Advances in human stem cell therapies:pre-clinical studies and the outlook for central nervous system regeneration

Cell transplantation has come to the forefront of regenerative medicine alongside the discovery and application of stem cells in both research and clinical settings.There are several types of stem cells currently being used for pre-clinical regenerative therapies,each with unique characteristics,benefits and limitations.This brief review will focus on recent basic science advancements made with embryonic stem cells and induced pluripotent stem cells.Both embryonic stem cells and induced pluripotent stem cells provide platforms for new neurons to replace dead and/or dying cells following injury.Due to their capacity for reprogramming and differentiation into any neuronal type,research in preclinical rodent models has shown that embryonic stem cells and induced pluripotent stem cells can integrate,survive and form connections in the nervous system similar to de novo cells.Going forward however,there are some limitations to consider with the use of either stem cell type.Ethically,embryonic stem cells are not an ideal source of cells,genetically,induced pluripotent stem cells are not ideal in terms of personalized treatment for those with certain genetic diseases the latter of which may guide regenerative medicine away from personalized stem cell based therapies and into optimized stem cell banks.Nonetheless,the potential of these stem cells in central nervous system regenerative therapy is only beginning to be appreciated.For example,through genetic modification,stem cells serve as ideal platforms to reintroduce missing or downregulated molecules into the nervous system to further induce regenerative growth.In this review,we highlight the limitations of stem cell based therapies whilst discussing some of the means of overcoming these limitations.

The necessary role of mTORC1 in central nervous system axon regeneration

Permanent loss of vital functions after central nervous system （CNS） injury, e.g., blindness in traumatic optic nerve （ON） injury or paralysis in spinal cord injury, occurs in part because axons in the adult mammalian CNS do not regenerate after injury. Growth failure is due to the diminished intrinsic regenerative capacity of mature neurons and the inhibitory environment of the adult CNS. Neutralizing extracellular inhibitory molecules genetically or pharmacologically yields only limited regeneration and functional recovery, highlighting the critical importance of neuron-intrinsic factors.

Serotonin controls axon and neuronal regeneration in the nervous system:lessons from regenerating animal models

Traumatic brain injury （TBI） is a mechanical injury to brain tissue that leads to an impairment of function and a broad spectrum of symptoms and disabilities; often, it is followed by diffuse axonal injury, which causes denaturation of the white matter and axon retraction, leaving patients with severe brain damage or even in a persistent vegetative state.

Distribution of paired immunoglobulin-like receptor B in the nervous system related to regeneration difficulties after unilateral lumbar spinal cord injury

Paired immunoglobulin-like receptor B（Pir B） is a functional receptor of myelin-associated inhibitors for axonal regeneration and synaptic plasticity in the central nervous system, and thus suppresses nerve regeneration. The regulatory effect of Pir B on injured nerves has received a lot of attention. To better understand nerve regeneration inability after spinal cord injury, this study aimed to investigate the distribution of Pir B（via immunofluorescence） in the central nervous system and peripheral nervous system 10 days after injury. Immunoreactivity for Pir B increased in the dorsal root ganglia, sciatic nerves, and spinal cord segments. In the dorsal root ganglia and sciatic nerves, Pir B was mainly distributed along neuronal and axonal membranes. Pir B was found to exhibit a diffuse, intricate distribution in the dorsal and ventral regions. Immunoreactivity for Pir B was enhanced in some cortical neurons located in the bilateral precentral gyri. Overall, the findings suggest a pattern of Pir B immunoreactivity in the nervous system after unilateral spinal transection injury, and also indicate that Pir B may suppress repair after injury.

Nanofibrous scaffolds for the regeneration of nervous tissue

Introductons The biophysical organization of extracellular matrix (ECM) plays an important role in tissue morphogenesis,remodeling and functions. In many types of tissues,e. g. ,blood vessel,nerve,heart,muscle,tendon and ligament,ECM has aniso-

Telemedicine and digital management in repair and regeneration after nerve injury and in nervous system diseases

To the editor, We read with interest the article, ＂Facilitating transparency in spinal cord injury studies using data standards and ontol- ogles＂ by Professor Vance E Lemmon, University of Miami, USA （Lemmon et al., 2014） and would like to add to the discussion on digital management in spinal cord injury. We have analyzed the advancements in the treatment of spinal cord injury, traumatic brain jury. Encouraging outcomes injury and peripheral nerve in- have been achieved in the area of regulating axon growth in vivo and in vitro. However, such a large amount of information neither provides in-depth insight for other scholars nor provides detailed therapeutic nrotocols for clinical studies.

The therapeutic potential of targeting exchange protein directly activated by cyclic adenosine 3',5'-monophosphate(Epac)for central nervous system trauma

Millions of people worldwide are affected by traumatic spinal cord injury,which usually results in permanent sensorimotor disability.Damage to the spinal cord leads to a series of detrimental events including ischaemia,haemorrhage and neuroinflammation,which over time result in further neural tissue loss.Eventually,at chronic stages of traumatic spinal cord injury,the formation of a glial scar,cystic cavitation and the presence of numerous inhibitory molecules act as physical and chemical barriers to axonal regrowth.This is further hindered by a lack of intrinsic regrowth ability of adult neurons in the central nervous system.The intracellular signalling molecule,cyclic adenosine 3′,5′-monophosphate(cAMP),is known to play many important roles in the central nervous system,and elevating its levels as shown to improve axonal regeneration outcomes following traumatic spinal cord injury in animal models.However,therapies directly targeting cAMP have not found their way into the clinic,as cAMP is ubiquitously present in all cell types and its manipulation may have additional deleterious effects.A downstream effector of cAMP,exchange protein directly activated by cAMP 2(Epac2),is mainly expressed in the adult central nervous system,and its activation has been shown to mediate the positive effects of cAMP on axonal guidance and regeneration.Recently,using ex vivo modelling of traumatic spinal cord injury,Epac2 activation was found to profoundly modulate the post-lesion environment,such as decreasing the activation of astrocytes and microglia.Pilot data with Epac2 activation also suggested functional improvement assessed by in vivo models of traumatic spinal cord injury.Therefore,targeting Epac2 in traumatic spinal cord injury could represent a novel strategy in traumatic spinal cord injury repair,and future work is needed to fully establish its therapeutic potential.

The emerging roles of transplanted radial glial cells in regenerating the central nervous system

Scientists conclude that a combination of treatments involving rehabilitation,drug delivery,surgery and cell transplantation are necessary to achieve significant progress in regenerating the injured central nervous system（CNS）.

Reassembly of the axon initial segment and nodes of Ranvier in regenerated axons of the central nervous system

Myelinated axons of the peripheral and central nervous system（PNS＆CNS）are divided into molecularly distinct excitable domains,including the axon initial segment（AIS）and nodes of Ranvier.The AIS is composed of a dense network of cytoskeletal proteins,cell adhesion molecules,and voltage gated ion channels and is located at the proximal most region of the axon（Koleand Stuart, 2012）.

Effect of glial cells on remyelination after spinal cord injury

Remyelination plays a key role in functional recovery of axons after spinal cord injury.Glial cells are the most abundant cells in the central nervous system.When spinal cord injury occurs,many glial cells at the lesion site are immediately activated,and different cells differentially affect inflammatory reactions after injury.In this review,we aim to discuss the core role of oligodendrocyte precursor cells and crosstalk with the rest of glia and their subcategories in the remyelination process.Activated astrocytes influence proliferation,differentiation,and maturation of oligodendrocyte precursor cells,while activated microglia alter remyelination by regulating the inflammatory reaction after spinal cord injury.Understanding the interaction between oligodendrocyte precursor cells and the rest of glia is necessary when designing a therapeutic plan of remyelination after spinal cord injury.

Repetitive transcranial magnetic stimulation improves consciousness disturbance in stroke patients A quantitative electroencephalography spectral power analysis

Repetitive transcranial magnetic stimulation is a noninvasive treatment technique that can directly alter cortical excitability and improve cerebral functional activity in unconscious patients. To investigate the effects and the electrophysiological changes of repetitive transcranial magnetic stimulation cortical treatment, 10 stroke patients with non-severe brainstem lesions and with disturbance of consciousness were treated with repetitive transcranial magnetic stimulation. A quantitative electroencephalography spectral power analysis was also performed. The absolute power in the alpha band was increased immediately after the first repetitive transcranial magnetic stimulation treatment, and the energy was reduced in the delta band. The alpha band relative power values slightly decreased at 1 day post-treatment, then increased and reached a stable level at 2 weeks post-treatment. Glasgow Coma Score and JFK Coma Recovery Scale-Revised score were improved. Relative power value in the alpha band was positively related to Glasgow Coma Score and JFK Coma Recovery Scale-Revised score. These data suggest that repetitive transcranial magnetic stimulation is a noninvasive, safe, and effective treatment technology for improving brain functional activity and promoting awakening in unconscious stroke patients.

Shuanghuanglian injection downregulates nuclear factor-kappa B expression in mice with viral encephalitis

A mouse model of viral encephalitis was induced by intracranial injection of a Coxsackie virus B3 suspension. Quantitative real-time reverse transcription-PCR and western blot assay were applied to detect mRNA and protein expression of intelectin-2 and nuclear factor-kappa B in the viral encephalitis and control groups. Nuclear factor-kappa B and intelectin-2 mRNA and protein expression were significantly increased in mice with viral encephalitis. After intraperitoneal injection of Shuanghuanglian at a dose of 1.5 mg/kg for 5 successive days, intelectin-2 and nuclear factor-kappa B protein and mRNA expression were significantly decreased. To elucidate the relationship between intelectin-2 and nuclear factor-kappa B, mice with viral encephalitis were administered an intracerebral injection of 107 pfu recombinant lentivirus expressing intelectin shRNA. Both protein and mRNA levels of intelectin and nuclear factor-kappa B in brain tissue of mice were significantly decreased. Experimental findings suggest that Shuanghuanglian injection may downregulate nuclear factor-kappa B production via suppression of intelectin production, thus inhibiting inflammation associated with viral encephalitis.

Neural differentiation of choroid plexus epithelial cells:role of human traumatic cerebrospinal fluid

As the key producer of cerebrospinal fluid（CSF）,the choroid plexus（CP） provides a unique protective system in the central nervous system.CSF components are not invariable and they can change based on the pathological conditions of the central nervous system.The purpose of the present study was to assess the effects of non-traumatic and traumatic CSF on the differentiation of multipotent stem-like cells of CP into the neural and/or glial cells.CP epithelial cells were isolated from adult male rats and treated with human non-traumatic and traumatic CSF.Alterations in m RNA expression of Nestin and microtubule-associated protein（MAP2）,as the specific markers of neurogenesis,and astrocyte marker glial fibrillary acidic protein（GFAP） in cultured CP epithelial cells were evaluated using quantitative real-time PCR.The data revealed that treatment with CSF（non-traumatic and traumatic） led to increase in m RNA expression levels of MAP2 and GFAP.Moreover,the expression of Nestin decreased in CP epithelial cells treated with non-traumatic CSF,while treatment with traumatic CSF significantly increased its m RNA level compared to the cells cultured only in DMEM/F12 as control.It seems that CP epithelial cells contain multipotent stem-like cells which are inducible under pathological conditions including exposure to traumatic CSF because of its compositions.