Bone marrow mesenchymal stem cells protect against n-hexane-induced neuropathy through beclin 1-independent inhibition of autophagy

Abstract

Chronic exposure to n-hexane, a widely used organic solvent in industry, induces central-peripheral neuropathy, which is mediated by its active metabolite, 2,5-hexanedione (HD). We recently reported that transplantation of bone marrow-mesenchymal stem cells (BMSC) significantly ameliorated HD-induced neuronal damage and motor deficits in rats. However, the mechanisms remain unclear. Here, we reported that inhibition of HD-induced autophagy contributed to BMSC-afforded protection. BMSC transplantation significantly reduced the levels of microtubule-associated protein 1 light chain 3-II (LC3-II) and the degradation of sequestosome-1 (p62) in the spinal cord and sciatic nerve of HD-intoxicated rats. Downregulation of autophagy by BMSC was also confirmed in VSC4.1 cells exposed to HD. Moreover, inhibition of autophagy by PIK III mitigated the neurotoxic effects of HD and, meanwhile, abolished BMSC-afforded neuroprotection. Furthermore, we found that BMSC failed to interfere with Beclin 1, but promoted activation of mammalian target of rapamycin (mTOR). Unc-like kinse 1 (ULK1) was further recognized as the downstream target of mTOR responsible for BMSC-mediated inhibition of autophagy. Altogether, BMSC transplantation potently ameliorated HD-induced autophagy through beclin 1-independent activation of mTOR pathway, providing a novel insight for the therapeutic effects of BMSC against n-hexane and other environmental toxicants-induced neurotoxicity.

Autophagy inhibition via Becn1 downregulation improves the mesenchymal stem cells antifibrotic potential in experimental liver fibrosis

“…Nevertheless, these cytokines (Dang et al, 2014) found that inflammatory condition hampered the immunoinhibitive potential of MSCs by priming autophagy in a mouse model of experimental autoimmune encephalitis, supporting our findings. Similar results indicating protective effect of bone MSCs on n-hexane-induced neuropathy through autophagy inhibition were also found in another study (Hao et al, 2018). Collectively, our results demonstrate that counteracting LF microenvironment-induced autophagy via stable knockdown of Becn1 remarkably promotes the antifibrotic effects of MSCs.…”

“…Importantly, proinflammatory cytokines are a prerequisite for MSCs to exert their immuneinhibitory functions (Ren et al, 2008). Nevertheless, these cytokines n-hexane-induced neuropathy through autophagy inhibition were also found in another study (Hao et al, 2018). Collectively, our results demonstrate that counteracting LF microenvironment-induced autophagy via stable knockdown of Becn1 remarkably promotes the antifibrotic effects of MSCs.…”

2,5-Hexanedione mediates neuronal apoptosis through suppression of NGF via PI3K/Akt signaling in the rat sciatic nerve

“…Motor neurons that originated from the Ventral sciatic nerve 4.1 (VSC4.1) [35,37,38] were produced and cultured. Briefly, embryonic motor neurons from the rat ventral sciatic nerve were fused with mouse neuroblastoma cells (N18TG2), which were grown at 37°C in poly-L−ornithine coated flasks in a 5% CO 2 incubation system.…”

Targeting autophagy to overcome drug resistance: further developments

“…Under the catalysis of E1-like enzyme ATG7 and E2-like enzyme ATG10, the formed ATG5/ATG12/ATG16(L) complex facilitates the recruitment and conversion of microtubule­associated protein light chain 3 (LC3-I) to the membrane-bound LC3-II form [ 11 ]. LC3-II also binds to the adaptor protein p62/sequestosome1 (SQSTM1) to degrade the ubiquitinated protein aggregates in autophagolysosome [ 12 ], and thus recycling amino acids and other metabolic building blocks to maintain cellular homeostasis.

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