Cell-Based Therapies for Traumatic Brain Injury: Therapeutic Treatments and Clinical Trials.

Traumatic brain injury (TBI) represents physical damage to the brain tissue that induces transitory or permanent neurological disabilities. TBI contributes to 50% of all trauma deaths, with many enduring long-term consequences and significant medical and rehabilitation costs. There is currently no therapy to reverse the effects associated with TBI. An increasing amount of research has been undertaken regarding the use of different stem cells (SCs) to treat the consequences of brain damage. Neural stem cells (NSCs) (adult and embryonic) and mesenchymal stromal cells (MSCs) have shown efficacy in pre-clinical models of TBI and in their introduction to clinical research. The purpose of this review is to provide an overview of TBI and the state of clinical trials aimed at evaluating the use of stem cell-based therapies in TBI. The primary aim of these studies is to investigate the safety and efficacy of the use of SCs to treat this disease. Although an increasing number of studies are being carried out, few results are currently available. In addition, we present our research regarding the use of cell therapy in TBI. There is still a significant lack of understanding regarding the cell therapy mechanisms for the treatment of TBI. Thus, future studies are needed to evaluate the feasibility of the transplantation of SCs in TBI.

Bone Marrow-derived Mesenchymal Stem Cells and Chronic Allograft Disease in a Bronchiolitis Obliterans Animal Model / Células mesenquimales derivadas de médula ósea y disfunción crónica del injerto en un modelo animal de bronquiolitis obliterante

INTRODUCTION: Bronchiolitis obliterans (BO) is the most common expression of chronic allograft dysfunction in lung transplantation. Moreover, BO represents the major cause of death in the long-term after this procedure. On the other hand, mesenchymal stem cells have been tested in animal models of BO aiming to interfere in its development. The aim of this experimental study is to explore the role of bone-marrow derived stem cells (BMSCs) as a preventive intervention of BO occurrence. MATERIALS AND METHODS: This an experimental randomized study. A bronchiolitis obliterans animal model in rats was reproduced: heterotopical tracheal transplant model in lung parenchyma. Five of these animals were used as control group. After setting up the model, individuals were divided in 3 groups of treatment (n = 15), in which BMSCs were administered in 3 different time points after the tracheal transplant (tracheal transplantation and BMSCs administration occurred the same day, group G0; after 7 days, group G7; after 14 days, group G14. In addition, within each group, BMSCs were administered through 3 different routes: endotracheally, endovascular and topically in the lung parenchyma). Animals were sacrificed at 21 days. Histology, fluorescence in situ hybridization and immunohistochemistry techniques were performed for identifying stem cells. RESULTS: Compared to control group, animals receiving BMSCs showed large neovessels in a loose fibrous matrix. Group G7 showed less fibrosis (p < 0.033) and edema (p < 0.028). Moreover, G7 animals receiving stem cells endotracheally showed no fibrosis (p < 0.008). Alveolar-like patches of tissue were observed among all groups (53.4%, 46.7% and 40% in G0, G7 and G14 respectively), consisting of cells expressing both stem and alveolar cells biomarkers. CONCLUSION: BMSCs modify the course of bronchiolitis obliterans and differentiate into alveolar cells. Endotracheal administration of BMSCs 7 days after the heterotopical tracheal transplant might be considered an effective way to prevent BO in this animal model

INTRODUCCIÓN: La bronquiolitis obliterante (OB) es la forma más frecuente de disfunción crónica del injerto en el trasplante pulmonar. Asimismo, representa la principal causa de mortalidad a largo plazo tras este procedimiento. Por otro lado, las células madre mesenquimales se han utilizado en diferentes modelos animales de BO, con el propósito de interferir en el desarrollo de dicha disfunción. El objetivo de este estudio experimental es explorar el papel del trasplante de células madre mesenquimales derivadas de la médula ósea (BMSC, por sus siglas en inglés) como tratamiento preventivo de la BO. MATERIAL Y MÉTODOS: Se trata de un estudio experimental y aleatorizado en el que se empleó un modelo de BO en ratas basado en el trasplante traqueal heterotópico en parénquima pulmonar. Los animales se dividieron en los siguientes grupos: grupo control (n = 5) y 3 grupos de tratamiento (n = 15) en los que las células madre mesenquimales derivadas de médula ósea se administraron a distintos tiempos tras el trasplante traqueal heterotópico (el mismo día [grupo G0]; a 7 días [grupo G7], y a 14 días [grupo G14]). Además, dentro de cada grupo, las células se trasplantaron mediante 3 vías diferentes: endotraqueal, endovascular y tópicamente en el parénquima pulmonar. Todos los animales se sacrificaron a los 21 días tras el trasplante traqueal. Las células madre se identificaron mediante técnicas histológicas utilizando hibridación fluorescente in situ (FISH) e inmunohistoquímica. RESULTADOS: Comparado con el grupo control, los animales que recibieron las BMSC mostraron neovasos de gran tamaño en una matriz muy laxa de tejido fibroso. En el grupo G7 se observó menor grado de fibrosis (p < 0,033) y edema (p < 0,028). Además, ninguno de los animales del grupo G7 que recibieron las células madre por vía endotraqueal desarrolló algún grado de fibrosis (p < 0,008). En todos los grupos se observaron parches de tejido con características histológicas similares al tejido alveolar (53,4, 46,7% y 40% in G0, G7 y G14, respectivamente) con expresión de marcadores tanto alveolares como de células madre. CONCLUSIONES: Las células madre mesenquimales derivadas de la médula ósea modifican el curso histopatológico de la BO y son capaces de diferenciarse a células de tipo alveolar. La administración endotraqueal de estas células a los 7 días del trasplante traqueal heterotópico podría considerarse una vía efectiva para prevenir el desarrollo de BO en este modelo animal

Bone Marrow-derived Mesenchymal Stem Cells and Chronic Allograft Disease in a Bronchiolitis Obliterans Animal Model.

INTRODUCTION: Bronchiolitis obliterans (BO) is the most common expression of chronic allograft dysfunction in lung transplantation. Moreover, BO represents the major cause of death in the long-term after this procedure. On the other hand, mesenchymal stem cells have been tested in animal models of BO aiming to interfere in its development. The aim of this experimental study is to explore the role of bone-marrow derived stem cells (BMSCs) as a preventive intervention of BO occurrence. MATERIALS AND METHODS: This an experimental randomized study. A bronchiolitis obliterans animal model in rats was reproduced: heterotopical tracheal transplant model in lung parenchyma. Five of these animals were used as control group. After setting up the model, individuals were divided in 3 groups of treatment (n=15), in which BMSCs were administered in 3 different time points after the tracheal transplant (tracheal transplantation and BMSCs administration occurred the same day, group G0; after 7 days, group G7; after 14 days, group G14. In addition, within each group, BMSCs were administered through 3 different routes: endotracheally, endovascular and topically in the lung parenchyma). Animals were sacrificed at 21 days. Histology, fluorescence in situ hybridization and immunohistochemistry techniques were performed for identifying stem cells. RESULTS: Compared to control group, animals receiving BMSCs showed large neovessels in a loose fibrous matrix. Group G7 showed less fibrosis (p<0.033) and edema (p<0.028). Moreover, G7 animals receiving stem cells endotracheally showed no fibrosis (p<0.008). Alveolar-like patches of tissue were observed among all groups (53.4%, 46.7% and 40% in G0, G7 and G14 respectively), consisting of cells expressing both stem and alveolar cells biomarkers. CONCLUSION: BMSCs modify the course of bronchiolitis obliterans and differentiate into alveolar cells. Endotracheal administration of BMSCs 7 days after the heterotopical tracheal transplant might be considered an effective way to prevent BO in this animal model.

Matrix metalloproteases and TIMPs as prognostic biomarkers in breast cancer patients treated with radiotherapy: A pilot study.

Breast cancer (BC) is the most common tumour in women and one of the most important causes of cancer death worldwide. Radiation therapy (RT) is widely used for BC treatment. Some proteins have been identified as prognostic factors for BC (Ki67, p53, E-cadherin, HER2). In the last years, it has been shown that variations in the expression of MMPs and TIMPs may contribute to the development of BC. The aim of this pilot work was to study the effects of RT on different MMPs (-1, -2, -3, -7, -8, -9, -10, -12 and -13) and TIMPs (-1 to -4), as well as their relationship with other variables related to patient characteristics and tumour biology. A group of 20 BC patients treated with RT were recruited. MMP and TIMP serum levels were analysed by immunoassay before, during and after RT. Our pilot study showed a slight increase in the levels of most MMP and TIMP with RT. However, RT produced a significantly decrease in TIMP-1 and TIMP-3 levels. Significant correlations were found between MMP-3 and TIMP-4 levels, and some of the variables studied related to patient characteristics and tumour biology. Moreover, MMP-9 and TIMP-3 levels could be predictive of RT toxicity. For this reason, MMP-3, MMP-9, TIMP-3 and TIMP-4 could be used as potential prognostic and predictive biomarkers for BC patients treated with RT.

Intrathecal cell therapy with autologous stromal cells increases cerebral glucose metabolism and can offer a new approach to the treatment of Alzheimer's type dementia.

BACKGROUND AIMS: After recent observations that intrathecal administration of autologous bone marrow mesenchymal stromal cells (MSCs) increases cerebral metabolism in patients with severe traumatic brain injury (TBI), we examined this type of cell therapy in Alzheimer's type dementia. METHODS: Three patients with clinical diagnosis of Alzheimer's disease received every 3 months 100million autologous MSCs by intrathecal route, until a total dose of 300million. RESULTS: During cell therapy the patients showed arrest in neurological deterioration and two of them manifested clear improvement of previous symptoms. A global increase in cerebral glucose metabolism, measured using 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET), was observed after every administration of cell therapy. CONCLUSIONS: Our present findings suggest that intrathecal administrations of autologous MSCs can be a new strategy for the treatment of Alzheimer's dementia.

Intrathecal administration of autologous mesenchymal stromal cells for spinal cord injury: Safety and efficacy of the 100/3 guideline.

BACKGROUND AIMS: Cell therapy with autologous mesenchymal stromal cells (MSCs) in patients with spinal cord injury (SCI) is beginning, and the search for its better clinical application is an urgent need. METHODS: We present a phase 2 clinical trial in patients with chronic SCI who received three intrathecal administrations of 100 x 106 MSCs and were followed for 10 months from the first administration. Efficacy analysis was performed on nine patients, and safety analysis was performed on 11 patients. Clinical scales, urodynamic, neurophysiological and neuroimaging studies were performed previous to treatment and at the end of the follow-up. RESULTS: The treatment was well-tolerated, without any adverse event related to MSC administration. Patients showed variable clinical improvement in sensitivity, motor power, spasms, spasticity, neuropathic pain, sexual function or sphincter dysfunction, regardless of the level or degree of injury, age or time elapsed from the SCI. In the course of follow-up three patients, initially classified as ASIA A, B and C, changed to ASIA B, C and D, respectively. In urodynamic studies, at the end of follow-up, 66.6% of the patients showed decrease in postmicturition residue and improvement in bladder compliance. At this time, neurophysiological studies showed that 55.5% of patients improved in somatosensory or motor-evoked potentials, and that 44.4% of patients improved in voluntary muscle contraction together with infralesional active muscle reinnervation. CONCLUSIONS: The present guideline for cell therapy is safe and shows efficacy in patients with SCI, mainly in recovery of sphincter dysfunction, neuropathic pain and sensitivity.

Cell therapy with autologous mesenchymal stromal cells in post-traumatic syringomyelia.

BACKGROUND AIMS: Recently, clinical studies show that cell therapy with mesenchymal stromal cells (MSCs) improves the sequelae chronically established in paraplegic patients, being necessary to know which of them can obtain better benefit. METHODS: We present here a phase 2 clinical trial that includes six paraplegic patients with post-traumatic syringomyelia who received 300 million MSCs inside the syrinx and who were followed up for 6 months. Clinical scales, urodynamic, neurophysiological, magnetic resonance (MR) and studies of ano-rectal manometry were performed to assess possible improvements. RESULTS: In all the cases, MR at the end of the study showed a clear reduction of the syrinx, and, at this time, signs of improvement in the urodynamic studies were found. Moreover, four patients improved in ano-rectal manometry. Four patients improved in neurophysiological studies, with signs of improvement in evoked potentials in three patients. In the American Spinal Injury Association (ASIA) assessment, only two patients improved in sensitivity, but clinical improvement in neurogenic bowel dysfunction was observed in four patients and three patients described improvement in bladder dysfunction. Spasms reduced in two of the five patients who had them previous to cell therapy, and spasticity was improved in the other two patients. Three patients had neuropathic pain before treatment, and it was reduced or disappeared completely during the study. Only two adverse events ocurred, without relation to the cell therapy. CONCLUSIONS: Cell therapy can be considered as a new alternative to the treatment of post-traumatic syringomyelia, achieving reduction of syrinx and clinical improvements in individual patients.

Cell Therapy as a New Approach to the Treatment of Posttraumatic Syringomyelia.

BACKGROUND: Cell transplantation with autologous bone marrow-derived mesenchymal stromal cells (MSCs) seems to be a therapeutic promise for patients with established spinal cord injury, achieving improvement in their quality of life, but there is no experience with the application of this type of cell therapy in patients suffering posttraumatic syringomyelia. OBJECTIVE: To study the possible utility of cell therapy with autologous MSCs in posttraumatic syringomyelia. METHODS: A 40-year-old man with complete paraplegia since 1991 as a consequence of a Th4 vertebral fracture showed a great posttraumatic syringomyelia that extended up to C2 vertebral level, without signs of recent worsening. Autologous MSCs (150 × 106) were injected into the syrinx, without drainage or aspiration. RESULTS: One year after cell therapy, syrinx was reduced without collapse of cervical spinal cord. During the course of follow-up, clear clinical improvement was observed, mainly in sphincter dysfunction. CONCLUSIONS: Injection of MSCs in the syrinx of posttraumatic syringomyelia is safe and is associated with clinical and neuroimaging improvement. The possibility of cell therapy as a new approach to posttraumatic syringomyelia, or even for idiopathic syringomyelia, is an open door that requires further study.

Repeated subarachnoid administrations of autologous mesenchymal stromal cells supported in autologous plasma improve quality of life in patients suffering incomplete spinal cord injury.

BACKGROUND AIMS: Cell therapy with mesenchymal stromal cells (MSCs) offers new hope for patients suffering from spinal cord injury (SCI). METHODS: Ten patients with established incomplete SCI received four subarachnoid administrations of 30 × 106 autologous bone marrow MSCs, supported in autologous plasma, at months 1, 4, 7 and 10 of the study, and were followed until the month 12. Urodynamic, neurophysiological and neuroimaging studies were performed at months 6 and 12, and compared with basal studies. RESULTS: Variable improvement was found in the patients of the series. All of them showed some degree of improvement in sensitivity and motor function. Sexual function improved in two of the eight male patients. Neuropathic pain was present in four patients before treatment; it disappeared in two of them and decreased in another. Clear improvement in bladder and bowel control were found in all patients suffering previous dysfunction. Before treatment, seven patients suffered spasms, and two improved. Before cell therapy, nine patients suffered variable degree of spasticity, and 3 of them showed clear decrease at the end of follow-up. At this time, nine patients showed infra-lesional electromyographic recordings suggesting active muscle reinnervation, and eight patients showed improvement in bladder compliance. After three administrations of MSCs, mean values of brain-derived neurotrophic factor, glial-derived neurotrophic factor, ciliary neurotrophic factor, and neurotrophin 3 and 4 showed slight increases compared with basal levels, but without statistically significant difference. CONCLUSIONS: Administration of repeated doses of MSCs by subarachnoid route is a well-tolerated procedure that is able to achieve progressive and significant improvement in the quality of life of patients suffering incomplete SCI.

Progressive increase in brain glucose metabolism after intrathecal administration of autologous mesenchymal stromal cells in patients with diffuse axonal injury.

BACKGROUND AIMS: Cell therapy in neurological disability after traumatic brain injury (TBI) is in its initial clinical stage. We describe our preliminary clinical experience with three patients with diffuse axonal injury (DAI) who were treated with intrathecal administration of autologous mesenchymal stromal cells (MSCs). METHODS: Three patients with established neurological sequelae due to DAI received intrathecally autologous MSCs. The total number of MSCs administered was 60 × 106 (one patient), 100 × 106 (one patient) and 300 × 106 (one patient). RESULTS: All three patients showed improvement after cell therapy, and subsequent studies with 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) showed a diffuse and progressive increase in brain glucose metabolism. CONCLUSION: Our present results suggest benefit of intrathecal administration of MSCs in patients with DAI, as well as a relationship between this type of treatment and increase in brain glucose metabolism. These preliminary findings raise the question of convenience of assessing the potential benefit of intrathecal administration of MSCs for brain diseases in which a decrease in glucose metabolism represents a crucial pathophysiological finding, such as Alzheimer's disease (AD) and other dementias.

Inexpensive Attachment Device for Cell Therapy Administration into Injured Spinal Cord.

BACKGROUND: Cell therapy is configured as a promising strategy for the treatment of spinal cord injury (SCI), but it requires reliable systems to achieve microinjections with different rates and volumes, according to the different characteristics of the injured spinal cord tissue and the targets previously selected. OBJECTIVE: We sought to describe an original and inexpensive device for support of microinjection systems in the course of spinal cord surgery. METHODS: Our attachment device consists of an arch and a system of bars that can be fixed to the operating table and on which a microinjection pump can be displaced and fixed in the course of surgery. RESULTS: This device has been used for therapy administration into injured spinal cords. It is easy to use and permits reproducible results. CONCLUSION: We have described an original attachment device for the support of a microinjection pump. It is applicable to spinal cord surgery and should be considered as a cheap solution for intralesional administration of cell therapy after spinal cord injury.

An approach to personalized cell therapy in chronic complete paraplegia: The Puerta de Hierro phase I/II clinical trial.

BACKGROUND AIMS: Cell transplantation in patients suffering spinal cord injury (SCI) is in its initial stages, but currently there is confusion about the results because of the disparity in the techniques used, the route of administration, and the criteria for selecting patients. METHODS: We conducted a clinical trial involving 12 patients with complete and chronic paraplegia (average time of chronicity, 13.86 years; SD, 9.36). The characteristics of SCI in magnetic resonance imaging (MRI) were evaluated for a personalized local administration of expanded autologous bone marrow mesenchymal stromal cells (MSCs) supported in autologous plasma, with the number of MSCs ranging from 100 × 10(6) to 230 × 10(6). An additional 30 × 10(6) MSCs were administered 3 months later by lumbar puncture into the subarachnoid space. Outcomes were evaluated at 3, 6, 9 and 12 months after surgery through clinical, urodynamic, neurophysiological and neuroimaging studies. RESULTS: Cell transplantation is a safe procedure. All patients experienced improvement, primarily in sensitivity and sphincter control. Infralesional motor activity, according to clinical and neurophysiological studies, was obtained by more than 50% of the patients. Decreases in spasms and spasticity, and improved sexual function were also common findings. Clinical improvement seems to be dose-dependent but was not influenced by the chronicity of the SCI. CONCLUSION: Personalized cell therapy with MSCs is safe and leads to clear improvements in clinical aspects and quality of life for patients with complete and chronically established paraplegia.

Dual Strategy With Oral Phosphodiesterase Type 5 Inhibition and Intracavernosal Implantation of Mesenchymal Stem Cells Is Superior to Individual Approaches in the Recovery of Erectile and Cavernosal Functions After Cavernous Nerve Injury in Rats.

INTRODUCTION: Novel effective therapeutic strategies are necessary for treating erectile dysfunction secondary to cavernous nerve injury (CNI). AIM: To functionally evaluate the benefits of long-term oral treatment with a phosphodiesterase type 5 inhibitor on the potential capacity of intracavernosal cell therapy to recover erectile function after CNI. METHODS: Bilateral crush CNI (BCNI) was produced in anesthetized male rats. After BCNI, rats were treated with the phosphodiesterase type 5 inhibitor tadalafil (TAD; 5 mg/kg/d orally; BCNI + TAD), a single intracavernosal injection of bone marrow-derived mesenchymal stem cells (BMSCs; BCNI + BMSC), or dual therapy (BCNI + BMSC + TAD). Ex vivo function of the corpus cavernosum (CC) and in vivo intracavernosal pressure responses to CN electrical stimulation were evaluated 4 weeks after BCNI. Trichrome staining and terminal 2'-deoxyuridine-5'-triphosphate nick-end labeling assay were used for fibrosis and apoptosis determination, respectively, in the CC. MAIN OUTCOME MEASURES: In vivo erectile responses in anesthetized rats, ex vivo evaluation of endothelium-dependent relaxation, neurogenic relaxation and neurogenic contraction in CC strips, and histologic evaluation of fibrosis and apoptosis in cavernosal tissue. RESULTS: BCNI resulted in a marked decrease of erectile responses that were partly recovered in the BCNI + TAD and BCNI + BMSC groups. Complete recovery of erectile function was achieved only in the BCNI + BMSC + TAD group. Endothelium-dependent and nitric oxide donor-induced relaxations of the CC were not altered by BCNI or the treatments. BCNI resulted in enhanced neurogenic adrenergic contractions and impaired nitrergic relaxations of the CC. The BCNI + TAD group displayed diminished neurogenic contractions, whereas the BCNI + TAD and BCNI + BMSC groups showed partly recovered nitrergic responses. In the BCNI + BMSC + TAD group, neurogenic contractions were decreased and nitrergic relaxations were normalized. Cavernosal apoptosis and fibrosis were similarly prevented in the BCNI + TAD, BCNI + BMSC, and BCNI + BMSC + TAD groups. CONCLUSION: A dual strategy combining the intracavernosal injection of BMSCs and oral administration of TAD was superior to individual approaches in normalizing neurogenic control of cavernosal tone and preserving erectile function after CNI, suggesting the potential of this dual strategy in the future management of erectile dysfunction after radical prostatectomy.

Hypofractionated Breast Radiation: Shorter Scheme, Lower Toxicity.

BACKGROUND: We analyzed the toxicity and cosmetic outcomes for patients who had undergone 3-dimensional conformal radiotherapy with a hypofractionated schedule and identified the risk factors associated with such a schedule. MATERIALS AND METHODS: A total of 143 patients were treated for breast cancer (stage 0-III) with a hypofractionated radiation schedule after breast-conserving surgery from 2006 to 2011. Most patients received 42.4 Gy in 16 daily fractions, 2.65 Gy per fraction to the whole breast plus an additional simultaneous integrated or sequential boost to the tumor bed. RESULTS: The median follow-up period was 36 months. Mild acute skin toxicity was observed in 62%; 7% of the patients developed moderate skin toxicity, but no grade 4 toxicity was observed. The prevalence of fibrosis within the boost area was 5%, but no grade ≥ 2 was observed. The prevalence of fibrosis of any grade was greater in the nonboost (23%) than in the boost area. Of all the patients, 91% had good or excellent cosmetic outcomes. From the multivariate analysis, the incidence of epithelitis correlated with the patient's treated volume (P = .044). The incidence of acute toxicity correlated with the boost type to the tumor bed and the total treatment dose (P = .012 and P = .002, respectively). Also, a poor to fair cosmetic outcome was significantly associated statistically with the surgery type (P = .05), boost type (P = .004), and total dose (P = .001). CONCLUSION: Delivering whole-breast irradiation with a hypofractionated schedule of 42.4 Gy plus a simultaneous integrated boost to the tumor bed appears to be a safe and effective technique, with good cosmetic results and lower toxicity.

Is the subarachnoid administration of mesenchymal stromal cells a useful strategy to treat chronic brain damage?

BACKGROUND AIMS: Traumatic brain injury (TBI) is a leading cause of mortality and morbidity worldwide. Developing effective protocols for the administration of mesenchymal stromal cells (MSCs) is a promising therapeutic strategy to treat TBI. It is important to develop alternatives to direct parenchymal injection at the injury site because direct injection is an expensive and invasive technique. Subarachnoid transplantation, a minimally invasive and low-risk procedure, may be an important and clinically applicable strategy. The aim of this study was to test the therapeutic effect of subarachnoid administration of MSCs on functional outcome 2 months after an experimental TBI in rats. METHODS: Two months after TBI, 30 female Wistar rats were divided into 3 groups (n = 10 in each group): sham, MSC (received 2 × 10(6) MSCs) and saline (received only saline) groups. Neurological function, brain and spinal cords samples and cerebrospinal fluid were studied. RESULTS: No significant differences were found in neurological evaluation and after histological analysis; differences in the expression of neurotrophins were present but were not statistically significant. MSCs survived in the host tissue, and some expressed neural markers. CONCLUSIONS: Similar to direct parenchymal injections, transplanted MSCs survive, migrate to the injury cavity and differentiate into mature neural cell types for at least 6 months after engraftment. These results open the possibility that MSC administration through subarachnoid administration may be a treatment for the consequences of TBI. The transplantation technique and cell number should be adjusted to obtain functional outcome and neurotrophin production differences.

Cell transplantation in paraplegic patients: the importance of properly assessing the spinal cord morphology.

INTRODUCTION: Cell transplantation in paraplegic patients is beginning, but scarce attention is paid to the morphology of lesions. MATERIAL AND METHODS: We studied using magnetic resonance imaging (MRI) the morphology of the injured spinal cord in 200 patients with chronic and complete paraplegia after spinal cord injury (SCI) at the thoracic level. RESULTS: When it was possible to undertake a correct study of the lesion, approximately 35% of patients had images showing spinal cord transection or showed fine tracts of tissue that connected both edges of a virtually transected spinal cord. Approximately 30% of patients had significant kyphosis with chronic spinal cord compression, and approximately 5% of cases had extensive spinal cord atrophy. In only approximately 30% of the patients, MRI revealed a centromedullary cavity, which was generally limited to the level of the vertebral fracture, and failed to show any apparent spinal cord transection. CONCLUSIONS: Humans suffering from chronically established paraplegia show a great variability of lesions, which differs from the standardized images of SCI obtained in animal models. When we design clinical trials, our goal should be to achieve a correct selection of patients, and the morphology of the spinal cord must be one of the main factors to consider.

Perilesional intrathecal administration of autologous bone marrow stromal cells achieves functional improvement in pigs with chronic paraplegia.

BACKGROUND AIMS: At present, on the basis of the great number of preclinical studies and preliminary clinical trials in humans, bone marrow stromal cell (BMSC) transplantation offers promise in the treatment of paraplegia. Nevertheless, there is not enough experience in humans about the best candidates for this type of cell therapy or details about the best parameters or best route of administration. METHODS: Two adult paraplegic pigs with chronic paraplegia were treated only with perilesional intrathecal administration of 40 × 10(6) autologous BMSC suspended in autologous plasma and followed for 1 year after cell transplantation. RESULTS: Our study showed clinical improvement, starting at 2 mo after BMSC administration and reaching stabilization at 10 mo. This was associated with recovery of previously abolished somatosensory-evoked potentials. At the end of the study, histological images suggested spinal cord regeneration. CONCLUSIONS: Our present findings suggest the possible utility of perilesional intrathecal administration of autologous BMSC in patients with chronic paraplegia.

Cell therapy with bone marrow stromal cells after intracerebral hemorrhage: impact of platelet-rich plasma scaffolds.

BACKGROUND AIMS: Cell therapy using bone marrow stromal cells (BMSCs) has been considered a promising strategy for neurologic sequelae after intracerebral hemorrhage (ICH). However, after intracerebral administration of BMSCs, most of the cells die, partly because of the absence of extracellular matrix. Intracerebral transplantation of BMSCs, supported in a platelet-rich plasma (PRP) scaffold, optimizes this type of cell therapy. METHODS: ICH was induced by stereotactic injection of 0.5 IU of collagenase type IV in the striatum of adult Wistar rats (n = 40). Two months later, the rats were subjected to intracerebral administration of 5 × 10(6) allogeneic BMSCs embedded in a PRP scaffold (n = 10), 5 × 10(6) allogeneic BMSCs in saline (n = 10), PRP-derived scaffold only (n = 10) or saline only (n = 10). Functional improvements in each group over the next 6 months were assessed using Rotarod and Video-Tracking-Box tests. Endogenous neurogenesis and survival of transplanted BMSCs were examined at the end of follow-up. RESULTS: Our study demonstrated neurologic improvement after BMSC transplantation and significantly better functional improvement for the group of animals that received BMSCs in the PRP-derived scaffold compared with the group that received BMSCs in saline. Histologic results showed that better functional outcome was associated with strong activation of endogenous neurogenesis. After intracerebral administration of BMSCs, donor cells were integrated in the injured tissue and showed phenotypic expression of glial fibrillary acidic protein and neuronal nucleus. CONCLUSIONS: PRP-derived scaffolds increase the viability and biologic activity of BMSCs and optimize functional recovery when this type of cell therapy is applied after ICH.

Perspectivas de la terapia celular en las secuelas del accidente cerebrovascular hemorrágico / No disponible

Introducción La hemorragia intracerebral (HIC) espontánea se asocia a una mortalidad que oscila entre el 40 y el 50% de los casos. Entre los supervivientes, únicamente el 10% serán independientes al mes, sin que exista ningún tratamiento eficaz de las secuelas, a excepción de las escasas posibilidades que aporta la rehabilitación. Objetivos En este artículo llamamos la atención acerca de las perspectivas que puede tener el trasplante intracerebral de células madre mesenquimales (CMM) de médula ósea como un posible tratamiento de las secuelas neurológicas producidas tras una HIC experimental. Material y métodos Describimos un modelo experimental de HIC, utilizando la administración intracerebral de colagenasa IV a nivel de ganglios basales en la rata Wistar. Los déficits neurológicos provocados por la HIC pueden ser cuantificados a lo largo de los meses siguientes mediante diversos test de valoración funcional (mNSS, Rota-rod, VTB-test). En un estudio previamente publicado, hemos aplicado este modelo a 10 animales que recibieron intracerebralmente 5×10CMM alogénicas, en 10μl de suero fisiológico, a los 2 meses de la HIC, mientras que en (..) (AU)

Complex form variant of dysembryoplastic neuroepithelial tumor of the cerebellum.

Dysembryoplastic neuroepithelial tumor (DNT) is a benign neoplasm with typical supratentorial location, but the possibility of these rare tumors can also be located in the posterior fossa must be taken into account. We report a 21-year-old woman that suffered gait instability, headache, and diplopia. On CT-scan, an intraparenchymatous cerebellar tumor was disclosed. It was isodense, showing light enhancement after contrast administration. On MRI (T1-weighted image) the tumor was isointense, showing inhomogeneous hyperintensity after-gadolinium administration. On T2-weighted MRI, the tumor was inhomogenously hyperintense. At surgery, a solid and hypervascularized tumor was completely removed. Two years after surgery, the patient is symptom-free. Pathological study showed coexistence of areas of pilocytic astrocytoma with areas in which small rounded oligodendrocyte-like cells (OLC), with strong synaptophysin expression were identified. These neurocytic areas showed an eosinophilic matrix forming microcysts, and cells with aspect of "floating neurons" were occasionally identified. A complex form variant of DNT was diagnosed. Our case suggests that in presence of a cerebellar tumor with features of pilocytic astrocytoma, the possibility of a complex form variant of DNT should be considered.