell cycle arrest, reduction of NAD + , apoptosis resistance, aging-associated inflammatory cytokine secretion, and altered metabolic and epigenetic signatures ( Kirkland and Tchkonia, 2017 ). Exosomes often contain biologically active proteins and genetic information, all of which play an important role in delaying cell aging ( Liao et al, 2021 ), such as inhibiting the synthesis of related aging factor-β-galactosidase (SA-β-Gal) ( Kim et al, 2021 ), and inhibiting skin photoaging ( Gao et al, 2021 ).…”