Co-transplantation of Human Embryonic Stem Cell-derived Neural Progenitors and Schwann Cells in a Rat Spinal Cord Contusion Injury Model Elicits a Distinct Neurogenesis and Functional Recovery

Co-transplantation of neural progenitors (NPs) with Schwann cells (SCs) might be a way to overcome low rate of neuronal differentiation of NPs following transplantation in spinal cord injury (SCI) and the improvement of locomotor recovery. In this study, we initially generated NPs from human embryonic stem cells (hESCs) and investigated their potential for neuronal differentiation and functional recovery when co-cultured with SCs in vitro and co-transplanted in a rat acute model of contused SCI. Co-cultivation results revealed that the presence of SCs provided a consistent status for hESC-NPs and recharged their neural differentiation toward a predominantly neuronal fate. Following transplantation, a significant functional recovery was observed in all engrafted groups (NPs, SCs, NPs+SCs) relative to the vehicle and control groups. We also observed that animals receiving co-transplants established a better state as assessed with the BBB functional test. Immunohistofluorescence evaluation five weeks after transplantation showed invigorated neuronal differentiation and limited proliferation in the co-transplanted group when compared to the individual hESC-NPs grafted group. These findings have demonstrated that the co-transplantation of SCs with hESC-NPs could offer a synergistic effect, promoting neuronal differentiation and functional recovery

Efficacy of motor imagery in post-stroke rehabilitation: a systematic review

BACKGROUND: Evaluation of how Motor Imagery and conventional therapy (physiotherapy or occupational therapy) compare to conventional therapy only in their effects on clinically relevant outcomes during rehabilitation of persons with stroke. DESIGN: Systematic review of the literature METHODS: We conducted an electronic database search in seven databases in August 2005 and also hand-searched the bibliographies of studies that we selected for the review.Two reviewers independently screened and selected all randomized controlled trials that compare the effects of conventional therapy plus Motor Imagery to those of only conventional therapy on stroke patients.The outcome measurements were: Fugl-Meyer Stroke Assessment upper extremity score (66 points) and Action Research Arm Test upper extremity score (57 points).Due to the high variability in the outcomes, we could not pool the data statistically. RESULTS: We identified four randomized controlled trials from Asia and North America. The quality of the included studies was poor to moderate. Two different Motor imagery techniques were used (three studies used audiotapes and one study had occupational therapists apply the intervention). Two studies found significant effects of Motor Imagery in the Fugl-Meyer Stroke Assessment: Differences between groups amounted to 11.0 (1.0 to 21.0) and 3.2 (-4 to 10.3) respectively and in the Action Research Arm Test 6.1 (-6.2 to 18.4) and 15.8 (0.5 to 31.0) respectively. One study did not find a significant effect in the Fugl-Meyer Stroke Assessment and Color trail Test (p = 0.28) but in the task-related outcomes (p > 0.001). CONCLUSION: Current evidence suggests that Motor imagery provides additional benefits to conventional physiotherapy or occupational therapy. However, larger and methodologically sounder studies should be conducted to assess the benefits of Motor imagery

Microgeographical, inter-individual, and intra-individual variation in the flower characters of Iberian pear Pyrus bourgaeana (Rosaceae)

Flower characteristics have been traditionally considered relatively constant within species. However, there are an increasing number of examples of variation in flower characteristics. In this study, we examined the variation in attracting and rewarding flower characters at several ecological levels in a metapopulation of Pyrus bourgaeana in the Doñana area (SW Spain). We answered the following questions: what are the variances of morphological and nectar characters of flowers? How important are intra-individual and inter-individual variance in flower characters? Are there microgeographical differences in flower characters? And if so, are they consistent between years? In 2008 and 2009, we sampled flowers of 72 trees from five localities. For six flower morphological and two nectar characteristics, we calculated coefficients of variation (CV). The partitioning of total variation among-localities, among-individuals, and within-individuals was estimated. To analyze differences among localities and their consistency between years, we conducted generalized linear mixed models. The CVs of nectar characters were always higher than those of morphological characters. As expected, inter-individual variation was the main source of variation of flower morphology, but nectar characters had significant variation at both intra- and inter-individual levels. For most floral traits, there were no differences among localities. Our study documents that variation is a scale-dependent phenomenon and that it is essential to consider intra- and inter-individual variance when investigating the causes and consequences of variation. It also shows that single year studies of floral characters should be viewed with caution

On the importance of long-term functional assessment after stroke to improve translation from bench to bedside

Despite extensive research efforts in the field of cerebral ischemia, numerous disappointments came from the translational step. Even if experimental studies showed a large number of promising drugs, most of them failed to be efficient in clinical trials. Based on these reports, factors that play a significant role in causing outcome differences between animal experiments and clinical trials have been identified; and latest works in the field have tried to discard them in order to improve the scope of the results. Nevertheless, efforts must be maintained, especially for long-term functional evaluations. As observed in clinical practice, animals display a large degree of spontaneous recovery after stroke. The neurological impairment, assessed by basic items, typically disappears during the firsts week following stroke in rodents. On the contrary, more demanding sensorimotor and cognitive tasks underline other deficits, which are usually long-lasting. Unfortunately, studies addressing such behavioral impairments are less abundant. Because the characterization of long-term functional recovery is critical for evaluating the efficacy of potential therapeutic agents in experimental strokes, behavioral tests that proved sensitive enough to detect long-term deficits are reported here. And since the ultimate goal of any stroke therapy is the restoration of normal function, an objective appraisal of the behavioral deficits should be done

Schwann-Spheres Derived from Injured Peripheral Nerves in Adult Mice - Their In Vitro Characterization and Therapeutic Potential

Multipotent somatic stem cells have been identified in various adult tissues. However, the stem/progenitor cells of the peripheral nerves have been isolated only from fetal tissues. Here, we isolated Schwann-cell precursors/immature Schwann cells from the injured peripheral nerves of adult mice using a floating culture technique that we call “Schwann-spheres." The Schwann-spheres were derived from de-differentiated mature Schwann cells harvested 24 hours to 6 weeks after peripheral nerve injury. They had extensive self-renewal and differentiation capabilities. They strongly expressed the immature-Schwann-cell marker p75, and differentiated only into the Schwann-cell lineage. The spheres showed enhanced myelin formation and neurite growth compared to mature Schwann cells in vitro. Mature Schwann cells have been considered a promising candidate for cell-transplantation therapies to repair the damaged nervous system, whereas these “Schwann-spheres" would provide a more potential autologous cell source for such transplantation

Fully functional hair follicle regeneration through the rearrangement of stem cells and their niches

Organ replacement regenerative therapy is purported to enable the replacement of organs damaged by disease, injury or aging in the foreseeable future. Here we demonstrate fully functional hair organ regeneration via the intracutaneous transplantation of a bioengineered pelage and vibrissa follicle germ. The pelage and vibrissae are reconstituted with embryonic skin-derived cells and adult vibrissa stem cell region-derived cells, respectively. The bioengineered hair follicle develops the correct structures and forms proper connections with surrounding host tissues such as the epidermis, arrector pili muscle and nerve fibres. The bioengineered follicles also show restored hair cycles and piloerection through the rearrangement of follicular stem cells and their niches. This study thus reveals the potential applications of adult tissue-derived follicular stem cells as a bioengineered organ replacement therapy

Axonal remodeling for motor recovery after traumatic brain injury requires downregulation of γ-aminobutyric acid signaling

Remodeling of the remnant neuronal network after brain injury possibly mediates spontaneous functional recovery; however, the mechanisms inducing axonal remodeling during spontaneous recovery remain unclear. Here, we show that altered γ-aminobutyric acid (GABA) signaling is crucial for axonal remodeling of the contralesional cortex after traumatic brain injury. After injury to the sensorimotor cortex in mice, we found a significant decrease in the expression of GABAAR-α1 subunits in the intact sensorimotor cortex for 2 weeks. Motor functions, assessed by grid walk and cylinder tests, spontaneously improved in 4 weeks after the injury to the sensorimotor cortex. With motor recovery, corticospinal tract (CST) axons from the contralesional cortex sprouted into the denervated side of the cervical spinal cord at 2 and 4 weeks after the injury. To determine the functional implications of the changes in the expression of GABAAR-α1 subunits, we infused muscimol, a GABA R agonist, into the contralesional cortex for a week after the injury. Compared with the vehicle-treated mice, we noted significantly inhibited recovery in the muscimol-treated mice. Further, muscimol infusion greatly suppressed the axonal sprouting into the denervated side of the cervical spinal cord. In conclusion, recovery of motor function and axonal remodeling of the CST following cortical injury requires suppressed GABAAR subunit expression and decreased GABAergic signaling

An Antagomir to MicroRNA Let7f Promotes Neuroprotection in an Ischemic Stroke Model

We previously showed that middle-aged female rats sustain a larger infarct following experimental stroke as compared to younger female rats, and paradoxically, estrogen treatment to the older group is neurotoxic. Plasma and brain insulin-like growth factor-1 (IGF-1) levels decrease with age. However, IGF-1 infusion following stroke, prevents estrogen neurotoxicity in middle-aged female rats. IGF1 is neuroprotective and well tolerated, but also has potentially undesirable side effects. We hypothesized that microRNAs (miRNAs) that target the IGF-1 signaling family for translation repression could be alternatively suppressed to promote IGF-1-like neuroprotection. Here, we report that two conserved IGF pathway regulatory microRNAs, Let7f and miR1, can be inhibited to mimic and even extend the neuroprotection afforded by IGF-1. Anti-mir1 treatment, as late as 4 hours following ischemia, significantly reduced cortical infarct volume in adult female rats, while anti-Let7 robustly reduced both cortical and striatal infarcts, and preserved sensorimotor function and interhemispheric neural integration. No neuroprotection was observed in animals treated with a brain specific miRNA unrelated to IGF-1 (anti-miR124). Remarkably, anti-Let7f was only effective in intact females but not males or ovariectomized females indicating that the gonadal steroid environment critically modifies miRNA action. Let7f is preferentially expressed in microglia in the ischemic hemisphere and confirmed in ex vivo cultures of microglia obtained from the cortex. While IGF-1 was undetectable in microglia harvested from the non-ischemic hemisphere, IGF-1 was expressed by microglia obtained from the ischemic cortex and was further elevated by anti-Let7f treatment. Collectively these data support a novel miRNA-based therapeutic strategy for neuroprotection following stroke

Restoring brain function after stroke - bridging the gap between animals and humans

Stroke is the leading cause of complex adult disability in the world. Recovery from stroke is often incomplete, which leaves many people dependent on others for their care. The improvement of long-term outcomes should, therefore, be a clinical and research priority. As a result of advances in our understanding of the biological mechanisms involved in recovery and repair after stroke, therapeutic opportunities to promote recovery through manipulation of poststroke plasticity have never been greater. This work has almost exclusively been carried out in preclinical animal models of stroke with little translation into human studies. The challenge ahead is to develop a mechanistic understanding of recovery from stroke in humans. Advances in neuroimaging techniques now enable us to reconcile behavioural accounts of recovery with molecular and cellular changes. Consequently, clinical trials can be designed in a stratified manner that takes into account when an intervention should be delivered and who is most likely to benefit. This approach is expected to lead to a substantial change in how restorative therapeutic strategies are delivered in patients after stroke