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.

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.

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.

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.

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)

[Perspectives of cell therapy in sequelae from cerebrovascular accidents]. / Perspectivas de la terapia celular en las secuelas del accidente cerebrovascular hemorrágico.

INTRODUCTION: Spontaneous intracerebral hemorrhage (ICH) is associated with mortality between 40 and 50% of cases. Among the survivors, only 10% are independent after one month, there is no effective treatment of sequelae, except for the limited possibilities providing for rehabilitation. OBJECTIVES: We review the current experience with intracerebral transplantation of mesenchymal stem cells (MSCs) obtained from bone marrow as a potential treatment of neurological sequelae occurring after experimental ICH. MATERIAL AND METHODS: We describe the model of ICH by intracerebral administration of collagenaseIV at basal ganglia level in Wistar rats. Neurological deficits caused by ICH can be quantified through a variety of functional assessment test (NMSS, Rota-rod, VTB-test). 5×10allogeneic MSCs in 10µl of saline were administered intracerebrally in 10 animals, 2 months after ICH. In another 10 animals (controls) the same volume of saline was administered. Changes in the functional deficits were assessed during the next 6 months in both experimental groups. RESULTS: The results suggested therapeutic efficacy of MSCs transplantation and showed that transplanted stem cells can survive in the injured brain, transforming into neurons and glial cells. This form of cell therapy induces reactivation of endogenous neurogenesis at the subventricular zone (SVZ) and achieves antiapoptotic protective effect in the injured brain. CONCLUSIONS: Cell therapy represents an important field of research with potential clinical application to treatment of neurological sequels, currently considered irreversible. Neurosurgeons should become involved in the development of these new techniques that are likely to shape the future of this specialty.

The severity of brain damage determines bone marrow stromal cell therapy efficacy in a traumatic brain injury model.

BACKGROUND: Patients who survive traumatic brain injury (TBI) can undergo serious sensorial and motor function deficits. Once damage occurs, there is no effective treatment to bring patients to full recovery. Recent studies, however, show bone marrow stromal cells (BMSC) as a potential therapy for TBI. METHODS: This study was designed to determine whether the degree of neurologic deficits influences the efficacy of cell therapy using intracerebral transplantation of BMSC in an experimental model of chronically established TBI. Adult Wistar rats were subjected to weight-drop impact causing TBI. Two months later, the animals were classified according to levels of neurologic deficits. To achieve this, we used two different functional tests: the modified Neurologic Severity Score test and internal zone Permanence Time in Video-Tracking-Box analysis. Saline only or saline containing BMSC was injected into injured brain tissue of the animals that were classified having moderate or severe neurologic damage depending on the level of established functional deficits. All experimental groups were evaluated in the course of the following 2 months to study the efficacy of BMSC administration. The animals were then killed and their brains were studied. RESULTS: Our results showed that significant functional improvement was seen when BMSC was injected into animals with moderate brain damage, but no significant improvement was found in animals with severe functional deficits when compared with controls. CONCLUSION: These findings suggest that the severity of neurologic damage may determine the potential effect of cell therapy when applied to chronically established TBI.

The pig model of chronic paraplegia: a challenge for experimental studies in spinal cord injury.

The regenerative medicine techniques that are beginning to be applied to the nervous system have led to increased hope in the treatment of diseases that have been considered incurable and that require experimental models on which to test new therapeutic strategies. We present our experience with adult pigs (minipigs) that have undergone a traumatic spinal cord injury (SCI) experimental model, and that have been followed for 1 year. We describe the surgical aspects of our SCI model by acute compression and also describe protocols for daily care and rehabilitation that are necessary to maintain the paraplegic pigs in good health during the months following the injury. Furthermore, we provide in detail the main complications that arise with this experimental model and the treatments used to address these complications. Suitable housing conditions, daily rehabilitation and prevention of complications (i.e., taking the same care applied to patients following SCI) are essential for achieving the absence of mortality and long-term maintenance of the animals. We consider the model that is described here to be feasible and useful for preliminary testing of novel therapeutic strategies aimed at regeneration of the injured spinal cord in paraplegic patients.

Allogeneic bone marrow stromal cell transplantation after cerebral hemorrhage achieves cell transdifferentiation and modulates endogenous neurogenesis.

BACKGROUND AIMS: When a severe neurologic lesion occurs as a consequence of intracerebral hemorrhage (ICH), there is no effective treatment available for improving the outcome. However, cell therapy has opened new perspectives on reducing neurologic sequels subsequent to this disease. METHODS: In this study, ICH was induced by stereotactic injection of 0.5 U collagenase type IV in the striatum of adult Wistar rats, and 2 h later a group of animals (n = 48) was subjected to intracerebral injection of 2 × 10(6) allogeneic bone marrow stromal cells (BMSC), while a control group (n = 48) received saline only. Eight animals from each group were killed at 48 h, 72 h, 7 days, 14 days, 21 days and 28 days. At these time-points, endogenous neurogenesis and survival of transplanted BMSC were studied. RESULTS: Our findings show that after allogeneic BMSC transplantation, donor cells can survive in the brain tissue expressing neuronal and astroglial markers. Furthermore, BMSC transplantation enhances endogenous neurogenesis and inhibits apoptosis of newborn neural cells. CONCLUSIONS: Although these results should be extrapolated to human disease with caution, it is obvious that cell therapy using allogeneic BMSC transplantation offers great promise for developing novel and efficacious strategies in patients suffering ICH.

Failure of delayed intravenous administration of bone marrow stromal cells after traumatic brain injury.

Traumatic brain injury (TBI) is a leading cause of mortality and morbidity worldwide. Currently, there is no effective strategy to treat the functional sequelae associated with TBI. Experimental evidence shows that the intravenous administration of bone marrow stromal cells (BMSC) during the first week after TBI prevents neurological deficits, but no experimental studies have shown evidence of the effect of intravenous BMSC on chronic brain injury sequelae. Here we studied the effect of intravenous administration of BMSC on functional outcomes 2 months after experimental TBI in rats. Adult Wistar rats were subjected to weight-drop impact causing severe brain injury, and 2 months later BMSC in saline, or saline alone, was intravenously injected. All experimental groups were evaluated by means of the modified Neurological Severity Score (mNSS), and internal zone Permanence Time (izPT) after video-tracking box (VTB) analysis, over the following 2 months to test the efficacy of BMSC therapy. At the end of the study period the animals were sacrificed and their brains were studied to evaluate possible differences between groups. Two months after BMSC administration no significant differences were detected in the motor and sensory evaluation between animals treated with BMSC and controls, and no differences were detected after histological study of the brains. Our present results suggest that intravenous administration of BMSC after TBI, when the neurological deficits are well established, has no beneficial effect in neurological outcomes or on brain tissue.

Late transplantation of allogeneic bone marrow stromal cells improves neurologic deficits subsequent to intracerebral hemorrhage.

BACKGROUND AIMS: Stem cell therapy seems to be a promising therapeutic tool for treating central nervous system (CNS) injuries. Bone marrow stromal cell (BMSC) transplantation influences functional outcome subsequent to intracerebral hemorrhage (ICH), and enhances endogenous neurogenesis in acute condition studies. We investigated whether late administration of BMSC improves functional deficits subsequent to ICH. METHODS: Experimental ICH was induced by stereotactic injection of 0.5 IU collagenase type IV in the striatum of adult female Wistar rats, and 2 months later intralesional administration of 5 × 10(6) allogeneic BMSC from male donors rats in saline (n = 10), or saline only (n = 10), was performed. In the following 6 months, functional outcome was evaluated in each animal by rotarod, modified neurologic severity score (mNSS) and video-tracking box (VTB) tests. To study the behavior of BMSC after transplantation, in situ hybridization studies were performed, with double labeling of the chromosome Y-linked SrY-gene, and neuronal nuclei (NeuN) protein or gliofibrillary acidic protein (GFAP). RESULTS: The assessment test revealed significant improvements in functional outcome for the BMSC-treated animals after 2 months of follow-up. Histologic results showed that functional outcome was associated with strong reactivation of endogenous neurogenesis. Furthermore, intralesional BMSC not only integrated in the injured tissue but also showed phenotypic expression of GFAP and NeuN. CONCLUSIONS: Late intracerebral transplantation of allogeneic BMSC induces functional recovery after ICH. The possibility of using this type of cell therapy to reverse the consequences of hemorrhagic stroke in humans should be considered.

Cell therapy for spinal cord repair: optimization of biologic scaffolds for survival and neural differentiation of human bone marrow stromal cells.

BACKGROUND AIMS: The suppression of cell apoptosis using a biodegradable scaffold to replace the missing or altered extracellular matrix (ECM) could increase the survival of transplanted cells and thus increase the effectiveness of cell therapy. METHODS: We studied the best conditions for the proliferation and differentiation of human bone marrow stromal cells (hBMSC) when cultured on different biologic scaffolds derived from fibrin and blood plasma, and analyzed the best concentrations of fibrinogen, thrombin and calcium chloride for favoring cell survival. The induction of neural differentiation of hBMSC was done by adding to these scaffolds different growth factors, such as nerve growth factor (NGF), brain-derived-neurotrophic factor (BDNF) and retinoic acid (RA), at concentrations of 100 ng/mL (NGF and BDNF) and 1 micro/mL (RA), over 7 days. RESULTS: Although both types of scaffold allowed survival and neural differentiation of hBMSC, the results showed a clear superiority of platelet-rich plasma (PRP) scaffolds, mainly after BDNF administration, allowing most of the hBMSC to survive and differentiate into a neural phenotype. CONCLUSIONS: Given that clinical trials for spinal cord injury using hBMSC are starting, these findings may have important clinical applications.

Video-Tracking-Box linked to Smart software as a tool for evaluation of locomotor activity and orientation in brain-injured rats.

Injuries of the Central Nervous System (CNS) cause devastating and irreversible losses of function. In order to analyze the deficits subsequent to brain injury it is necessary to use behavioral tests which evaluate cerebral dysfunction. In this study, we describe a new tool, the Video-Tracking-Box (VTB) linked to Smart software. This new method adequately quantifies parameters related to locomotor activity and orientation in brain-injured rats. This method has been used in our laboratory in order to measure behavioral outcome after brain injury caused by intracerebral hemorrhage (ICH) in adult Wistar rats. In our experimental model, ICH was induced by stereotactic injection of 0.5U of collagenase type IV in striatum. ICH injured rats decreased its motor coordination and presented deficits in cognitive memory. VTB-Smart test was sensitive to chronic locomotor and orientation dysfunction, and it was performed between 1 and 5 months after ICH. Our results revealed a significant increase in motor latency and loss of spatial orientation in the damaged-animals compared with intact animals. The data demonstrate that our VTB, joined to Smart software, offers a reliable measure to assess motor dysfunction and orientation after brain injury.

Delayed intralesional transplantation of bone marrow stromal cells increases endogenous neurogenesis and promotes functional recovery after severe traumatic brain injury.

PRIMARY OBJECTIVE: To investigate the utility of delayed transplantation of bone marrow stromal cells (BMSC) to improve the neurological sequels after traumatic brain injury (TBI). METHODS: Adult Wistar rats were subjected to weight-drop impact causing severe brain injury, and 2 months later, BMSC in saline, or saline alone, were injected into injured brain tissue. Both experimental groups were evaluated by means of rotarod and modified neurologic severity scores (mNSS) tests in the course of the two following months. At this time, the animal were sacrificed and their brains were studied by means of histological and immunohistochemical techniques. RESULTS: Rotarod and mNSS tests showed progressive functional recovery in the BMSC- transplanted rats, compared with controls. Two months after transplantation, BMSC survived in the host tissue, and some of them showed expression of Neu-N or GFAP, suggesting neuronal and astroglial transdifferentiation. Furthermore, significant increase of endogenous neurogenesis was found in BMSC-transplanted rats, compared with controls. CONCLUSIONS: These findings suggest the utility of delayed intracerebral transplantation of BMSC for the treatment of established sequels after TBI.

Functional recovery of chronic paraplegic pigs after autologous transplantation of bone marrow stromal cells.

BACKGROUND: Bone marrow stromal cells (BMSC) transplantation offers promise in the treatment of chronic paraplegia in rodents. Here, we report the effect of this cell therapy in adult pigs suffering chronic paraplegia. METHODS: Three months after spinal cord injury, autologous BMSC in autologous plasma was injected into lesion zone and adjacent subarachnoid space in seven paraplegic pigs. On the contrary, three paraplegic pigs only received autologous plasma. Functional outcome was measured weekly until the end of the follow-up, 3 months later. RESULTS: Our present study showed progressive functional recovery in transplanted pigs. At this time, intramedullary posttraumatic cavities were filled by a neoformed tissue containing several axons, together with BMSC that expressed neuronal or glial markers. Furthermore, in the treated animals, electrophysiological studies showed recovery of the previously abolished somatosensory-evoked potentials. CONCLUSIONS: These findings confirm previous observations in rodents and support the possible utility of BMSC transplantation in humans suffering chronic paraplegia.

Neural transdifferentiation of bone marrow stromal cells obtained by chemical agents is a short-time reversible phenomenon.

Bone marrow stromal cells (BMSC) can acquire morphological and immunohistochemical features of neural cells when they are treated with diverse chemical agents, a finding interpreted as result of cell transdifferentiation. With the purpose of a better knowledge of the possible utility of BMSC for strategies of Nervous System (NS) repair, we have studied the morphological and immunohistochemical changes induced in BMSC by chemical agents, in comparison with those that happen when BMSC are co-cultured with Schwann cells. While chemical BMSC transdifferentiation is a short-time reversible phenomenon, BMSC transdifferentiation obtained by Schwann cell-derived neurotrophic factors remains stable after it has been reached. These findings question the possible clinical utility of BMSC trandifferentiation using chemical agents, and support that neural transdifferentiation of BMSC is a biological phenomenon that can be obtained in vivo because of the presence of environmental factors.

Neurotrophic Schwann-cell factors induce neural differentiation of bone marrow stromal cells.

Neural transdifferentiation of bone marrow stromal cells has been questioned, because cell fusion could explain the development of new cell types, misinterpreted as transdifferentiated cells. We performed here cocultures of bone marrow stromal cells and Schwann cells, without possibility that both cell types can establish contact. In these conditions, bone marrow stromal cells expressed nestin 4 h after beginning cocultures, and strong expression of neuronal markers was disclosed at 72 h, increasing at 1 and 2 weeks. Our results support that neural transdifferentiation of bone marrow stromal cells is induced by soluble factors provided by glial cells, and suggest that cell fusion should not be significant when local bone marrow stromal cells administration for neural repair is considered.