Intracerebroventricular Administration of hNSCs Improves Neurological Recovery after Cardiac Arrest in Rats

Abstract

Irreversible brain injury and neurological dysfunction induced by cardiac arrest (CA) have long been a clinical challenge due to lack of effective therapeutic interventions to reverse neuronal loss and prevent secondary reperfusion injury. The neuronal regenerative potential of neural stem cells (NSCs) provides a possible solution to this clinical deficit. We investigated the neuronal recovery potential of human neural stem cells (hNSCs) via intracerebroventricular (ICV) xenotransplantation after CA in rats and the effects of transplanted NSCs on the proliferation and migration of endogenous NSCs. Outcome measures included neurological functional recovery measured by neurological deficit score (NDS), electrophysiologic analysis of EEG, and assessment of proliferation and migration at the cellular level and the Wnt/β-catenin pathway at the molecular level. Neurological functional assessment based on aggregate neurological deficit score (NDS) showed better recovery of function after hNSCs therapy (P < 0.05). Tracking of stem cells' proliferation with Ki67 antibody suggested that the NSCs group had more prominent proliferation compared to control group (number of Ki67+ cells, Control VS. NSC: 89.0 ± 31.6 VS. 352.7 ± 97.3, P < 0.05). In addition, cell migration tracked by Dcx antibody showed more Dcx + cells migrated to the far distance zone from SVZ in the treatment group (P < 0.05). Further immunofluorescence staining confirmed that the expression of the Wnt signaling pathway protein (β-catenin) was upregulated in the NSC group (P < 0.05). ICV delivery of hNSCs promotes endogenous NSC proliferation and migration and ultimately enhances neuronal survival and neurological functional recovery. Wnt/β-catenin pathway may be involved in the initiation and maintenance of this enhancement.

Metabolically Glycoengineered Neural Stem Cells Boost Neural Repair After Cardiac Arrest

“…Mechanistically, these behavioral improvements were achieved, at least in part, due to the replacement of injured neuronal cells by differentiation of the engrafted cells into neuronal cells with mature functions that facilitate brain recovery. [ 7a ] These findings, where MGE‐modified NSCs have a beneficial effect on neuronal recovery in rodents, suggest that a similar approach could benefit stem cell therapy for brain injury in humans.…”

“…In the first, we demonstrated that transplanted NSCs can promote endogenous NSC proliferation and migration in the subventricular zone and enhance neuronal survival and neurological functional recovery of the injured brain after CA. [ 7a ] However, the clinical application of stem cell therapy for ischemic brain injury has been hampered by the limited neuronal differentiation and poor long‐term survival of transplanted stem cells. [ 18 ] To overcome these difficulties, we turned to MGE, a strategy using non‐natural monosaccharide analogs that we reasoned could overcome difficulties in efforts to use transplanted NSCs to treat brain injuries.…”

“…[ 4a,6 ] Recently, we have shown that transplantation of exogenous human neural stem cells (NSCs) partially attenuated brain damage and improved neurological functional recovery in rats. [ 4b,7 ] The healing effects of the engrafted NSCs are mediated by establishing functional contact with surrounding cells, [ 8 ] modulating neuroinflammation, [ 4b ] releasing neurotrophic factors, and differentiating into multiple cell types. [ 6 ] These responses, along with the engrafted cells’ ability to mobilize the endogenous stem cells, contribute to neural reconstruction assisting the recuperation from ischemia/reperfusion‐induced cell death.…”

“…[ 6 ] These responses, along with the engrafted cells’ ability to mobilize the endogenous stem cells, contribute to neural reconstruction assisting the recuperation from ischemia/reperfusion‐induced cell death. [ 6,7 ] Despite the promise of treating ischemic brain injury with NSCs, major limitations for clinical translation remain. These difficulties include poor cell viability due to the harsh in vivo microenvironment, the loss of cell adhesion which leads to poor cell retention and integration at the site of injury, and a lack of efficient differentiation into the desired cell types.…”

Combination of cell-penetrating peptides with nanomaterials for the potential therapeutics of central nervous system disorders: a review

“…Common approaches for the treatment of CNS diseases include bypassing the BBB and increasing the permeability of the BBB. Methods of bypassing the BBB include intracerebroventricular [ 58 ], intracerebral [ 59 ], intrathecal [ 60 ], intranasal [ 61 ] and intratympanic [ 62 ] routes of administration, by which route the drug is delivered to the brain through the sense of smell and the trigeminal nerve [ 63 ]. Modification with antibodies or ligands of high expression on brain endothelial cells can increase the permeability of the BBB [ 64 ], and the combined application of CPP is also used to improve delivery efficiency [ 8 ].…”