Exploring the Potential of Mesenchymal Stem Cell-Based Therapy in Mouse Models of Vascular Cognitive Impairment

Abstract

Closely linked to Alzheimer’s disease (AD), the pathological spectrum of vascular cognitive impairment (VCI) is known to be wide and complex. Considering that multiple instead of a single targeting approach is considered a treatment option for such complicated diseases, the multifaceted aspects of mesenchymal stem cells (MSCs) make them a suitable candidate to tackle the heterogeneity of VCI. MSCs were delivered via the intracerebroventricular (ICV) route in mice that were subjected to VCI by carotid artery stenosis. VCI was induced in C57BL6/J mice wild type (C57VCI) mice by applying a combination of ameroid constrictors and microcoils, while ameroid constrictors alone were bilaterally applied to 5xFAD (transgenic AD mouse model) mice (5xVCI). Compared to the controls (minimal essential medium (MEM)-injected C57VCI mice), changes in spatial working memory were not noted in the MSC-injected C57VCI mice, and unexpectedly, the mortality rate was higher. In contrast, compared to the MEM-injected 5xVCI mice, mortality was not observed, and the spatial working memory was also improved in MSC-injected 5xVCI mice. Disease progression of the VCI-induced mice seems to be affected by the method of carotid artery stenosis and due to this heterogeneity, various factors must be considered to maximize the therapeutic benefits exerted by MSCs. Factors, such as the optimal MSC injection time point, cell concentration, sacrifice time point, and immunogenicity of the transplanted cells, must all be adequately addressed so that MSCs can be appropriately and effectively used as a treatment option for VCI.

Exosomal miR-132-3p from mesenchymal stromal cells improves synaptic dysfunction and cognitive decline in vascular dementia

“…Ischemia-induced neuron damage as well as dendritic and synaptic abnormalities can lead to neuronal dysfunction, which is the primary cause of cognitive impairment in VD [1]. MSCs are known as "sentinel and safe-guards of injury" and promote neuroprotection in various neurological diseases, including AD, ischemic stroke (IS), and vascular cognitive impairment (VCI) [28]. It was found that the neuroprotective effects of MSC depended primarily on exosome-mediated paracrine rather than cell replacement [29].…”

Immunosuppressant Drugs Mitigate Immune Responses Generated by Human Mesenchymal Stem Cells Transplanted into the Mouse Parenchyma

“…Human mesenchymal stem cells (hMSCs) were prepared as described previously 14 , 24 . Human MSCs were expanded in media containing minimal essential alpha 1x medium (MEMα1x; Gibco, Waltham, MA, USA), 10% fetal bovine serum (FBS; Biowest, Riverside, MO, USA), and 0.5% gentamicin (Gibco, Waltham, MA, USA) at 37°C in a 5% CO2 incubator.…”

“…The expressions of immune and inflammatory markers and engraftment of hMSCs were evaluated by performing immunohistochemical (IHC) staining. IHC was carried out by referring to studies reported previously 14 , 24 . On Day 7, mice that were randomly allocated to undergo IHC analysis was sacrificed via cardiac perfusion.…”

“…1). The dosage and administration routes for tacrolimus and dexamethasone were determined by referring to previous reports [21][22][23][24] . Tacrolimus (PROGRAF ® ) was purchased from Astellas Pharma (Tokyo, Japan).…”

Exosomal miR-132-3p from Mesenchymal Stromal Cells Improve Synaptic Dysfunction and Cognitive Decline in Vascular Dementia

“…Ischemia-induced neuron damage as well as dendritic and synaptic abnormalities can lead to neuronal dysfunction, which is the primary cause of cognitive impairment in VD [1]. MSCs are known as "sentinel and safe-guards of injury" and promote neuroprotection in various neurological diseases, including AD, ischemic stroke (IS), and vascular cognitive impairment (VCI) [21]. It was found that the neuroprotective effects of MSC depended primarily on exosome-mediated paracrine rather than cell replacement [22].…”