Human umbilical cord-derived mesenchymal stem cell transplantation supplemented with curcumin improves the outcomes of ischemic stroke via AKT/GSK-3β/β-TrCP/Nrf2 axis

Abstract

Background Human umbilical cord-derived mesenchymal stem cell (hUC-MSC) engraftment is a promising therapy for acute ischemic stroke (AIS). However, the harsh ischemic microenvironment limits the therapeutic efficacy of hUC-MSC therapy. Curcumin is an anti-inflammatory agent that could improve inflammatory microenvironment. However, whether it enhances the neuroprotective efficacy of hUC-MSC transplantation is still unknown. In the present study, we investigated the therapeutic efficacy and the possible mechanism of combined curcumin and hUC-MSC treatment in AIS. Methods Middle cerebral artery occlusion (MCAO) mice and oxygen glucose deprivation (OGD) microglia were administrated hUC-MSCs with or without curcumin. Neurological deficits assessment, brain water content and TTC were used to assess the therapeutic effects of combined treatment. To elucidate the mechanism, MCAO mice and OGD microglia were treated with AKT inhibitor MK2206, GSK3β activator sodium nitroprusside (SNP), GSK3β inhibitor TDZD-8 and Nrf2 gene knockout were used. Immunofluorescence, flow cytometric analysis, WB and RT-PCR were used to evaluate the microglia polarization and the expression of typical oxidative mediators, inflammatory cytokines and the AKT/GSK-3β/β-TrCP/Nrf2 pathway protein. Results Compared with the solo hUC-MSC-grafted or curcumin groups, combined curcumin-hUC-MSC therapy significantly improved the functional performance outcomes, diminished the infarct volumes and the cerebral edema. The combined treatment promoted anti-inflammatory microglia polarization via Nrf2 pathway and decreased the expression of ROS, oxidative mediators and pro-inflammatory cytokines, while elevating the expression of the anti-inflammatory cytokines. Nrf2 knockout abolished the antioxidant stress and anti-inflammation effects mediated with combined treatment. Moreover, the combined treatment enhanced the phosphorylation of AKT and GSK3β, inhibited the β-TrCP nucleus translocation, accompanied with Nrf2 activation in the nucleus. AKT inhibitor MK2206 activated GSK3β and β-TrCP and suppressed Nrf2 phosphorylation in nucleus, whereas MK2206 with the GSK3β inhibitor TDZD-8 reversed these phenomena. Furthermore, combined treatment followed by GSK3β inhibition with TDZD-8 restricted β-TrCP nucleus accumulation, which facilitated Nrf2 expression. Conclusions We have demonstrated that combined curcumin-hUC-MSC therapy exerts anti-inflammation and antioxidant stress efficacy mediated by anti-inflammatory microglia polarization via AKT/GSK-3β/β-TrCP/Nrf2 axis and an improved neurological function after AIS.

One-Pot Self-Assembly of Core-Shell Nanoparticles within Fibers by Coaxial Electrospinning for Intestine-Targeted Delivery of Curcumin

“…Curcumin (Cur) is a natural active substance extracted from the tubers of herbs such as Curcuma longa [ 1 ], Rhizoma zedoariae [ 2 ] and Radix curcumae [ 3 ], and it has broad application prospects in the fields of foods [ 4 , 5 ] and medicines [ 6 , 7 ]. It has a strong coloration ability and various physiological effects including anti-oxidation, anti-inflammation [ 8 ], anti-tumor [ 9 ], bacteriostasis, and promoting wound healing [ 10 ]. However, several factors, including the insolubility [ 11 ], low stability at light and thermal changes [ 12 ], and low in vivo bioavailability [ 13 ] of free Cur in water largely affect its application to be even more.…”

Role and limitation of cell therapy in treating neurological diseases

“…A recent notable advancement has been made by scientists who successfully transplanted brain tissue organoids derived from human cells into mice suffering from stroke 133 . This transplantation procedure effectively restored impaired tissue and reinstated motor functions 134,135 . Furthermore, upon transplantation into the visual cortex of rat brains, the brain organoids exhibited seamless integration into the host tissue, exhibiting progressive development of blood vessels, enlargement in size, generation of neuronal projections, and establishment of synaptic connections 136,137 .…”

MiR‐9‐enriched mesenchymal stem cells derived exosomes prevent cystitis‐induced bladder pain via suppressing TLR4/NLRP3 pathway in interstitial cystitis mice

“…Mesenchymal stem cells (MSCs) effectively alleviate neurological deficits and improve rehabilitation in patients with acute or chronic neurological diseases and injuries 16,17 . In addition, intrathecal delivery of bone marrow‐derived MSCs can inhibit spinal cord inflammation and pain caused by nerve injury 18 .…”

“…Mesenchymal stem cells (MSCs) effectively alleviate neurological deficits and improve rehabilitation in patients with acute or chronic neurological diseases and injuries. 16,17 In addition, intrathecal delivery of bone marrow-derived MSCs can inhibit spinal cord inflammation and pain caused by nerve injury. 18 However, MSCs engrafting to central nervous system (CNS) tissues may cause capillary embolism, and genetic material variation after repeated subculture in vitro.…”