Therapeutic potentials of mesenchymal stem cells for cognitive impairment in stroke: Evidence from preclinical studies

Abstract

Stroke is a debilitating neurological disorder that frequently results in cognitive impairments, significantly affecting the quality of life of post-stroke patients. Current therapeutic options for poststroke cognitive impairment (PSCI) are limited. Mesenchymal stem cells (MSCs) have emerged as a promising strategy for enhancing neurological recovery, including cognitive function. This review evaluates the application of MSCs in improving cognitive function in stroke patients, focusing on data from preclinical studies. Approximately 75% of strokes occur in the elderly population, and animal models have been developed to study the effects of MSCs on ischemic stroke in aged rats, as well as in the presence of comorbidities such as hypertension and diabetes. The potential of MSCs to enhance cognitive function following a stroke is believed to involve multiple mechanisms, including the secretion of trophic factors, immunomodulation, differentiation into neural cell types, promotion of angiogenesis, and replacement of damaged cells. However, several challenges remain to be addressed, including a lack of clear understanding of the biological processes contributing to MSC efficacy, standardization of MSC preparation, and determination of optimal treatment protocols. Further studies on the specific mechanisms of action and clinical application of MSCs are required to confirm their therapeutic efficacy for stroke patients. The development of innovative and targeted therapies for PSCI will ultimately improve the quality of life for stroke survivors.


Introduction

Stroke is a neurological deficit attributed to a sudden disruption in cerebral blood flow. There are two types of strokes: ischemic strokes, which comprise 87% of the cases and are caused by blockages in blood flow, and hemorrhagic strokes, which account for 13% and are caused by vessel rupture1. Annually, stroke affects approximately 15 million people globally, with five million fatalities and another five million people experiencing long-term disabilities2. At present, treatment options for stroke patients are restricted to dissolving thrombi using tissue plasminogen activators like alteplase or performing mechanical thrombectomy3. Thrombolysis is highly effective in treating strokes within 4.5 hours of onset, but its efficacy is limited for large thrombi or severe strokes4. Unfortunately, fewer than 5% of patients with ischemic stroke have access to these treatments, and many continue to experience neurological deficits post-treatment, with no available therapy to aid recovery5. Consequently, stroke patients may experience cognitive deficits in memory, language, attention, executive function, and orientation domains, significantly affecting their functional outcomes6.

Recently, the application of mesenchymal stem cells (MSCs) has gained significant attention as a promising therapy for stroke. Mesenchymal stem cells exert therapeutic effects through their capacity to proliferate, differentiate into various cell types, and regulate immune responses7. Mesenchymal stem cells have anti-inflammatory, anti-apoptotic, angiogenic, and neurogenic effects, which may contribute to their therapeutic potentials3. While several reviews have explored MSC therapy in stroke, our study focuses on preclinical evidence specifically related to cognitive improvement. Preclinical studies play a crucial role in understanding the potential mechanisms, efficacy, and safety of MSC therapy before it can be translated into clinical applications. Unlike many existing reviews that focus broadly on stroke recovery, this paper specifically highlights the effects of MSCs on cognitive function post-stroke. Additionally, this review discusses studies using animal models with comorbidities like aging, hypertension, and diabetes, which are common in stroke patients but often overlooked in research8.

Stroke and Cognitive Impairment

Post-stroke cognitive impairment (PSCI) is common and related to poor patient outcomes. Recent studies suggest that 20-80% of stroke survivors experience cognitive deficits within the first three months post-stroke, and 7-23% of them progress to post-stroke dementia9. Post-stroke cognitive impairment affects multiple cognitive domains such as memory, attention, executive function, language, and visuospatial skills. These deficits can significantly impact the quality of life, independence, and overall functionality of patients with stroke. Individuals with PSCI may struggle with daily activities, maintain social relationships, and return to work, leading to increased disability and reliance on others10. Additionally, PSCI is associated with a higher risk of developing dementia, highlighting the importance of early detection and intervention9. As shown in Table 1, several neural regions affected by stroke can have a significant impact on cognitive function.

Table 1.

Brain damage and corresponding cognitive function impairments in patients with stroke

Brain area damage Cognitive Function Impaired References Frontal Lobe Executive function, attention, working memory, behaviour change 11 Parietal Lobe Visuospatial abilities, attention, language, body awareness 12 Temporal Lobe Memory, language, auditory processing 12 Hippocampus Episodic memory formation and retrieval 12 Amygdala Emotional processing, fear conditioning, memory modulation 12 Basal Ganglia Motor control, procedural learning, cognitive flexibility 12 Cerebellum Coordination, motor skills, working memory, language processing 12

Given the significant impact of PSCI on patients' quality of life and the limitations of current therapeutic approaches, there is an urgent need for innovative treatments that can effectively address cognitive deficits following stroke. Despite notable advances in stroke treatment and rehabilitation, effective therapies for PSCI remain limited. Current strategies, including pharmacological treatments and cognitive rehabilitation, offer only modest improvements in cognitive function following stroke and often come with limitations in terms of efficacy, safety, and applicability across diverse patient populations13. Pharmacological treatments, such as cholinesterase inhibitors and memantine, have produced mixed and inconclusive results regarding their effectiveness in treating PSCI, and may also have side effects or be unsuitable for some patients14. Cognitive rehabilitation has the potential to enhance specific cognitive areas, but the benefit of these improvements to everyday functioning and long-term outcomes remains uncertain, and access to specialized cognitive rehabilitation services can be limited in resource-poor settings15. The mechanisms underlying PSCI include oxidative stress, neuroinflammation, and impaired synaptic plasticity16, 17. Mesenchymal stem cells have emerged as a promising therapeutic approach to address these pathologies due to their multifaceted properties. Given the potential of mesenchymal stem cells, it is crucial to examine the specific ways in which these cells can target and mitigate the underlying pathological processes.

Preclinical Evidence

Before diving into the mechanisms, we briefly summarize the findings from preclinical studies of MSCs for stroke therapy, particularly using animal models. The majority of these studies utilized murines to develop a model of ischemic stroke via middle cerebral artery occlusion (MCAO). These models are frequently employed under various conditions, including aging, hypertension, and diabetes. Additionally, spontaneously hypertensive rats (SHRs) have been used in studies investigating the association between hypertension and stroke.

Approximately 75% of strokes occur in the elderly population18. Shen et al. (2007) created an ischemic stroke model using 10-12-month-old female retired breeder rats and confirmed the long-term neuroprotective effects of MSCs on ischemic stroke19. It is known that cerebral ischemia is associated with Ca2+-induced calcineurin (CaN) hyperactivation, leading to neuronal apoptosis. Intra-arterial injection of MSCs in a rat model of ischemic stroke was able to reduce CaN expression, rescuing neurons and promoting their survival20.

As hypertension is a common comorbidity in patients with stroke, animal models with hypertensive ischemic stroke have been developed using stroke-prone spontaneously hypertensive rats (SHRSP), which spontaneously develop hypertension and exhibit cerebrovascular pathology akin to human hypertension21. In this model, MSC administration prevented neural cell death through increased expression of anti-apoptotic proteins and improved antioxidative mechanisms22. Furthermore, treatment with maternal-derived MSCs remarkably improved functional outcomes and reduced infarct lesions in hypertensive ischemic mice23.

Diabetes has been established as a significant risk factor for stroke, particularly ischemic stroke. Therefore, it is crucial to study the molecular mechanisms underpinning the increased stroke incidence in diabetes. Hyperglycemic mice exhibited greater infarct volume following permanent MCAO compared to non-hyperglycemic counterparts. This study showed that treatment with human ADSCs did not reduce the lesion size in hyperglycemic stroke rats but significantly improved neurological function24. In addition, intravenous administration of BM-MSCs significantly decreased blood-brain barrier leakage and enhanced vascular and white matter regeneration in type 1 (56) and type 2 (57) diabetic rats, suggesting that MSCs may have neuroprotective effects on stroke patients25.

Table 2.

Review of experimental stroke treatments using mesenchymal stem cells in animals

Animal species Comorbidity Cell source Cell number Timing Key findings Limitations References SD - BM 10 5 10 days Neuronal regeneration Limited to hypoxia-preconditioned MSCs 26 SD - BM 3x10 6 8 days Reduce infarction volume Small sample size 27

留言 (0)

沒有登入
gif