Because of their strong proliferative capacity and multi-potency, placenta-derived mesenchymal stem cells have gained interest as a cell source in the field of nerve damage repair. In the present study, human placenta-derived mesenchymal stem cells were induced to differentiate into neural stem cells, which were then transplanted into the spinal cord after local spinal cord injury in rats. The motor functional recovery and pathological changes in the injured spinal cord were observed for 3 successive weeks. The results showed that human placenta-derived mesenchymal stem cells can differentiate into neuron-like cells and that induced neural stem cells contribute to the restoration of injured spinal cord without causing transplant rejection. Thus, these cells promote the recovery of motor and sensory functions in a rat model of spinal cord injury. Therefore, human placenta-derived mesenchymal stem cells may be useful as seed cells during the repair of spinal cord injury.

Propofol is a neuroprotective anesthetic. Whether propofol can promote spinal cord injury repair by bone marrow mesenchymal stem cells remains poorly understood. We used rats to investigate spinal cord injury repair using bone marrow mesenchymal stem cell transplantation combined with propofol administration via the tail vein. Rat spinal cord injury was clearly alleviated; a large number of newborn non-myelinated and myelinated nerve fibers appeared in the spinal cord, the numbers of CM-Dil-labeled bone marrow mesenchymal stem cells and fluorogold-labeled nerve fibers were increased and hindlimb motor function of spinal cord-injured rats was markedly improved. These improvements were more prominent in rats subjected to bone marrow mesenchymal cell transplantation combined with propofol administration than in rats receiving monotherapy. These results indicate that propofol can enhance the therapeutic effects of bone marrow mesenchymal stem cell transplantation on spinal cord injury in rats.

Previous studies have shown that transplantation of human bone marrow mesenchymal stem cells promotes neural functional recovery after stroke, but the neurorestorative mechanisms remain largely unknown. We hypothesized that functional recovery of myelinated axons may be one of underlying mechanisms. In this study, an ischemia/reperfusion rat model was established using the middle cerebral artery occlusion method. Rats were used to test the hypothesis that intravenous transplantation of human bone marrow mesenchymal stem cells through the femoral vein could exert neuroprotective effects against cerebral ischemia via a mechanism associated with the ability to attenuate axonal injury. The results of behavioral tests, infarction volume analysis and immunohistochemistry showed that cerebral ischemia caused severe damage to the myelin sheath and axons. After rats were intravenously transplanted with human bone marrow mesenchymal stem cells, the levels of axon and myelin sheath-related proteins, including microtubule-associated protein 2, myelin basic protein, and growth-associated protein 43, were elevated, infarct volume was decreased and neural function was improved in cerebral ischemic rats. These findings suggest that intravenously transplanted human bone marrow mesenchymal stem cells promote neural function. Possible mechanisms underlying these beneficial effects include resistance to demyelination after cerebral ischemia, prevention of axonal degeneration, and promotion of axonal regeneration.

In the present study, we transplanted bone marrow-derived mesenchymal stem cells into the CA3 area of the hippocampus of chronic epilepsy rats kindled by lithium chloride-pilocarpine. Immunofluorescence and western blotting revealed an increase in adenosine A1 receptor expression and a decrease in adenosine A2a receptor expression in the brain tissues of epileptic rats 3 months after transplantation. Moreover, the imbalance in the A1 adenosine receptor/A2a adenosine receptor ratio was improved. Electroencephalograms showed that frequency and amplitude of spikes in the hippocampus and frontal lobe were reduced. These results suggested that mesenchymal stem cell transplantation can reconstruct the normal function of the adenosine system in the brain and greatly improve epileptiform discharges.

In this study, we successfully constructed a composite of bone marrow mesenchymal stem cells and a chitosan-collagen scaffold in vitro, transplanted either the composite or bone marrow mesenchymal stem cells alone into the ischemic area in animal models, and compared their effects. At 14 days after co-transplantation of bone marrow mesenchymal stem cells and the hitosan-collagen scaffold, neurological function recovered noticeably. Vascular endothelial growth factor expression and nestin-labeled neural precursor cells were detected in the ischemic area, surrounding tissue, hippocampal dentate gyrus and subventricular zone. Simultaneously, a high level of expression of glial fibrillary acidic protein and a low level of expression of neuron-specific enolase were visible in BrdU-labeled bone marrow mesenchymal stem cells. These findings suggest that transplantation of a composite of bone marrow mesenchymal stem cells and a chitosan-collagen scaffold has a neuroprotective effect following ischemic stroke.

An important factor in improving functional recovery from spinal cord injury using stem cells is maximizing the number of transplanted cells at the lesion site. Here, we established a contusion model of spinal cord injury by dropping a weight onto the spinal cord at T7-8. Superparamagnetic iron oxide-labeled bone marrow mesenchymal stem cells were transplanted into the injured spinal cord via the subarachnoid space. An outer magnetic field was used to successfully guide the labeled cells to the lesion site. Prussian blue staining showed that more bone marrow mesenchymal stem cells reached the lesion site in these rats than in those without magnetic guidance or superparamagnetic iron oxide labeling, and immunofluorescence revealed a greater number of complete axons at the lesion site. Moreover, the Basso, Beattie and Bresnahan (BBB) locomotor rating scale scores were the highest in rats with superparamagnetic labeling and magnetic guidance. Our data confirm that superparamagnetic iron oxide nanoparticles effectively label bone marrow mesenchymal stem cells and impart sufficient magnetism to respond to the external magnetic field guides. More importantly, superparamagnetic iron oxide-labeled bone marrow mesenchymal stem cells can be dynamically and non-invasively tracked in vivo using magnetic resonance imaging. Superparamagnetic iron oxide labeling of bone marrow mesenchymal stem cells coupled with magnetic guidance offers a promising avenue for the clinical treatment of spinal cord injury.

Cell therapy using stem cell transplantation against cerebral ischemia has been reported. However, it remains controversial regarding the optimal time for cell transplantation and the transplantation route. Rat models of cerebral ischemia were established by occlusion of the middle cerebral artery. At 1, 12 hours, 1, 3, 5 and 7 days after cerebral ischemia, bone marrow mesenchymal stem cells were injected via the tail vein. At 28 days after cerebral ischemia, rat neurological function was evaluated using a 6-point grading scale and the pathological change of ischemic cerebral tissue was observed by hematoxylin-eosin staining. Under the fluorescence microscope, the migration of bone marrow mesenchymal stem cells was examined by PKH labeling. Caspase-3 activity was measured using spectrophotometry. The optimal neurological function recovery, lowest degree of ischemic cerebral damage, greatest number of bone marrow mesenchymal stem cells migrating to peri-ischemic area, and lowest caspase-3 activity in the ischemic cerebral tissue were observed in rats that underwent bone marrow mesenchymal stem cell transplantation at 12 hours after cerebral ischemia. These findings suggest that 12 hours after cerebral ischemia is the optimal time for tail vein injection of bone marrow mesenchymal stem cell transplantation against cerebral ischemia, and the strongest neuroprotective effect of this cell therapy appears at this time.

In the present study, we transplanted adipose-derived mesenchymal stem cells into the hippocampi of APP/PS1 transgenic Alzheimer's disease model mice. Immunofluorescence staining revealed that the number of newly generated (BrdU(+)) cells in the subgranular zone of the dentate gyrus in the hippocampus was significantly higher in Alzheimer's disease mice after adipose-derived mesenchymal stem cell transplantation, and there was also a significant increase in the number of BrdU(+)/DCX(+) neuroblasts in these animals. Adipose-derived mesenchymal stem cell transplantation enhanced neurogenic activity in the subventricular zone as well. Furthermore, adipose-derived mesenchymal stem cell transplantation reduced oxidative stress and alleviated cognitive impairment in the mice. Based on these findings, we propose that adipose-derived mesenchymal stem cell transplantation enhances endogenous neurogenesis in both the subgranular and subventricular zones in APP/PS1 transgenic Alzheimer's disease mice, thereby facilitating functional recovery.

Bone marrow mesenchymal stem cell transplantation is an effective treatment for neonatal hypoxic-ischemic brain damage. However, the in vivo transplantation effects are poor and their survival, colonization and differentiation efficiencies are relatively low. Red or near-infrared light from 600-1,000 nm promotes cellular migration and prevents apoptosis. Thus, we hypothesized that the combination of red light with bone marrow mesenchymal stem cell transplantation would be effective for the treatment of hypoxic-ischemic brain damage. In this study, the migration and colonization of cultured bone marrow mesenchymal stem cells on primary neurons after oxygen-glucose deprivation were detected using Transwell assay. The results showed that, after a 40-hour irradiation under red light-emitting diodes at 660 nm and 60 mW/cm(2), an increasing number of green fluorescence-labeled bone marrow mesenchymal stem cells migrated towards hypoxic-ischemic damaged primary neurons. Meanwhile, neonatal rats with hypoxic-ischemic brain damage were given an intraperitoneal injection of 1 × 10(6) bone marrow mesenchymal stem cells, followed by irradiation under red light-emitting diodes at 660 nm and 60 mW/cm(2) for 7 successive days. Shuttle box test results showed that, after phototherapy and bone marrow mesenchymal stem cell transplantation, the active avoidance response rate of hypoxic-ischemic brain damage rats was significantly increased, which was higher than that after bone marrow mesenchymal stem cell transplantation alone. Experimental findings indicate that 660 nm red light emitting diode irradiation promotes the migration of bone marrow mesenchymal stem cells, thereby enhancing the contribution of cell transplantation in the treatment of hypoxic-ischemic brain damage.

Emerging evidence suggests that bone marrow-derived mesenchymal stem cell transplantation improves neurological function after cardiac arrest and cardiopulmonary resuscitation; however, the precise mechanisms remain unclear. This study aimed to investigate the effect of bone marrow-derived mesenchymal stem cell treatment on expression profiles of multiple cytokines in the brain after cardiac arrest and cardiopulmonary resuscitation. Cardiac arrest was induced in rats by asphyxia and cardiopulmonary resuscitation was initiated 6 minutes after cardiac arrest. One hour after successful cardiopulmonary resuscitation, rats were injected with either phosphate-buffered saline (control) or 1 × 106 bone marrow-derived mesenchymal stem cells via the tail vein. Serum S100B levels were measured by enzyme-linked immunosorbent assay and neurological deficit scores were evaluated to assess brain damage at 3 days after cardiopulmonary resuscitation. Serum S100B levels were remarkably decreased and neurological deficit scores were obviously improved in the mesenchymal stem cell group compared with the phosphate-buffered saline group. Brains were isolated from the rats and expression levels of 90 proteins were determined using a RayBio Rat Antibody Array, to investigate the cytokine profiles. Brain levels of the inflammatory mediators tumor necrosis factor-α, interferon-γ, macrophage inflammatory protein-1α, macrophage inflammatory protein-2, macrophage inflammatory protein-3α, macrophage-derived chemokine, and matrix metalloproteinase-2 were decreased ≥ 1.5-fold, while levels of the anti-inflammatory factor interleukin-10 were increased ≥ 1.5-fold in the mesenchymal stem cell group compared with the control group. Donor mesenchymal stem cells were detected by immunofluorescence to determine their distribution in the damaged brain, and were primarily observed in the cerebral cortex. These results indicate that bone marrow-derived mesenchymal stem cell transplantation attenuates brain damage induced by cardiac arrest and cardiopulmonary resuscitation, possibly via regulation of inflammatory mediators. This experimental protocol was approved by the Institutional Animal Care and Use Committee of Fujian Medical University, China in January 2016 (approval No. 2016079).

Transplantation of umbilical cord-derived mesenchymal stem cells (UC-MSCs) for repair of traumatic brain injury has been used in the clinic. Hyperbaric oxygen (HBO) treatment has long been widely used as an adjunctive therapy for treating traumatic brain injury. UC-MSC transplantation combined with HBO treatment is expected to yield better therapeutic effects on traumatic brain injury. In this study, we established rat models of severe traumatic brain injury by pressurized fluid (2.5-3.0 atm impact force). The injured rats were then administered UC-MSC transplantation via the tail vein in combination with HBO treatment. Compared with monotherapy, aquaporin 4 expression decreased in the injured rat brain, but growth-associated protein-43 expression, calaxon-like structures, and CM-Dil-positive cell number increased. Following combination therapy, however, rat cognitive and neurological function significantly improved. UC-MSC transplantation combined with HBO therapyfor repair of traumatic brain injury shows better therapeutic effects than monotherapy and significantly promotes recovery of neurological functions.

Results from the present study demonstrated that transplantation of autologous bone marrow-derived mesenchymal stem cells into the lesion site in rat brain significantly ameliorated brain tissue pathological changes and brain edema, attenuated glial cell proliferation, and increased brain-derived neurotrophic factor expression. In addition, the number of cells double-labeled for 5-bromodeoxyuridine/glial fibrillary acidic protein and cells expressing nestin increased. Finally, blood vessels were newly generated, and the rats exhibited improved motor and cognitive functions. These results suggested that transplantation of autologous bone marrow-derived mesenchymal stem cells promoted brain remodeling and improved neurological functions following traumatic brain injury.

Although bone marrow mesenchymal stem cells (BMSCs) might have therapeutic potency in ischemic stroke, the benefits are limited. The current study investigated the effects of BMSCs engineered to overexpress vascular endothelial growth factor (VEGF) on behavioral defects in a rat model of transient cerebral ischemia, which was induced by middle cerebral artery occlusion. VEGF-BMSCs or control grafts were injected into the left striatum of the infarcted hemisphere 24 hours after stroke. We found that compared with the stroke-only group and the vehicle- and BMSCs-control groups, the VEGF-BMSCs treated animals displayed the largest benefits, as evidenced by attenuated behavioral defects and smaller infarct volume 7 days after stroke. Additionally, VEGF-BMSCs greatly inhibited destruction of the blood-brain barrier, increased the regeneration of blood vessels in the region of ischemic penumbra, and reducedneuronal degeneration surrounding the infarct core. Further mechanistic studies showed that among all transplant groups, VEGF-BMSCs transplantation induced the highest level of brain-derived neurotrophic factor. These results suggest that BMSCs transplantation with vascular endothelial growth factor has the potential to treat ischemic stroke with better results than are currently available.

The developing approaches of thrombolytic therapy, endovascular treatment, neuroprotective therapy, and stem cell therapy have enabled breakthroughs in stroke treatment. In this study, we summarize and analyze trends and progress in stem cell transplantation for stroke treatment by retrieval of literature from Thomson Reuters Web of Science database, the NIH Clinical Trial Planning Grant Program, and Clinical Trials Registration Center in North America. In the last 10 years, there has been an increasing number of published articles on stem cell transplantation for stroke treatment. In particular, research from the USA and China has focused on stem cell transplantation. A total of 2,167 articles addressing stem cell transplantation for stroke treatment from 2004 to 2013 were retrieved from the Thomson Reuters Web of Science database. The majority of these articles were from the USA (854, 39.4%), with the journal Stroke publishing the most articles (145, 6.7%). Of the published articles, 143 were funded by the National Institutes of Health (accounting for 6.6% of total publications), and 91 by the National Natural Science Foundation of China. Between 2013 and 2014, the National Institutes of Health provided financial support ($130 million subsidy) for 329 research projects on stroke therapy using stem cell transplantation. In 2014, 215 new projects were approved, receiving grants of up to $70,440,000. Ninety clinical trials focusing on stem cell transplantation for stroke were registered in the Clinical Trial Registration Center in North America, with 40 trials registered in the USA (ranked first place). China had the maximum number of registered research or clinical trials (10 projects).

To investigate the supplement of lost nerve cells in rats with traumatic brain injury by intravenous administration of allogenic bone marrow mesenchymal stem cells, this study established a Wistar rat model of traumatic brain injury by weight drop impact acceleration method and administered 3 × 10(6) rat bone marrow mesenchymal stem cells via the lateral tail vein. At 14 days after cell transplantation, bone marrow mesenchymal stem cells differentiated into neurons and astrocytes in injured rat cerebral cortex and rat neurological function was improved significantly. These findings suggest that intravenously administered bone marrow mesenchymal stem cells can promote nerve cell regeneration in injured cerebral cortex, which supplement the lost nerve cells.

Following successful establishment of a rat model of spinal cord hemisection injury by resecting right spinal cord tissues, bone marrow stem cells were transplanted into the spinal cord lesions via the caudal vein while maintaining rectal temperature at 34 ± 0.5°C for 6 hours (mild hypothermia). Hematoxylin-eosin staining showed that astrocytes gathered around the injury site and formed scars at 4 weeks post-transplantation. Compared with rats transplanted with bone marrow stem cells under normal temperature, rats transplanted with bone marrow stem cells under hypothermia showed increased numbers of proliferating cells (bromodeoxyuridine-positive cells), better recovery of somatosensory-evoked and motor-evoked potentials, greater Basso, Beattie, and Bresnahan locomotor rating scores, and an increased degree of angle in the incline plate test. These findings suggested that hypothermia combined with bone marrow mesenchymal stem cells transplantation effectively promoted electrical conduction and nerve functional repair in a rat model of spinal cord hemisection injury.

This study investigated whether bone marrow mesenchymal stem cell (BMSC) transplantation protected ischemic cerebral injury by stimulating endogenous erythropoietin. The model of ischemic stroke was established in rats through transient middle cerebral artery occlusion. Twenty-four hours later, 1 × 10(6) human BMSCs (hBMSCs) were injected into the tail vein. Fourteen days later, we found that hBMSCs promoted the release of endogenous erythropoietin in the ischemic region of rats. Simultaneously, 3 μg/d soluble erythropoietin receptor (sEPOR) was injected into the lateral ventricle, and on the next 13 consecutive days. sEPOR blocked the release of endogenous erythropoietin. The neurogenesis in the subventricular zone was less in the hBMSCs + sEPOR group than in the hBMSCs + heat-denatured sEPOR group. The adhesive-removal test result and the modified Neurological Severity Scores (mNSS) were lower in the hBMSCs + sEPOR group than in the heat-denatured sEPOR group. The adhesive-removal test result and mNSS were similar between the hBMSCs + heat-denatured sEPOR group and the hBMSCs + sEPOR group. These findings confirm that BMSCs contribute to neurogenesis and improve neurological function by promoting the release of endogenous erythropoietin following ischemic stroke.

Bone marrow mesenchymal stem cell transplantation has been shown to be therapeutic in the repair of spinal cord injury. However, the low survival rate of transplanted bone marrow mesenchymal stem cells in vivo remains a problem. Neurotrophin-3 promotes motor neuron survival and it is hypothesized that its transfection can enhance the therapeutic effect. We show that in vitro transfection of neurotrophin-3 gene increases the number of bone marrow mesenchymal stem cells in the region of spinal cord injury. These results indicate that neurotrophin-3 can promote the survival of bone marrow mesenchymal stem cells transplanted into the region of spinal cord injury and potentially enhance the therapeutic effect in the repair of spinal cord injury.

Currently, there is no effective strategy to promote functional recovery after a spinal cord injury. Collagen scaffolds can not only provide support and guidance for axonal regeneration, but can also serve as a bridge for nerve regeneration at the injury site. They can additionally be used as carriers to retain mesenchymal stem cells at the injury site to enhance their effectiveness. Hence, we hypothesized that transplanting human umbilical cord-mesenchymal stem cells on collagen scaffolds would enhance healing following acute complete spinal cord injury. Here, we test this hypothesis through animal studies and a phase I clinical trial. (1) Animal experiments: Models of completely transected spinal cord injury were established in rats and canines by microsurgery. Mesenchymal stem cells derived from neonatal umbilical cord tissue were adsorbed onto collagen scaffolds and surgically implanted at the injury site in rats and canines; the animals were observed after 1 week-6 months. The transplantation resulted in increased motor scores, enhanced amplitude and shortened latency of the motor evoked potential, and reduced injury area as measured by magnetic resonance imaging. (2) Phase I clinical trial: Forty patients with acute complete cervical injuries were enrolled at the Characteristic Medical Center of Chinese People's Armed Police Force and divided into two groups. The treatment group (n = 20) received collagen scaffolds loaded with mesenchymal stem cells derived from neonatal umbilical cord tissues; the control group (n = 20) did not receive the stem-cell loaded collagen implant. All patients were followed for 12 months. In the treatment group, the American Spinal Injury Association scores and activities of daily life scores were increased, bowel and urinary functions were recovered, and residual urine volume was reduced compared with the pre-treatment baseline. Furthermore, magnetic resonance imaging showed that new nerve fiber connections were formed, and diffusion tensor imaging showed that electrophysiological activity was recovered after the treatment. No serious complication was observed during follow-up. In contrast, the neurological functions of the patients in the control group were not improved over the follow-up period. The above data preliminarily demonstrate that the transplantation of human umbilical cord-mesenchymal stem cells on a collagen scaffold can promote the recovery of neurological function after acute spinal cord injury. In the future, these results need to be confirmed in a multicenter, randomized controlled clinical trial with a larger sample size. The clinical trial was approved by the Ethics Committee of the Characteristic Medical Center of Chinese People's Armed Police Force on February 3, 2016 (approval No. PJHEC-2016-A8). All animal experiments were approved by the Ethics Committee of the Characteristic Medical Center of Chinese People's Armed Police Force on May 20, 2015 (approval No. PJHEC-2015-D5).

We examined the restorative effect of modified biodegradable chitin conduits in combination with bone marrow mesenchymal stem cell transplantation after right spinal cord hemisection injury. Immunohistochemical staining revealed that biological conduit sleeve bridging reduced glial scar formation and spinal muscular atrophy after spinal cord hemisection. Bone marrow mesenchymal stem cells survived and proliferated after transplantation in vivo, and differentiated into cells double-positive for S100 (Schwann cell marker) and glial fibrillary acidic protein (glial cell marker) at 8 weeks. Retrograde tracing showed that more nerve fibers had grown through the injured spinal cord at 14 weeks after combination therapy than either treatment alone. Our findings indicate that a biological conduit combined with bone marrow mesenchymal stem cell transplantation effectively prevented scar formation and provided a favorable local microenvironment for the proliferation, migration and differentiation of bone marrow mesenchymal stem cells in the spinal cord, thus promoting restoration following spinal cord hemisection injury.