Cerebrovascular accident (CVA) is a major global contributor to death and disability. As part of its medical management, researchers have recognized the importance of promising neuroprotective strategies, where stem cell transplantation (SCT) is thought to confer advantages via trophic and neuroprotective effects.

To evaluate the current state of research on SCT in patients with CVA, assess key trends and highlight literature gaps.

PubMed was screened for SCT in CVA-related articles in October 2023, for each country during the period between 2000 and 2023. Using the World Bank data, total population and gross domestic product were collected for comparison. VOSviewer_1.6.19 was used to create the VOS figure using the results of the same query. Graphs and tables were obtained using Microsoft Office Excel.

A total of 6923 studies were identified on SCT in CVA, making 0.03% of all published studies worldwide. Approximately, 68% were conducted in high-income countries, with a significant focus on mesenchymal stem cells. The journal "Stroke" featured the largest share of these articles, with mesenchymal SCT having the highest rate of inclusion, followed by hematopoietic SCT. Over time, there has been a noticeable shift from in vitro studies, which assess stem cell proliferation and neurogenesis, to in vivo studies aimed at evaluating efficacy and safety. Additionally, the number of reviews increased along this approach.

This bibliometric analysis provides a comprehensive guide for physicians and researchers in the field through an objective overview of research activity, and highlights both current trends and gaps. Having a potential therapeutic role in CVA, more research is needed in the future to focus on different aspects of SCT, aiming to reach a better treatment strategy and improve life quality in patients.

Mesenchymal cell populations, referred to as mesenchymal stem cells or multipotent stromal cells (MSCs), which include bone marrow stromal cells (BMSCs), umbilical cord stromal cells and adipose stromal cells (ASCs), participate in tissue repair when transplanted into damaged or degenerating tissues. The trophic support and immunomodulation provided by MSCs can protect against tissue damage, and the differentiation potential of these cells may help to replace lost cells. MSCs are easily accessible and can be expanded on a large scale. In addition, BMSCs and ASCs can be harvested from the patient himself. Thus, MSCs are considered promising candidates for cell therapy. In this review, I will discuss recently discovered high-efficiency induction systems for deriving Schwann cells and neurons from MSCs. Other features of MSCs that are important for tissue repair include the self-renewing property of stem cells and their potential for differentiation. Thus, I will also discuss the stemness of MSCs and describe the discovery of a certain stem cell type among adult MSCs that can self-renew and differentiate into cells of all three germ layers. Furthermore, I will explore the prospects of using this cell population for cell therapy.

Bone marrow stromal cells (MSCs) are a useful source of cells because of their abundant supply and few associated ethical problems. We have previously reported that neural progenitor cells (NS-MSCs) can be effectively induced from MSCs and differentiate into neurons to contribute to functional recovery when transplanted into the rat stroke model. In this study, we attempted to enhance the therapeutic effects of NS-MSCs with a collagen sponge and basic fibroblast growth factor (bFGF) releasing microspheres. NS-MSCs were generated from MSCs by transfection of Notch-1 intracellular domain followed by culturing the cells in a free-floating culture system. The resulting NS-MSCs were transplanted into the rats with induced brain ischemia by using collagen sponges as scaffolds for transplanted cells, and with bFGF incorporated into gelatin microspheres to aid neovascularization around the transplanted region and proliferation of neural stem cells/neural progenitor cells. In culture, NS-MSCs successfully formed spheres containing cells highly expressing neural progenitor markers. Cell survival, neovascularization, and proliferation of host neural stem cells/neural progenitor cells were improved in animals that received NS-MSCs together with these biomaterials. Behavioral analysis also revealed significant functional recovery. These observations demonstrate that transplantation of NS-MSCs in combination with a collagen sponge and bFGF releasing microspheres significantly improves histological and functional recovery in the rat stroke model. When used with these biomaterials, NS-MSCs would be a promising cell source for treating stroke and neurodegenerative diseases.

Studies in animal models of ischemic stroke have shown that stem cells transplanted into the brain can lead to functional improvement. However, to date, evidence for the benefits of stem cell transplantation in ischemic stroke patients is lacking.

To assess the efficacy and safety of stem cell transplantation compared with conventional treatments in patients with ischemic stroke.

We searched the Cochrane Stroke Group Trials Register (last searched February 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, Issue 3), MEDLINE (1966 to August 2008), EMBASE (1980 to August 2008), Science Citation Index (1900 to August 2008), and BIOSIS (1926 to August 2008). We handsearched potentially relevant conference proceedings, screened reference lists, and searched ongoing trials and research registers (last searched November 2008). We also contacted individuals active in the field and stem cell manufacturers (last contacted December 2008).

We included randomized controlled trials (RCTs) recruiting patients with ischemic stroke, in any phase of the disease, and an ischemic lesion confirmed by computerized tomography or magnetic resonance imaging scan. We included all types of stem cell transplantation regardless of cell source (autograft, allograft, or xenograft; embryonic, fetal, or adult; from brain or other tissues), route of cell administration (systemic or local), and dosage. The primary outcome was efficacy (assessed as combined functional outcome or disability and dependency) at longer follow-up (minimum six months). Secondary outcomes included post-procedure safety outcomes (death, worsening of neurological deficit, infections and neoplastic transformation).

Two review authors independently extracted data and assessed trial quality. We contacted study authors for additional information.

We identified three very small RCTs. Two are still awaiting classification because only subgroups of patients could be included in this meta-analysis and additional unpublished data are needed. The third trial randomized 30 patients to intravenous transplantation of autologous mesenchymal stem cell (10 participants) or reference group (20 participants) (five participants, initially randomized to the intervention group, refused the treatment and were allocated to the reference group) and found a statistically non-significant functional improvement in treated patients at longer follow-up. No adverse cell-related events were reported.

No large trials of stem cell transplantation have been performed in ischemic stroke patients and it is too early to know whether this intervention can improve functional outcome. Large, well-designed trials are needed.

Cell replacement therapy has been evaluated as a regenerative strategy for patients with fixed neurologic deficits after ischemic stroke. Animal models have identified specific cell lines which lead to regeneration and improvement in behavior and motor function after implantation into areas of ischemic injury. This has led to the development of pilot studies in humans, which have mainly investigated the safety and pilot efficacy of such approaches with promising early results. As research in this area progresses, further prospective trials are necessary not only to demonstrate clinical efficacy but also to understand the mechanisms underlying the early positive experiences, to select appropriate patients for cell replacement therapy, and to elucidate the optimal timing and mode of cell delivery.

Currently, the most important therapeutic approaches in the acute phase of ischemic stroke are focused on the restoration of regional cerebral blood flow, early admission to a stroke unit and the attempt to block, using neuroprotective drugs, the biochemical and metabolic changes involved in the 'ischemic cascade'. Treatment with rt-PA in the acute phase, although very effective, is still limited to a small number of patients and positive preclinical results of neuroprotective treatment have not, as yet, been endorsed in clinical trials. The remarkable lack of concordance between the positive results in experimental models and the negative results obtained in clinical trials has led to a change in attitude in the conduct of preclinical studies as well as to a modification of the design of clinical trials, with special attention being paid to patient selection criteria and clinical evaluation. Some neuroprotective drugs, such as citicoline, have shown some efficacy in subgroups of patients with cerebral infarction, even with a therapeutic window of up to 24 h, which would suggest a possible neurorestorative effect. Different degrees of functional recovery, weeks or months after the ischemic event, are currently observed in clinical practice and have been related to endogenous self-repair mechanisms. The growing understanding of the mechanisms involved in the phenomena of brain plasticity and their modulation, together with the possibility of restoring functional deficits by encouraging endogenous neurogenesis or by cell therapy, open up new directions in the treatment of stroke patients.

To evaluate the effect of lipofection, particle size, and surface coating on labeling efficiency of mammalian cells with superparamagnetic iron oxides (SPIOs).

Institutional Review Board approval was not required. Different human cell lines (lung and breast cancer, fibrosarcoma, leukocytes) were tagged by using carboxydextran-coated SPIOs of various hydrodynamic diameters (17-65 nm) and a dextran-coated iron oxide (150 nm). Cells were incubated with increasing concentrations of iron (0.01-1.00 mg of iron [Fe] per milliliter), including or excluding a transfection medium (TM). Cellular iron uptake was analyzed qualitatively at light and electron microscopy and was quantified at atomic emission spectroscopy. Cell visibility was assessed with gradient- and spin-echo magnetic resonance (MR) imaging. Effects of iron concentration in the medium and of lipofection on cellular SPIO uptake were analyzed with analysis of variance and two-tailed Student t test, respectively.

Iron oxide uptake increased in a dose-dependent manner with higher iron concentrations in the medium. The TM significantly increased the iron load of cells (up to 2.6-fold, P < .05). For carboxydextran-coated SPIOs, larger particle size resulted in improved cellular uptake (65 nm, 4.37 microg +/- 0.08 Fe per 100 000 cells; 17 nm, 2.14 microg +/- 0.06 Fe per 100 000 cells; P < .05). Despite larger particle size, dextran-coated iron oxides did not differ from large carboxydextran-coated particles (150 nm, 3.81 microg +/- 0.46 Fe per 100 000 cells; 65 nm, 4.37 microg +/- 0.08 Fe per 100 000 cells; P > .05). As few as 10 000 cells could be detected with clinically available MR techniques by using this approach.

Lipofection-based cell tagging is a simple method for efficient cell labeling with clinically approved iron oxide-based contrast agents. Large particle size and carboxydextran coating are preferable for cell tagging with endocytosis- and lipofection-based methods.

The present study examined the neuroprotective effects of immunosuppressant cyclosporine-A (CsA) and anti-inflammatory methylprednisolone (MP) in a stroke model. Adult Sprague-Dawley rats were initially subjected to transient middle cerebral artery occlusion (MCAo) then randomly assigned to one of the following treatment conditions: low dose CsA, MP, low dose CsA plus MP, high dose CsA, or vehicle. Ischemic animals that received low dose CsA, MP or vehicle exhibited significant cognitive impairments, as revealed by passive avoidance and Morris water maze tasks, at days 1-3 after stroke. In contrast, ischemic animals that received high dose CsA exhibited near normal cognitive performance throughout the test period. Ischemic animals that received low dose CsA plus MP also showed significantly less cognitive deficits but such attenuation of stroke-induced behavioral impairments was only consistently reflected in the passive avoidance task, while performance in the Morris water maze task deteriorated over time. Histological analysis at 3 days post-stroke revealed that only those ischemic animals treated with high dose CsA had significantly reduced cerebral infarcts. These observations suggest that despite overt cerebral damage, alterations in simple, but not complex, cognitive tasks produced by MCAo could be ameliorated by low dose CsA when combined with MP.

A patient with intracerebral hemorrhage is considered ineligible for hematopoietic stem cell transplantation (HSCT). We report a 49-year-old woman with myelodysplastic syndrome (MDS) complicated by refractoriness to platelet transfusion and intracerebral hemorrhage, who underwent allogeneic bone marrow transplantation from an HLA-identical unrelated male donor. Nine days before the scheduled transplantation, she developed dysarthria and right hemiparesis; computed tomography (CT) of the brain disclosed an acute hematoma in the left parietal lobe exceeding 3 cm in diameter. She underwent conditioning with reduced-intensity, including fludarabine (30 mg/m2/day on days -8 to -3), busulfan (4 mg/kg/day on days -6 and -5), and total body irradiation (4 Gy on day -2). Two weeks after transplantation, dysarthria and right hemiparesis began to resolve, and CT showed spontaneous resolution of the hematoma. Simultaneously, engraftment was confirmed. Thus, recent stroke may be not an absolute contraindication for HSCT.

We investigated the neuroprotective effects of immunosuppressant cyclosporine-A (CsA) and the anti-inflammatory methylprednisolone (MP) in a stroke model. Adult Sprague-Dawley rats underwent middle cerebral artery (MCA) occlusion then were randomly treated with either: low dose CsA, MP, low dose CsA plus MP, high dose CsA, or vehicle. Ischemic animals that received low dose CsA, MP or vehicle displayed profound motor and neurological impairments at days 1-3 after stroke. In contrast, ischemic animals that received high dose CsA exhibited near normal motor and neurological functions throughout the test period. Of note, ischemic animals that received low dose CsA plus MP showed significantly less motor and neurological deficits at day 1, but thereafter displayed behavioral impairments. Histological analysis at 3 days post-stroke revealed that only those ischemic animals treated with high dose CsA had significantly reduced cerebral infarcts. This study is the first report to demonstrate partial and transient neuroprotection against stroke by low dose CsA when combined with MP.