CTRP9 ameliorates cellular senescence via PGC‑1α/AMPK signaling in mesenchymal stem cells

Abstract

Stroke is the second most common cause of death worldwide, and thus, it imposes great financial burdens on both individuals and society. Mesenchymal stem cell (MSC) therapy is a promising approach for ischemic brain injury. However, MSC treatment potential is progressively reduced with age, limiting their therapeutic efficacy for brain repair post‑stroke. C1q and tumor necrosis factor‑related protein 9 (CTRP9) is a novel cytoprotective cytokine with antioxidant effects, which is highly expressed in brain tissue. The present study tested the hypothesis that CTRP9 might act as an antisenescence factor to promote the rejuvenation of aged MSCs. MSCs were isolated from the bone marrow of young (8‑weeks‑old) and aged (18‑months‑old) male C57BL/6 mice. Cell proliferation was measured by Cell Counting Kit‑8 assay and cell viability was determined by MTT assay. Gene expression levels of interleukin (IL)‑6 and IL‑10 were evaluated with reverse transcription‑quantitative polymerase chain reaction, and secretion of vascular endothelial growth factor, basic fibroblast growth factor, hepatocyte growth factor, and insulin‑like growth factor were measured by ELISA. The expression levels of proteins in the peroxisome proliferator‑activated receptor γcoactivator (PGC)‑1α/AMP‑activated protein kinase (AMPK) signaling pathway were investigated with western blotting. Oxidative stress was evaluated by detecting mitochondrial membrane potential, reactive oxygen species, superoxide dismutase activity and malondialdehyde. MSCs isolated from aged mice exhibited reduced proliferation and viability, and impaired immunoregulatory and paracrine abilities, compared with MSCs from younger mice. CTRP9 had a significant antisenescence effect in aged MSCs by activating PGC‑1α/AMPK signaling and decreasing the oxidative response. Silencing either PGC‑1α or AMPK abolished the above effects of CTRP9. These results suggest that CTRP9 may have a critical role in cellular senescence by facilitating stem cell rejuvenation, and may therefore have the potential to enhance the efficacy of stem cell therapy.

Identification of senescent cells in multipotent mesenchymal stromal cell cultures: Current methods and future directions

“…In another study, the supplementation of MSCs with nicotinamide (a precursor of NAD + that has been shown to reduce ROS generation) noticeably extended their replicative life span with a significant postponement in the onset of senescence [143]. Recent studies treating animal MSCs with ascorbic acid, or with an antioxidant cytokine C1q and tumor necrosis factor related protein 9 (CTRP9) [144], have also shown promise and need to be tested on human MSCs. In terms of selecting MSC tissue source for expansion, apart from tissue's propensity for certain lineage differentiation or trophic factor secretion, greater consideration should be given to MSC oxidative stress resistance [145] and desirably, longer onset of senescence.…”

Administration of rCTRP9 Attenuates Neuronal Apoptosis Through AdipoR1/PI3K/Akt Signaling Pathway after ICH in Mice

“…Two recent studies suggest that the anti-apoptotic effects of AdipoR1 agonists are mediated via the phosphatidylinositol 3-kinase (PI3 K)/ protein kinase B (Akt) signaling pathway 19,20 . It has been shown that CTRP9 exerts a high affinity to AdipoR1 21 , and emerging evidence suggests that CTRP9 has the potential to carry out neuroprotective functions on diverse CNS disease 22 . However, the anti-apoptotic effects of CTRP9 following ICH have not yet been illustrated.…”

C1q/TNF‐related protein 9: A novel therapeutic target in ischemic stroke?

“…Similarly, mouse CTRP9 and human CTRP9 share 84% amino acid identity as well. CTRP9 mainly expresses in adipose tissue, adipocytes and adipose stromal cells and is detectable in variety of tissues and organs, such as skeletal muscle, brain, liver, and kidney (Li, Zhu et al, ; Yang et al, ). It is noteworthy that only human and primates (chimpanzee and rhesus macaque) possess the CTRP9B so far, even though at extremely low expression levels (Peterson et al, ).…”