HDAC1 Silence Promotes Neuroprotective Effects of Human Umbilical Cord-Derived Mesenchymal Stem Cells in a Mouse Model of Traumatic Brain Injury via PI3K/AKT Pathway

Abstract

Stem cell transplantation is a promising therapy for traumatic brain injury (TBI), but low efficiency of survival and differentiation of transplanted stem cells limits its clinical application. Histone deacetylase 1 (HDAC1) plays important roles in self-renewal of stem cells as well as the recovery of brain disorders. However, little is known about the effects of HDAC1 on the survival and efficacy of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in vivo. In this study, our results showed that HDAC1 silence promoted hUC-MSCs engraftment in the hippocampus and increased the neuroprotective effects of hUC-MSCs in TBI mouse model, which was accompanied by improved neurological function, enhanced neurogenesis, decreased neural apoptosis, and reduced oxidative stress in the hippocampus. Further mechanistic studies revealed that the expressions of phosphorylated PTEN (p-PTEN), phosphorylated Akt (p-Akt), and phosphorylated GSK-3β (p-GSK-3β) were upregulated. Intriguingly, the neuroprotective effects of hUC-MSCs with HDAC1 silence on behavioral performance of TBI mice was markedly attenuated by LY294002, an inhibitor of the PI3K/AKT pathway. Taken together, our findings suggest that hUC-MSCs transplantation with HDAC1 silence may provide a potential strategy for treating TBI in the future.

Human umbilical cord-derived mesenchymal stem cells ameliorate insulin resistance via PTEN-mediated crosstalk between the PI3K/Akt and Erk/MAPKs signaling pathways in the skeletal muscles of db/db mice

“…MSCs, as a source of seed cells, have garnered increasing attention in the eld of stem cell therapy. At present, a large number of studies have discussed the clinical e cacy of stem cell therapy [21][22][23]; however, the safety and effectiveness of the optimal route for HUC-MSC transplantation have not been extensively considered. The safety of MSC administration has been reported in numerous clinical trials [24][25][26][27][28][29][30].…”

Potential of mesenchymal stem cells alone, or in combination, to treat traumatic brain injury

“…MSC‐derived exosomes have also been tested in porcine model of TBI coupled with hemorrhagic shock; consistent with the rodent data, the pigs had fewer cognitive deficits as determined with a neurological severity score and recovered faster than nontreated pigs . There is also evidence for MSC inducing immune suppression and anti‐inflammation; stimulating neurogenesis and angiogenesis; activating survival pathways and inhibiting apoptotic pathways; and enhancing neuroplasticity through neurite outgrowth and synaptogenesis …”

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

“…When MSCs were transplanted into TBI rats, it was observed that the cells improved neurological function . Report also indicates that treatment of TBI with MSCs or histone deacetylase 1 silenced MSCs promotes neuroprotection and reduced oxidative stress . The study reveals that the neuroprotective effect acts via inhibition of the P13K/AKT pathway.…”

“…44 Report also indicates that treatment of TBI with MSCs or histone deacetylase 1 silenced MSCs promotes neuroprotection and reduced oxidative stress. 45 The study reveals that the neuroprotective effect acts via inhibition of the P13K/AKT pathway. In another study, treatment of TBI mice with MSCs stimulates the injured brain to induce trophic events that resulted in improvement in neurological function.…”