Long noncoding RNA MALAT1 in exosomes drives regenerative function and modulates inflammation-linked networks following traumatic brain injury

Abstract

BackgroundNeuroinflammation is a common therapeutic target for traumatic brain injury (TBI) due to its contribution to delayed secondary cell death and has the potential to occur for years after the initial insult. Exosomes from adipose-derived stem cells (hASCs) containing the long noncoding RNA MALAT1 are a novel, cell-free regenerative approach to long-term recovery after traumatic brain injury (TBI) that have the potential to modulate inflammation at the genomic level. The long noncoding RNA MALAT1 has been shown to be an important component of the secretome of hASCs.MethodsWe isolated exosomes from hASC containing or depleted of MALAT1. The hASC-derived exosomes were then administered intravenously to rats following a mild controlled cortical impact (CCI). We followed the rats with behavior, in vivo imaging, histology, and RNA sequencing (RNA Seq).ResultsUsing in vivo imaging, we show that exosomes migrate into the spleen within 1 h following administration and enter the brain several hours later following TBI. Significant recovery of function on motor behavior as well as a reduction in cortical brain injury was observed after TBI in rats treated with exosomes. Treatment with either exosomes depleted of MALAT1 or conditioned media depleted of exosomes showed limited regenerative effects, demonstrating the importance of MALAT1 in exosome-mediated recovery. Analysis of the brain and spleen transcriptome using RNA Seq showed MALAT1-dependent modulation of inflammation-related pathways, cell cycle, cell death, and regenerative molecular pathways. Importantly, our data demonstrates that MALAT1 regulates expression of other noncoding RNAs including snoRNAs.ConclusionWe demonstrate that MALAT1 in hASC-derived exosomes modulates multiple therapeutic targets, including inflammation, and has tremendous therapeutic potential for treatment of TBI.

Retracted Article: Exosome-derived PTENP1 suppresses cisplatin resistance of bladder cancer (BC) by suppressing cell proliferation, migration and inducing apoptosis via the miR-103a/PDCD4 axis

“…[6][7][8] Exosomes are vesicles secreted by cells and they could transfer and exchange lncRNAs between tumors and extracellular microenvironment. 9 LncRNA PTEN pseudogene-1 (PTENP1) mapped on chromosome 10 was recognized as a tumor suppressor to reduce tumorigenesis and progression of various cancers. 10 It was reported that PTENP1 existed in serum exosomes of cancer patients.…”

Extracellular Vesicles: The New Frontier of Stem Cell Regenerative Medicine?

“…Indeed, Chuang and co-workers discovered that MSC-EVs could promote nerve and endothelial cell regeneration, increase VEGF production involved in angiogenesis [182], and also reduce the local inflammatory response [183]. A reduction of the inflammatory response was observed by Kim et al too [184,185]. A diminished inflammation was even observed in spinal cord injury, probably via neuronal apoptosis inhibition, angiogenesis stimulation, A1 astrocytes inactivation and up-regulation of anti-inflammatory IL-10 and TGF-β as well as down-regulation of the pro-inflammatory TNF-α and IL-1β [171,[186][187][188][189]].…”

Mesenchymal stromal cell secretome as a therapeutic strategy for traumatic brain injury

“…In addition, several other studies have reported the therapeutic efficacy of MSC‐derived exosomes in TBI. Exosomes derived from human ADSCs have also been shown to improve functional recovery on motor behavior, reduced inflammation, and cortical brain injury in TBI rats that was attributed to MALAT1 in the exosomes . This is because exosomes depleted of MALAT1 exhibit limited regenerative activity, indicating this long noncoding RNA is essential for exosome‐mediated functional improvement.…”

“…Exosomes derived from human ADSCs have also been shown to improve functional recovery on motor behavior, reduced inflammation, and cortical brain injury in TBI rats that was attributed to MALAT1 in the exosomes. 87 This is because exosomes depleted of MALAT1 exhibit limited regenerative activity, indicating this long noncoding RNA is essential for exosome-mediated functional improvement. In another study, treatment of TBI rats with MSC exosomes improved spatial learning and sensorimotor functional recovery as evidenced by a reduction in neurological deficits and foot-fault frequency.…”