Oswald Steward

Demyelination contributes to loss of function after spinal cord injury, and thus a potential therapeutic strategy involves replacing myelin-forming cells. Here, we show that transplantation of human embryonic stem cell (hESC)-derived oligodendrocyte progenitor cells (OPCs) into adult rat spinal cord injuries enhances remyelination and promotes improvement of motor function. OPCs were injected 7 d or 10 months after injury. In both cases, transplanted cells survived, redistributed over short distances, and differentiated into oligodendrocytes. Animals that received OPCs 7 d after injury exhibited enhanced remyelination and substantially improved locomotor ability. In contrast, when OPCs were transplanted 10 months after injury, there was no enhanced remyelination or locomotor recovery. These studies document the feasibility of predifferentiating hESCs into functional OPCs and demonstrate their therapeutic potential at early time points after spinal cord injury.

Deficiencies in methods reporting in animal experimentation lead to difficulties in reproducing experiments; the authors propose a set of reporting standards to improve scientific communication and study design. Animal studies have contributed immensely to our understanding of diseases and assist the development of new therapies, but inadequate experimental reporting can sometimes render such studies difficult to reproduce and to translate into the clinic. This year, a US National Institute of Neurological Disorders and Stroke workshop addressed this issue, and its conclusions are discussed in a Perspective piece in this issue of Nature. The main workshop recommendation is that at a minimum, studies should report on randomization, blinding, sample-size estimation and how the data were handled. The US National Institute of Neurological Disorders and Stroke convened major stakeholders in June 2012 to discuss how to improve the methodological reporting of animal studies in grant applications and publications. The main workshop recommendation is that at a minimum studies should report on sample-size estimation, whether and how animals were randomized, whether investigators were blind to the treatment, and the handling of data. We recognize that achieving a meaningful improvement in the quality of reporting will require a concerted effort by investigators, reviewers, funding agencies and journal editors. Requiring better reporting of animal studies will raise awareness of the importance of rigorous study design to accelerate scientific progress.

The present study re-examines, with autoradiographic methods, the pattern of termination of fibers originating from various medio-lateral divisions of the entorhinal cortex on dentate granule cells and on hippocampal pyramidal cells of the rat. Entorhinal fibers were found to distribute in a proximo-distal gradient along the dendrites of dentate granule cells, with afferents from the medial entorhinal area terminating in the innermost portion of the entorhinal synaptic field, afferents from the lateral entorhinal area terminating in the most superficial portions of the entorhinal synaptic field, and intermediate medio-lateral locations in the entorhinal area terminating in intermediate locations in the entorhinal synaptic zone. A similar graded pattern of termination of medial and lateral entorhinal fibers was apparent in the very slight crossed projection of the entorhinal area to the contralateral dentate gyrus. In addition, a comparable gradient in the pattern of termination of entorhinal fibers was evident in the entorhinal projection field in the distal regions of the pyramidal cells of regio inferior of the hippocampus proper. Entorhinal projections to regio superior were, however, organized in quite a different fashion. In this zone, there was no evidence of a proximo-distal gradient in the patterns of termination of medial and lateral entorhinal areas along the dendrites of regio superior pyramidal cells. Rather, the medio-lateral organization was in a longitudinal dimension, with medial entorhinal afferents terminating in the portions of regio superior near the CA1-CA2 transition, and lateral entorhinal afferents terminating furthest from the CA1-CA2 transition, immediately adjacent to the CA1-subicular transition, and in the molecular layer of the subiculum proper. A comparable longitudinal organization of entorhinal projections to regio superior was also evident in the zones of termination of the crossed temporo-ammonic tract, contralateral to the injection. These results demonstrate a heretofore unrecognized complexity in the patterns of projection of the entorhinal area to the hippocampal formation, and illustrate that the entorhinal cortex cannot be divided into only two discrete divisions on the basis of the pattern of projection.

The pathway from the entorhinal cortical region to the hippocampal formation has previously been shown to be comprised of two sub-systems, one of which projects predominantly to the ipsilateral fascia dentata and regio inferior of the hippocampus proper, and a second which projects bilaterally to regio superior. The goal of the present investigation was to determine if these two pathways might originate from different cell populations within the entorhinal area. The cells of origin of these entorhinal pathways were identified by retrograde labeling with horseradish peroxidase (HRP). Injections which labeled the entorhinal terminal fields in both the fascia dentata and regio superior resulted in the retrograde labeling of two populations of cells in the entorhinal area. Ipsilateral to the injection, HRP reaction product was found in the cells of layer II (predominantly stellate cells) and the cells of layer III (predominantly pyramidal cells). Contralateral to the injections, however, the reaction product was found almost exclusively in the cells of layer III. With selective injections of the entorhinal terminal field in regio superior, only the cells of layer III were labeled, but these were labeled bilaterally. Selective injection of the entorhinal terminal field in the fascia dentata, however, resulted in the labeling of cells of layer II, but not of layer III, and these cells of layer II were labeled almost exclusively ipsilaterally. A very small number of labeled cells in layer II were, however, found contralateral to the injection as well. No labeled cells were found either in the presubiculum or parasubiculum following injections of the hippocampal formation. These cell populations were found capable of retrograde transport of HRP, however, since cells in both presubiculum and parasubiculum were labeled following HRP injections into the contralateral entorhinal area. These results suggest that the projections to the fascia dentata originate from the cells of layer II, while the projections to regio superior originate from the cells of layer III of the entorhinal region proper. The very slight crossed projection from the entorhinal area to the contralateral area dentata probably originates from the small population of cells in layer II which are labeled following HRP injections in the contralateral area dentata.