Abstract
Stress-induced premature cell senescence is well recognized to be accompanied by emerging the senescence-associated secretory phenotype (SASP). Secreted SASP factors can promote the senescence of normal neighboring cells through autocrine/paracrine pathways and regulate the senescence response, as well. Regarding human endometrium-derived mesenchymal stem cells (MESCs), the SASP regulation mechanisms as well as paracrine activity of senescent cells have not been studied yet. Here, we examined the role of insulin-like growth factor binding protein 3 (IGFBP3) in the paracrine senescence induction in young MESCs. The H2O2-induced premature senescence of MESCs led to increased IGFBP3 in conditioned media (CM). The inhibitory analysis of both MAPK and PI3K signaling pathways showed that IGFBP3 releasing from senescent cells is mainly regulated by PI3K/Akt pathway activity. IGFBP3 appears to be an important senescence-mediating factor as its immunodepletion from the senescent CM weakened the pro-senescent effect of CM on young MESCs and promoted their growth. In contrast, young MESCs acquired the senescence phenotype in response to simultaneous addition of recombinant IGFBP3 (rIGFBP3). The mechanism of extracellular IGFBP3 internalization was also revealed. The present study is the first to demonstrate a significant role of extracellular IGFBP3 in paracrine senescence induction of young MESCs.
Highlights
The insulin-like growth factor (IGF) binding proteins (IGFBPs) belong to a superfamily of six high-affinity IGF-binding proteins [1,2,3]
According to our data obtained with applying high-resolution mass spectrometry, among senescenceassociated secretory phenotype (SASP) factors secreted by mesenchymal stem cells (MESCs) the upregulated insulinlike growth factor binding protein 3 (IGFBP3) and plasminogen activator inhibitor 1 (PAI-1) have been identified
The senescence development during 6 days was accompanied by gradually increase in the protein expression of IGFBP3 as well as PAI-1, suggesting that these endogenous proteins may mediate H2O2-induced senescence of MESCs
Summary
The insulin-like growth factor (IGF) binding proteins (IGFBPs) belong to a superfamily of six high-affinity IGF-binding proteins [1,2,3]. The IGFs are bound with IGFBPs either in a binary complex or a ternary complex contained IGF, IGFBP3 (rarely IGFBP5), and a glycoprotein called acid labile subunit (ALS) [1]. In addition to their ability to suppress or enhance IGF actions, the IGFBPs are capable of influencing cell proliferation, migration, differentiation, angiogenesis, and apoptosis in IGF/IGF-1R independent manner [2, 5]. IGFBP3 is a secreted glycoprotein that has multiple roles both outside and inside the cell In the serum, it circulates as a 150-kDa ternary complex with IGF mitogenic peptides, principally IGF-I, and ALS, protecting them from rapid degradation, and regulates their bioavailability [1, 3]. The type V TGF-β receptor and the low-density lipoprotein receptor-related protein1/α2M receptor have been proposed as the cognate cell surface receptors for IGFBP3 [5, 6]
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