Can regenerating axons recapitulate developmental guidance during recovery from spinal cord injury?

The precise wiring of the adult mammalian CNS originates during a period of stunning growth, guidance and plasticity that occurs during and shortly after development. When injured in adults, this intricate system fails to regenerate. Even when the obstacles to regeneration are cleared, growing adult CNS fibres usually remain misdirected and fail to reform functional connections. Here, we attempt to fill an important niche related to the topics of nervous system development and regeneration. We specifically contrast the difficulties faced by growing fibres within the adult context to the precise circuit-forming capabilities of developing fibres. In addition to focusing on methods to stimulate growth in the adult, we also expand on approaches to recapitulate development itself.     

Regenerative medicine for the treatment of spinal cord injury: more than just promises?

Spinal cord injury triggers a complex set of events that lead to tissue healing without the restoration of normal function due to the poor regenerative capacity of the spinal cord. Nevertheless, current knowledge about the intrinsic regenerative ability of central nervous system axons, when in a supportive environment, has made the prospect of treating spinal cord injury a reality. Among the range of strategies under investigation, cell‐based therapies offer the most promising results, due to the multifactorial roles that these cells can fulfil. However, the best cell source is still a matter of debate, as are clinical issues that include the optimal cell dose as well as the timing and route of administration. In this context, the role of biomaterials is gaining importance. These can not only act as vehicles for the administered cells but also, in the case of chronic lesions, can be used to fill the permanent cyst, thus creating a more favourable and conducive environment for axonal regeneration in addition to serving as local delivery systems of therapeutic agents to improve the regenerative milieu. Some of the candidate molecules for the future are discussed in view of the knowledge derived from studying the mechanisms that facilitate the intrinsic regenerative capacity of central nervous system neurons. The future challenge for the multidisciplinary teams working in the field is to translate the knowledge acquired in basic research into effective combinatorial therapies to be applied in the clinic.     

Is obesity a risk factor for deep tissue injury in patients with spinal cord injury?

Deep tissue injury (DTI) is a severe form of pressure ulcers that occur in subcutaneous tissue under intact skin by the prolonged compression of soft tissues overlying bony prominences. Pressure ulcers and DTI in particular are common in patients with impaired motosensory capacities, such as those with a spinal cord injury (SCI). Obesity is also common among subjects with SCI, yet there are contradicting indications regarding its potential influence as a risk factor for DTI in conditions where these patients sit in a wheelchair without changing posture for prolonged times. It has been argued that high body mass may lead to a greater risk for DTI due to increase in compressive forces from the bones on overlying deep soft tissues, whereas conversely, it has been argued that the extra body fat associated with obesity may reduce the risk by providing enhanced subcutaneous cushioning that redistributes high interface pressures. No biomechanical evaluation of this situation has been reported to date. In order to elucidate whether obesity can be considered a risk factor for DTI, we developed computational finite element (FE) models of the seated buttocks with 4° of obesity, quantified by body mass index (BMI) values of 25.5, 30, 35 and 40 kg/m². We found that peak principal strains, strain energy densities (SED) and von Mises stresses in internal soft tissues (muscle, fat) overlying the ischial tuberosities (ITs) all increased with BMI. With a rise in BMI from 25.5 to 40 kg/m², values of these parameters increased 1.5 times on average. Moreover, the FE simulations indicated that the bodyweight load transferred through the ITs has a greater effect in increasing internal tissue strains/stresses than the counteracting effect of thickening of the adipose layer which is concurrently associated with obesity. We saw that inducing some muscle atrophy (30% reduction in muscle volume, applied to the BMI=40 kg/m² model) which is also characteristic of chronic SCI resulted in further substantial increase in all biomechanical measures reflecting geometrical distortion of muscle tissue, that is, SED, tensile stress, shear stress and von Mises stress. This result highlights that obesity and muscle atrophy, which are both typical of the chronic phase of SCI, contribute together to the state of elevated tissue loads, which consequently increases the likelihood of DTI in this population.     

What is the potential of oligodendrocyte progenitor cells to successfully treat human spinal cord injury?

Background  

Spinal cord injury is a serious and debilitating condition, affecting millions of people worldwide. Long seen as a permanent injury, recent advances in stem cell research have brought closer the possibility of repairing the spinal cord. One such approach involves injecting oligodendrocyte progenitor cells, derived from human embryonic stem cells, into the injured spinal cord in the hope that they will initiate repair. A phase I clinical trial of this therapy was started in mid 2010 and is currently underway.     

Up-regulation of Μ-opioid receptors in the spinal cord of morphine-tolerant rats

Though morphine remains the most powerful drug for treating pain, its effectiveness is limited by the development of tolerance and dependence. The mechanism underlying development of tolerance to morphine is still poorly understood. One of the factors could be an alteration in the number of Μ-receptors within specific parts of the nervous system. However, reports on changes in the Μ-opioid receptor density in the spinal cord after chronic morphine administration are conflicting. Most of the studies have used subcutaneously implanted morphine pellets to produce tolerance. However, it does not simulate clinical conditions, where it is more common to administer morphine at intervals, either by injections or orally. In the present study, rats were made tolerant to morphine by injecting increasing doses of morphine (10-50 mg/kg, subcutaneously) for five days.In vitro tissue autoradiography for localization of Μ-receptor in the spinal cord was done using [³H]-DAMGO. As compared to the spinal cord of control rats, the spinal cord of tolerant rats showed an 18.8% increase or up-regulation in the density of Μ-receptors in the superficial layers of the dorsal horn. This up-regulation of Μ-receptors after morphine tolerance suggests that a fraction of the receptors have been rendered desensitized, which in turn could lead to tolerance     

Propagation of activity along the “stepping strip” of the cat spinal cord

Three points located approximately 8 mm apart were identified in a dorsolateral funiculus of the lower thoracic spinal cord in mesencephalic cats, each producing stepping movements on the ipsilateral hindlimb when stimulated. An area 5–17 mm caudal to the caudal stepping point (SP) was scanned for neurons responding synaptically to stimulating the rostral or caudal SP prior and subsequent to electrolytic coagulation of the medial SP. Relative incidence of neurons excited by stimulating the caudal SP did not change following this type of lesioning, although stimulation of the rostral SP at the rate of 4 Hz induced response 5 times less frequently than before. Even stimulation of the rostral SP at the rate of 40–60 Hz, which had considerably increased firing index prior to coagulation, could only produce excitation in tiny numbers of neurons. This indicates that synaptic excitation of neurons becomes considerably more difficult once the stepping strip between stimulation and recording sites has been damaged.Institute for Research into Information Transmission, Academy of Sciences of the USSR, Moscow. Translated from Neirofiziologiya, Vol. 20, No. 6, pp. 763–769, November–December, 1988.     

Construction of rat spinal cord injury model based on Allen’s animal model

The aim of this study is to explore the construction of rat spinal cord injury model guided by Allen's model. Methods: Male rats aged 4–5 weeks and weighing about 250 g are selected as subjects in the Animal Laboratory Center of XX Hospital. Rats are divided into two groups, which are experimental group 1 and experimental group 2, respectively, so as to construct spinal cord injury model in rats. The first group is given 300 g.cm hitting force of T10 spinal cord, and the second group is given 500 g.cm hitting force of T10 spinal cord. Within 25 days after spinal cord injury in Allen's rats, the survival, neurological function, diet, motor ability, tactile ability and auditory ability of the two groups are monitored and evaluated daily. Results: In terms of survival, the survival rate of rats in group 1 is 85%, while that of rats in group 2 is 21%, and there is a concentrated death phenomenon in group 2. In terms of neurological function recovery, experimental group 1 is stable and gets 7 points and experimental group 2 is stable and gets 3 points. In terms of diet, the experimental group 1 is stable and gets 5 points and the experimental group 2 is stable and gets 2 points. In terms of motor ability, the experimental group 1 is stable and gets 5 points and the experimental group 2 is stable and gets 2 points. In tactile sense, experimental group 1 is stable and gets 17 points and experimental group 2 is stable and gets 12 points. It can be seen that the post-operative recovery ability of the experimental group 1 is better than that of the experimental group 2. Conclusion: Under the guidance of Allen's model, compared with the group 2, the experimental group 1 of the rat spinal cord injury model has better recovery in each index. It can be seen that the smaller impact strength is more beneficial to the recovery of rats after spinal cord injury surgery.     

Abnormal myelination in the spinal cord of PTPα-knockout mice

PTPα interacts with F3/contactin to form a membrane-spanning co-receptor complex to transduce extracellular signals to Fyn tyrosine kinase. As both F3 and Fyn regulate myelination, we investigated a role for PTPα in this process. Here, we report that both oligodendrocytes and neurons express PTPα that evenly distributes along myelinated axons of the spinal cord. The ablation of PTPα in vivo leads to early formation of transverse bands that are mainly constituted by F3 and Caspr along the axoglial interface. Notably, PTPα deficiency facilitates abnormal myelination and pronouncedly increases the number of non-landed oligodendrocyte loops at shortened paranodes in the spinal cord. Small axons, which are normally less myelinated, have thick myelin sheaths in the spinal cord of PTPα-null animals. Thus, PTPα may be involved in the formation of axoglial junctions and ensheathment in small axons during myelination of the spinal cord.     

“Axonal spheroids” in the spinal cord of normal rabbits

Summary Within the gray matter and the white matter of the spinal cord of apparently healthy rabbits, myelinated and unmyelinated axonal swellings, so called axonal spheroids, occur. Most of the spheroids contain mitochondria, dense bodies, vesicles and fragments of the tubular or smooth endoplasmic reticulum. In myelinated spheroids the process of swelling is effected by slippage of the myelin leaflets. At the periphery of the unmyelinated parts of the spheroids, synapses are regularly found. The presynaptic terminal bouton is formed by the spheroid. A few myelinated and unmyelinated spheroids are packed with fine granular material while mitochondria are lacking. The axonal spheroids may represent a physiological, perhaps age dependent phenomenon.Dedicated to Prof. Dr. Berta Scharrer on the occasion of her 70^th birthdayThe author wishes to thank Mrs. Helga Zuther-Witzsch, Mrs. Elisabeth Schöngarth and Miss Hildegard Schöning for excellent technical assistance. Supported by the Deutsche Forschungsgemeinschaft, Projekt Le 69/7-13     

Effect of aging on the substance P receptor,NK–1, in the spinal cord of rats with peripheral nerve injury

Substance P (SP) levels in the spinal cords of very old rats are less than the levels in younger rats (Bergman et al., 1996). After injury to a peripheral nerve in young rats, immunoreactivity (ir) to the SP receptor, NK–1 (neurokinin-1), increases in the spinal cord ipsilateral to the injury and the increases are correlated with the development of thermal hyperalgesia (Goff et al., 1998). Thus we postulated that aged rats might display an increased sensitivity to thermal stimulation before peripheral nerve injury and that they might respond differently to injury than do younger rats. To test this hypothesis, we used the Bennett and Xie model (1988) of chronic constriction injury (CCI) to the sciatic nerve to induce a neuropathic pain condition. We investigated the effect of age on changes in NK-1 ir in superficial layers of the dorsal horn and on numbers of NK ir cells in deeper laminae at the L4-L5 levels of the spinal cord after CCI. NK-1 receptors were tagged immunohistochemically and their distribution quantified by use of computer-assisted image analysis. NK-1 ir changes were related to alterations in thermal and tactile sensitivity that developed after CCI in young, mature and aged (4-6, 14-16, and 24-26 months) Fischer F344 BNF1 hybrid rats. No differences in thermal or tactile sensitivity of young and aged rats were seen in the absence of nerve injury. After injury, aged rats developed thermal hyperalgesia and tactile allodynia more slowly than did the younger rats. NK-1 receptor ir and numbers of NK-1 ir cells in the dorsal horn increased with time post-injury in all three groups. NK-1 ir increases were correlated with the development of thermal hyperalgesia in those rats that displayed hyperalgesia. However, some rats developed an increased threshold to thermal stimuli (analgesia) and that also was correlated with increases in NK-1 ir. Thus NK-1 ir extent, while correlated with thermal sensitivity in the absence of injury, is not a specific marker for disturbances in one particular sensory modality; rather it increases with peripheral nerve injury per se.     

Are induced pluripotent stem cells the future of cell‐based regenerative therapies for spinal cord injury?

Despite advances in medical and surgical care, current clinical therapies for spinal cord injury (SCI) are limited. During the last two decades, the search for new therapies has been revolutionized by the discovery of stem cells, inspiring scientists and clinicians to search for stem cell‐based reparative approaches for many disorders, including neurotrauma. Cell‐based therapies using embryonic and adult stem cells in animal models of these disorders have provided positive outcome results. However, the availability of clinically suitable cell sources for human application has been hindered by both technical and ethical issues. The recent discovery of induced pluripotent stem (iPS) cells holds the potential to revolutionize the field of regenerative medicine by offering the option of autologous transplantation, thus eliminating the issue of host rejection. Herein, we will provide the rationale for the use of iPS cells in SCI therapies. In this review, we will evaluate the recent advancements in the field of iPS cells including their capacity for differentiation toward neural lineages that may allow iPS cells transplantation in cell‐based therapy for spinal cord repair. J. Cell. Physiol. 222: 515–521, 2010. © 2009 Wiley‐Liss, Inc.     

Evolution of the vertebrate motor system — from forebrain to spinal cord

A comparison of the vertebrate motor systems of the oldest group of now living vertebrates (lamprey) with that of mammals shows that there are striking similarities not only in the basic organization but also with regard to synaptic properties, transmitters and neuronal properties. The lamprey dorsal pallium (cortex) has a motor, a visual and a somatosensory area, and the basal ganglia, including the dopamine system, are organized in a virtually identical way in the lamprey and rodents. This also applies to the midbrain, brainstem and spinal cord. However, during evolution additional capabilities such as systems for the control of foreleg/arms, hands and fingers have evolved. The findings suggest that when the evolutionary lineages of mammals and lamprey became separate around 500 million years ago, the blueprint of the vertebrate motor system had already evolved.     

Histochemical study of the pre—and postnatal development of acetylcholinesterase in the rat spinal cord

The distribution of acetylcholinesterase(AChE)-positive structures in the developing rat spinal cord was studied with AChE-histochemistry.AChE-positive perikarya were first seen on embryonic day 14(E14) in the ventrolateral portion of the spinal cord.From that time onward.AChE=containing cells appeared gradually in the intermediate gray,dorsal horn and lateral spinal nucleus of the spinal cord in a ventral-to-dorsal,and lateral-to-medial order.No obvious rostral-to-caudal sequence was found.At birth,the distribution pattern of AChE-positive perikarya was basically similar to that in adults.After birth a dramatic increase in the AChE staining intensity extended from postnatal day 5(P5) to postnatal day 21(P21),In addition,two phases of transient AChE staining were observed in the external surface of the dorsal horn from embryonic day 15(E15) to embryonic day 21(E21) and in the marginal layer from embryonic day 21(E21) to postnatal day 14(P14),respectively.     

Quantifying food web interactions in the North Pacific – a data-based approach

As part of its annual bottom-trawl survey program, the Alaska Fisheries Science Center (AFSC) has been collecting and analyzing the stomach contents of groundfish predators since 1981. Between 1981 and 2011, a total of 233,451 fish stomachs were collected and analyzed from the eastern Bering Sea, the Gulf of Alaska, and the Aleutian Islands large marine ecosystems; these data are now available online as AFSC’s Groundfish Trophic Interactions Database. Here, we discuss features of the survey and data to aid in the interpretation and use of this extensive dataset for the Alaska region. The primary fish sampled include walleye pollock (Gadus chalcogrammus), Pacific cod (Gadus macrocephalus), Pacific halibut (Hippoglossus stenolepis), and arrowtooth flounder (Atheresthes stomias), although 159 predator species have been included in the stomach content analysis. Prey length measurements are included for important commercial prey and can identify age or size classes of prey prior to their recruitment into fisheries and most other surveys. With these data, one can track time trends in growth, mortality, and prey composition as ecosystem indicators, and include food web interactions in fish stock assessments for ecosystem-based fisheries management.