It was shown as long as half a century ago that bone marrow is a source of not only hematopoietic stem cells, but also stem cells of mesenchymal tissues. Then the term “mesenchymal stem cells” (MSCs) was coined in the early 1990s, and more than a decade later, the criteria for defining MSCs have been released by the International Society for Cellular Therapy. The easy derivation from a variety of fetal and adult tissues and undemanding cell culture conditions made MSCs an attractive research object. It was followed by the avalanche of reports from preclinical studies on potentially therapeutic properties of MSCs, such as immunomodulation, trophic support and capability for a spontaneous differentiation into connective tissue cells, and differentiation into the majority of cell types upon specific inductive conditions. Although ontogenesis, niche, and heterogeneity of MSCs are still under investigation, there is a rapid boost of attempts at clinical applications of MSCs, especially for a flood of civilization‐driven conditions in so quickly aging societies, not only in the developed countries, but also in the populous developing world. The fields of regenerative medicine and oncology are particularly extensively addressed by MSC applications, in part due to the paucity of traditional therapeutic options for these highly demanding and costly conditions. There are currently almost 1,000 clinical trials registered worldwide at ClinicalTrials.gov, and it seems that we are starting to witness the snowball effect with MSCs becoming a powerful global industry; however, the spectacular effects of MSCs in the clinic still need to be shown. Stem Cells 2019;37:855–864

Neurological disorders are becoming a growing burden as society ages, and there is a compelling need to address this spiraling problem. Stem cell‐based regenerative medicine is becoming an increasingly attractive approach to designing therapies for such disorders. The unique characteristics of mesenchymal stem cells (MSCs) make them among the most sought after cell sources. Researchers have extensively studied the modulatory properties of MSCs and their engineering, labeling, and delivery methods to the brain. The first part of this review provides an overview of studies on the application of MSCs to various neurological diseases, including stroke, traumatic brain injury, spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, and other less frequently studied clinical entities. In the second part, stem cell delivery to the brain is focused. This fundamental but still understudied problem needs to be overcome to apply stem cells to brain diseases successfully. Here the value of cell engineering is also emphasized to facilitate MSC diapedesis, migration, and homing to brain areas affected by the disease to implement precision medicine paradigms into stem cell‐based therapies.

Myopia is a relatively prevalent and increasing public health concern, particularly in East Asia, where it has already reached a pandemic level.¹ An estimated 2.5 billion people will be affected by myopia in 2020.² The prevalence has been reported to be 80% or higher in the young adult population in certain Asian countries or areas, such as Singapore, Hong Kong, and Taiwan.^3-5 Similarly, in the United States, the prevalence of myopia is 20% to 50% among the population older than 12 years.⁶ This silent epidemic should not be ignored.⁷ The worldwide prevalence of myopia and high myopia is estimated to increase substantially, affecting nearly 5 billion and 1 billion people, respectively, by 2050.⁸ In addition, the cost of uncorrected refractive error is a very real existing problem, affecting as many as 88% of children with myopia, and thus, the implications of increasing myopia prevalence worldwide are significant.^8,9 Apart from the substantial socioeconomic cost, severe sight-threatening complications associated with high myopia substantially compromise quality of life.¹⁰ An excellent review by Flitcroft^11(p622) clearly demonstrates that no safe threshold for myopic refractive errors exists, which suggests that no such thing as “physiological myopia” exists. A recent study¹² reported that axial lengths of 26 mm or greater and refractive errors of −6 diopters (D) or greater are significantly associated with an increased lifetime risk for visual impairment. Therefore, an effective treatment to slow or even stop myopia progression in young children is urgently needed. Researchers and clinicians have proposed approaches to treat myopia for many years. However, to date, no ideal approach has been identified as efficacious for the prevention and treatment of myopia with sufficient safety and clinical acceptability.¹³

Mesenchymal stem cells (MSCs) are non-hematopoietic, multipotent stem cells derived from mesoderm, which can be easily isolated from many sources such as bone marrow, umbilical cord or adipose tissue. MSCs provide support for hematopoietic stem cells and have an ability to differentiate into multiple cell lines. Moreover, they have proangiogenic, protective and immunomodulatory properties. MSCs have the capacity to modulate both innate and adaptive immune responses, which accompany many diseases, by inhibiting pro-inflammatory reactions and stimulating anti-inflammatory activity. Recent findings revealed that the positive effect of MSCs is at least partly associated with the production of extracellular vesicles (EVs). EVs are small membrane structures, containing proteins, lipids and nuclei acids, which take part in intra-cellular communication. Many studies indicate that EVs contain protective and pro-regenerative properties and can modulate an immune response that is activated in various diseases such as CNS diseases, myocardial infarction, liver injury, lung diseases, ulcerative colitis or kidney injury. Thus, EVs have similar functions as their cells of origin and since they do not carry the risk of cell transplantation, such as tumor formation or small vessel blockage, they can be considered a potential therapeutic tool for cell-free therapy.

Ischemic stroke is the third cause of death in the developed countries and the main reason of severe disability. Brain ischemia leads to the production of damage-associated molecular patterns (DAMPs) by neurons and glial cells which results in astrocyte and microglia activation, pro-inflammatory cytokines and chemokines production, blood-brain barrier (BBB) disruption, infiltration of leukocytes from the peripheral blood into the infarcted area, and further exacerbation of tissue damage. However, some immune cells such as microglia or monocytes are capable to change their phenotype to anti-inflammatory, produce anti-inflammatory cytokines, and protect injured nervous tissue. In this situation, therapies, which will modulate the immune response after brain ischemia, such as transplantation of mesenchymal stem cells (MSCs) are catching interest. Many experimental studies of ischemic stroke revealed that MSCs are able to modulate immune response and act neuroprotective, through stimulation of neurogenesis, oligodendrogenesis, astrogenesis, and angiogenesis. MSCs may also have an ability to replace injured cells, but the release of paracrine factors directly into the environment or via extracellular vesicles (EVs) seems to play the most pronounced role. EVs are membrane structures containing proteins, lipids, and nucleic acids, and they express similar properties as the cells from which they are derived. However, EVs have lower immunogenicity, do not express the risk of vessel blockage, and have the capacity to cross the blood-brain barrier. Experimental studies of ischemic stroke showed that EVs have immunomodulatory and neuroprotective properties; therefore, they can stimulate neurogenesis and angiogenesis. Up to now, 20 clinical trials with MSC transplantation into patients after stroke were performed, from which two concerned on only hemorrhagic stroke and 13 studied only on ischemic stroke. There is no clinical trial with EV injection into patients after brain ischemia so far, but the case with miR-124-enriched EVs administration is planned and probably there will be more clinical studies with EV transplantation in the near future.

Introduction: Intra-arterial cell infusion is an efficient delivery route with which to target organs such as the ischemic brain. However, adverse events including microembolisms and decreased cerebral blood flow were recently reported after intra-arterial cell delivery in rodent models, raising safety concerns. We tested the hypothesis that cell dose, infusion volume, and velocity would be related to the severity of complications after intra-arterial cell delivery. Methods: In this study, 38 rats were subjected to a sham middle cerebral artery occlusion (sham-MCAO) procedure before being infused with allogeneic bone-marrow mesenchymal stem cells at different cell doses (0 to 1.0 × 10⁶), infusion volumes (0.5 to 1.0 ml), and infusion times (3 to 6 minutes). An additional group (n = 4) was infused with 1.0 × 10⁶ cells labeled with iron oxide for in vivo tracking of cells. Cells were infused through the external carotid artery under laser Doppler flowmetry monitoring 48 hours after sham-MCAO. Magnetic resonance imaging (MRI) was performed 24 hours after cell infusion to reveal cerebral embolisms or hemorrhage. Limb placing, cylinder, and open field tests were conducted to assess sensorimotor functions before the rats were perfused for histology. Results: A cell dose-related reduction in cerebral blood flow was noted, as well as an increase in embolic events and concomitant lesion size, and sensorimotor impairment. In addition, a low infusion velocity (0.5 ml/6 minutes) was associated with high rate of complications. Lesions on MRI were confirmed with histology and corresponded to necrotic cell loss and blood-brain barrier leakage. Conclusions: Particularly cell dose but also infusion velocity contribute to complications encountered after intra-arterial cell transplantation. This should be considered before planning efficacy studies in rats and, potentially, in patients with stroke.