Feasibility and Efficacy of Intra-Arterial Administration of Embryonic Stem Cell Derived-Mesenchymal Stem Cells in Animal Model of Alzheimer’s Disease

Abstract

Mesenchymal stem cells (MSCs) promote functional recoveries in pathological experimental models of the central nervous system and are currently being tested in clinical trials for neurological disorders. However, no studies have examined the various roles of embryonic stem cell derived (ES)-MSCs in eliciting therapeutic effects for Alzheimer's disease (AD). In the present study, we investigated the neuroprotective effect of ES-MSCs in cellular and animal models of AD, as well as the safety of the intra-arterial administration of ES-MSCs in an AD animal model. ES-MSCs displayed higher cell viability than that of bone marrow (BM)-MSCs in amyloid-␤ (A␤)-induced cellular models. Moreover, the efficacy of autophagy induction in ES-MSCs was comparable to that of BM-MSCs; however, intracellular A␤ levels were more significantly reduced in ES-MSCs than in BM-MSCs. In a rat model of AD, ES-MSCs significantly inhibited A␤-induced cell death in the hippocampus and promoted autophagolysosomal clearance of A␤, which was concomitantly followed by decreased levels of A␤ in the hippocampus. Furthermore, ES-MSC treatment in A␤-treated rats featured a higher memory performance than that of rats injected solely with A␤. Finally, intra-arterial administration of an appropriate cell density of ES-MSCs was safe and free from in situ occlusion or cerebral ischemia. These data support the therapeutic potential of ES-MSCs and clinical applications of the intra-arterial route of ES-MSC administration in AD.

Mesenchymal stem cells: As a multi-target cell therapy for clearing β-amyloid deposition in Alzheimer’s disease

“…In addition, MSCs treatment can up-regulate the expression of Beclin1 in vivo and in vitro experiments (Shin et al, 2014). Moreover, the efficacy of autophagy induction in ES-MSCs was comparable to that of BM-MSCs (Kim et al, 2020a). A recent study proved that cytokines secreted by MSCs can enhance the expression of autophagy-related proteins in microglia.…”

“…Recent studies have shown that clearance mechanisms of MSC-secretomes or exosomes in Aβ are likely multifaceted, including immune regulation, increased Aβdegrading factors, enhanced autophagy, reduced OS, and correction of SL metabolism, which suggests the potential of clinical application for the treatment of AD (Fig. 5) (Yokokawa et al, 2019;Kim et al, 2018a;Shin et al, 2014;Kim et al, 2013;Park et al, 2020a;Lee et al, 2010a;Marfia et al, 2016;Jiao et al, 2016;Kim et al, 2020a).…”

The Clinical Trials of Mesenchymal Stromal Cells Therapy

“…In general, eight administration methods have been proposed for applying MSCs. These methods include intravenous injection (IV) [ 95 , 96 ], intra-arterial injection (IA) [ 97 , 98 ], intrathecal injection (IT) [ 99 , 100 ], intracardiac injection (IC) [ 101 ], intra-articular injection (IAT) [ 102 , 103 ], intramuscular injection (IM) [ 104 ], intraosseous injection (IO) [ 105 ], and implant for cells incorporated into a matrix or an implanted device [ 106 , 107 ]. According to the study on the clinical trials of MSCs over 2014-2018, the most common administration method used in clinical trials was IV.…”

Application of mesenchymal stem cells derived from human pluripotent stem cells in regenerative medicine

“…ESC-MSCs significantly decreased Aβ-induced cell death and promoted autophagolysosomal clearance of Aβ in a rat model of Alzheimer's disease, leading to higher memory performance. Intra-arterially transplanted ESC-MSCs were safe and free from cerebral ischemia[ 96 ]. iPSC-MSCs markedly decreased brain-infarct volume and improved neurological function mainly by inhibiting inflammation[ 97 ].…”