Cell-Based Therapies for Stroke: Promising Solution or Dead End? Mesenchymal Stem Cells and Comorbidities in Preclinical Stroke Research

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Cell-Based Therapies for Stroke: Promising Solution or Dead End? Mesenchymal Stem Cells and Comorbidities in Preclinical Stroke Research

Fernando Laso-García^†, Luke Diekhorst^†, Mari Carmen Gómez-de Frutos, Laura Otero-Ortega, Blanca Fuentes, Gerardo Ruiz-Ares, Exuperio Díez-Tejedor and María Gutiérrez-Fernández^*

• Neuroscience and Cerebrovascular Research Laboratory, Department of Neurology and Stroke Center, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autonoma University of Madrid, Madrid, Spain

Stroke is a major health problem worldwide. It has been estimated that 90% of the population attributable risk of stroke is due to risk factors such as aging, hypertension, hyperglycemia, diabetes mellitus and obesity, among others. However, most animal models of stroke use predominantly healthy and young animals. These models ignore the main comorbidities associated with cerebrovascular disease, which could be one explanation for the unsuccessful bench-to-bedside translation of protective and regenerative strategies by not taking the patient's situation into account. This lack of success makes it important to incorporate comorbidities into animal models of stroke in order to study the effects of the various therapeutic strategies tested. Regarding cell therapy, the administration of stem cells in the acute and chronic phases has been shown to be safe and effective in experimental animal models of stroke. This review aims to show the results of studies with promising new therapeutic strategies such as mesenchymal stem cells, which are being tested in preclinical models of stroke associated with comorbidities and in elderly animals.

Introduction

Stroke is still the most common cause of permanent disability in adults and the second leading cause of death in the world (1). The pathology of stroke is poorly understood; however, it has been shown that the majority of patients with stroke have at least one comorbidity (2). The contribution of various risk factors to worldwide stroke burden is unknown. The INTERSTROKE study has demonstrated that five risk factors accounted for more than 80% of the global risk for all strokes (either ischemic stroke or intracerebral hemorrhage [ICH]): hypertension, current smoking, abdominal obesity, diet and physical activity (3). Furthermore, stroke incidence rises with increased in age (4). This high prevalence of comorbidities in stroke patients indicates the need for therapies in preclinical studies that take these comorbidities into account (Figure 1).

FIGURE 1

Figure 1. Comparative evolution of the evaluation of the effect of various comorbidities in animal models of stroke as well as in clinical research. An advanced search was performed in PubMed in December 2018 to find, for each year of publication, all articles using the text word stroke with the given term as text word: age or aging; hypertension or hypertensive or high blood pressure; diabetes or diabetes mellitus; hyperglycemia or hyperglycemic or high blood sugar or high glucose levels; or obesity or overweight. Year of final publication (and not advanced online date) of articles in English (and not other languages) was taken into account. Manual elimination of articles describing a non-comorbid stroke association were excluded.

Of 502 experimental therapies for acute focal ischemic stroke, only 10% were tested in animals with hypertension. Hypertensive animals have larger infarct sizes and reduced efficacy with therapeutic intervention (5, 6). Even fewer preclinical studies assess the effects of diabetes or acute hyperglycemia on the response to therapeutic intervention (7). The majority of preclinical studies for novel therapies use young healthy animal models and this may play a role in the fact that of 1,026 treatments tested on animal models, only one has been effective in clinical trials (8).

In particular, stem cell therapy has been proven to be effective mostly in healthy animals. Various types of stem cells have been used in preclinical stroke models: embryonic stem cells, neural stem cells, induced pluripotent stem cells, mesenchymal stem cells (MSCs) and hematopoietic stem cells (9). Cell therapy has been shown to promote functional recovery, participating in processes such as immunomodulation, neurogenesis, synaptogenesis, oligodendrogenesis, axonal connectivity, and myelin formation, improvement in blood brain barrier (BBB) integrity, neovascularization and reduced lesion size, showing efficacy not only in grey matter, but also white matter injury (10–17). However, its mechanisms of action has not yet been clarified. Recent evidence has suggested that it might be related to long-distance cell-to-cell communication by paracrine function through secretory factors in the extracellular environment. Intercellular communication between stem cells and the damaged organ was thought to be regulated via the release of free molecules that transmit the signal by binding to a receptor. These molecules could in part be trophic factors, inflammation modulators and even exosomes. In order to avoid previous translation failure in stem cell therapy, STAIR guidelines suggest that further studies should be performed on animals with comorbid conditions such as hypertension and diabetes in order to improve the quality of preclinical studies of purported stroke therapies (18).

This review is focused on MSC therapies being tested in preclinical models of stroke with the most common comorbidities (hypertension, hyperglycemia, diabetes, obesity), as well as in elderly animals. We intend to provide insight into the viability of this new strategy, which could lead to an improved translation of cell therapy from bench to bedside.