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Spinal Cord Treatment Problems – Site not the Cells?

Therapeutic Activities of Engrafted Neural Stem/Precursor Cells Are Not Dormant in the Chronically Injured Spinal Cord

From Stem Cells

Neural stem or precursor cells (NSPCs) have tremendous promise for use in cell-based therapies for the treatment of spinal cord injury (SCI) as they have been shown to provide trophic support following transplantation, allowing modification of the host environment to allow some endogenous regeneration and repair in animal models (Aboody et al, Barnabe-Heider and Frisen, and Martino and Pluchino).   However, few studies have assessed their role in the chronic phase of SCI (Tetzlaff et al) and any correlation to microenvironmental factors (Thuret et al), which is potentially important for the behaviour of transplanted NSPCs.   Now, in a study published in Stem Cells from the laboratory of Seiji Okada at Kyushu University, Japan, Kumamaru et al combine flow-cytometric isolation and RNA-Seq to analyse the transcriptome of NSPCs transplanted into SCI during the chronic phase, and have demonstrated that while the cells have a positive therapeutic effect, the refractory state of the chronically injured spinal cord hampers locomotory recovery.

Explosive research reveals the dynamics of adult human neurogenesis

Original paper “Dynamics of Hippocampal Neurogenesis in Adult Humans” from Cell by Spalding et al.

In the last two decades the central dogma which dictated that no new neurons are born in the adult brain has been refuted, and the mammalian subventricular zone (SVZ) of the lateral ventricles and subgranular zone (SGZ) of the hippocampal dentate gyrus are now recognised sites of adult neurogenesis.   Newborn neurons from the SVZ migrate to the olfactory bulb to provide new granule cell neurons throughout life and adult-born hippocampal neurons are implicated in pattern separation (the ability to form and use memories arising from similar stimuli) and memory formation.   Yet while some evidence exists for this capacity in adult humans, the dynamics and functional contribution of these newly generated cells to brain function still elicits strong scientific debate.   An innovative technique1 developed by Kirsty Spalding and Jonas Frisen at the Karolinska Institute in Stockholm, Sweden, which utilises the radioactive carbon 14 isotope (14C) curve created by the dramatic increase in atmospheric 14C levels following above-ground nuclear bomb testing during the Cold War and subsequent decline following the Partial Nuclear Test Ban Treaty in 1963, has now been used to examine the cell turnover dynamics of the adult human hippocampus.2   Their method takes advantage of the fact that new cells incorporate 14C into their genomic DNA at a concentration that mirrors atmospheric 14C at the time of their birth, creating a ‘date mark’ in the DNA.   Extrapolation of 14C concentration to the atmospheric 14C curve can therefore allow the accurate determination of the period during which a cell was born.   In their article recently published in Cell, Spalding et al.2 report their findings and reveal that a surprising proportion of human neural cells are subject to turnover, which may indicate a cognitive role for these newly generated adult cells.

Nestin Mediated NSC Purification

“Lineage-Specific Purification of Neural Stem-Progenitor Cells from Differentiated Mouse Induced Pluripotent Stem Cells”

From Stem Cells Translational Medicine.

While protocols for the differentiation of specific cell lineages from pluripotent cell types abound; the problem of the purification of these cells still remains unsolved.   Problems include the presence of remaining pluripotent stem cells in differentiated cultures which may cause tumourigenesis and the presence of other unwanted cell types.   To get around this problem, fluorescence-activated cell sorting (FACS) (Fukuda et al and Ladewig et al) or drug selection strategies (Li et al) have been proposed and used.   FACS purification of neural stem cells (NSCs) is difficult as many markers are not cell surface antigens (Lendahl et al and Kaneko et al), and so researchers from the laboratory of Tetsuo Sugimoto at the Kansai Medical University, Osaka, Japan have utilised a drug selection strategy, as is reported in Stem Cells Translational Medicine.   Using Nestin regulatory sequences in a rat model they report the successful isolation of pure NSCs using drug selection (Maruyama et al).

In pursuit of the optimal graft site for spinal cord injury

Original article from STEM CELLS TRANSLATIONAL MEDICINE

 “Safety of epicentre versus intact parenchyma as a transplantation site for human neural stem cells for spinal cord injury therapy”

The ability to successfully replace lost or dysfunctional neurons of the central nervous system (CNS) by transplanting de novo cells is an on-going pursuit which represents one of the only therapeutic possibilities for functional restoration in many forms of neural trauma and disease. The complex nature of the CNS microenvironment however makes this an arduous task. This is especially true for spinal cord injury (SCI), where multiple differing layers of damage exist around the core of the insult, and reconstitution not only requires the replacement of damaged cells, but long distance axonal regeneration along growth-inhibitory tracts and the establishment of topographically correct connections once the target has been reached. Further, the epicentre of the injury becomes ‘shut off’ by a glial scar, which encloses the centre of damage to limit inflammation and restores the integrity of the blood-brain barrier, but unfortunately also makes the core of the injury inaccessible for any regeneration to occur. Nonetheless, the epicenter represents an easily accessible site for the delivery of new cells, and avoids additional damage to remaining healthy spinal tissue. Human CNS-derived stem cells (hCNS-SCns) can be enriched from 16-20 week foetal brain tissue by FACS sorting for the CD133+CD24-/lo population. Studies have previously reported that hCNS-SCns transplanted both rostral and caudal to a SCI in immunocompromised NOD-scid mice can differentiate into oligodendrocytes capable of myelination which can improve locomotor function.1-3 In a recent study, which has emerged from multiple centres in California and is published in Stem Cells Translational Medicine, following on from this previous work Piltti et al.4 have directly compared the transplantation of hCNS-SCns into intact parenchyma adjacent to the injury epicentre, or into the epicenter itself, in an adult rat model of contusion SCI. Their results reveal that there are still lessons to be learnt about the impact of the host immune system and graft location upon the behaviour of transplanted cells. 

NPs OK for ALS

“Neural Progenitors Derived From Human Induced Pluripotent Stem Cells Survive and Differentiate Upon Transplantation into a Rat Model of Amyotrophic Lateral Sclerosis”

From Stem Cells Translational Medicine

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease which ultimately leads to death by failure of the respiratory muscles at 3–5 years post-diagnosis (Mitchell and Borasio). Currently, there are no effective treatments or preventive strategies in humans although stem-cell-based therapies may represent a possible solution. However studies which evaluated bone marrow-derived-human mesenchymal stem cells and human umbilical cord blood cells showed little or no therapeutic benefit (Lindvall and Kokaia). Additionally, while studies have described the generation of induced pluripotent stem cells (iPSCs) from ALS patients and their differentiation into motor neurons for ALS disease modeling (Bilican et al, Dimos et al, Egawa et al and Mitne-Neto et al), there has been no description of their fate after transplantation. To this end, researchers from the laboratory of Delphine Bohl (Institut Pasteur, Paris, France) and Roland Pochet (Université Libre de Bruxelles, Brussels, Belgium) have studied the intraparenchymal transplantation of human iPSC-derived neural progenitors (iPSC-NPs) into an ALS environment and report their successful differentiation into human mature neurons, some having motoneuronal morphologies, in the grey matter of the brain (Popescu et al).

Do Glial Cells Aid NSC Therapeutics through Cell Fusion?

"Embryonic Stem Cell-Derived Neural Stem Cells Fuse with Microglia and Mature Neurons"

Recent studies into the transplantation of neural stem cells (NSCs) in animal models have suggested that this may represent a novel strategy in combating loss of function in human brain disorders. However, the proposed mechanisms by which this is accomplished are many; neuron replacement, supply of trophic factors, modulation of inflammation, stimulation of angiogenesis and neuroprotection, amongst others (Lindvall and Kokaia). Importantly, inflammation activates innate immune cells, such as microglia, which are known to fuse with mature resident neurons (Ackman et al.) possibly exerting a protective role (Alvarez-Dolado 2007) as fusion is enhanced by inflammation and tissue damage (Espejel et al., Johansson et al. and Nygren et al.). Now, in a study published in Stem Cells, researchers from the group of Zaal Kokaia at the Laboratory of Stem Cells and Restorative Neurology, University Hospital/Lund Stem Cell Center, Sweden have demonstrated that microglial cells do fuse with mature neurons and that they also mediate the fusion of NSCs with mature neurons (Cusulin and Monni et al.).

Stem Cell Therapy for Mood and Memory

Original article from STEM CELLS Translational Medicine

“Neural Stem Cell Grafting Counteracts Hippocampal Injury-Mediated Impairments in Mood, Memory, and Neurogenesis”

Injury to the hippocampus, an organ vital for cognitive and mood function (Deng et al and Samuels and Hen), is understood to lead to increased neurogenesis from neural stem cells (NSCs) in early stages (Gray and Sundstrom and Hattiangady et al 2008) thought of as a compensatory mechanism for injury-mediated dysfunction. This early stage upregulation in NSC is short lived; reduced NSC proliferation in the neurogenic subgranular zone (SGZ) of the dentate gyrus (DG) and aberrant hippocampal neurogenesis are linked to mood and memory dysfunction observed after hippocampal injuries (Jorge et al and Potvin et al). This therefore suggests that therapeutic strategies such as NSC transplantation therapy to enhance neurogenesis beyond the early stage may allow the alleviation of post-injury afflictions. NSCs have the ability to survive, migrate, and engraft into brain regions exhibiting neuron loss (Blurton-Jones et al), are able to introduce new neurotrophic-secreting astrocytes (Waldau et al) and also can stimulate endogenous NSCs in the neurogenic SGZ (Hattiangady et al, 2007). Now, in a study published in the September edition of Stem Cells Translational Medicine, Hattiangady and Shetty have studied the effect on NSC grafting into the hippocampus shortly after injury on counteracting impairments in mood and memory function and neurogenesis.

Stem Cells Pass First Trial for ALS. “Lumbar intraspinal injection of neural stem cells in patients with ALS - Results of a Phase I trial in 12 patients”

 

Amyotrophic lateral sclerosis (ALS) causes muscle weakness and atrophy throughout the body and is caused by the degeneration of motor neurons.   Stem cell therapy has been proposed as a possible treatment for ALS through cell replacement or through additional support to affected neurons (Lunn et al).   Human spinal cord-derived stem cells (HSSCs) derived from an 8-week gestation foetus (Guo et al) have shown some therapeutic benefit in rat models of ALS and ischemic spinal cord injury (SCI) (Cizkovaet al and Xu et al) and therefore suggests that they may also be applicable to stem cell therapy in humans.   Now, published in Stem Cells, the results of a successful phase I trial of intraspinal injections of fetal-derived neural stems cells (NSCs) in patients with ALS have been reported (Glass et al).

A Therapeutic Stroke in the Right Direction?

‘Implantation site and lesion topology determine efficacy of a human neural stem cell line in a rat model of chronic stroke’

From Stem Cells
Commentary by Carla B. Mellough

Stroke remains one of the leading causes of mortality and adult disability in developed nations1-3. For the survivors of stroke, the resulting disability is often persistent in nature and severely affects an individual’s quality of life, with the additional possibility of recurrent stroke events a grim reality. Over the past four decades, while the incidence of stroke has declined in high-income countries there has been a greater than 100% increase in low to middle-income countries, highlighting the magnitude of this cardiovascular problem.3 Yet strategies to maximize recovery and help improve patient outcome following stroke have made little progress, with only 3% of patients currently gaining any benefit from existing treatment strategies, such as the use of thrombolytic agents.4 There is therefore an obvious need for the development of restorative therapies which would help to address the loss of neurons and glia in the brain following stroke. For a cell-based therapeutic approach, determining the optimal cell type for use that will apply to a broad cross section of stroke patients while giving consistent results and minimal complications is key. Various cell types have been tested in experimental stroke ranging from embryonic, mesenchymal and neural stem cells to human umbilical cord blood, in addition to some less obvious candidates such as adipose and menstrual blood cells, with preclinical studies indicating varying positive outcomes but, importantly, that many different cell types can elicit encouraging results.4,5 Many of the cell types that have been tested appear to exert their effects not by cell replacement, but by their neurotrophic and anti-inflammatory effects on affected tissues, and therefore act by minimizing damage and providing protection to brain tissues. Neuronal precursors derived from human embryonic stem cells (hESCs) tested in a rat model of stroke were shown to elicit some functional recovery,6 but the application of such strategies to the clinic remain somewhat hampered by the potential tumorigenicity of any residual stem cells which may be transplanted alongside more differentiated cell types. Until measures to reduce this potentiality are optimized, human neural stem cells (hNSCs) represent a good alternative. In the current study, Smith et al.7 report on the use of a human cortical neuroepithelium-derived hNSC line (CTX0E03) which, in previous studies has shown efficacy in improving sensorimotor function in a dose-dependent manner and, unlike other hNSCs, shows limited migration capacity thereby providing a locally-acting cell based therapy which makes it potentially safer than other hNSC types. This work represents a collaborative study from Kings College London, the UK based company ReNeuron and the University of Pittsburgh in Pennsylvania.

Rejuvenation of Regeneration in the Aging Central Nervous System

From Cell Stem Cell
By Stuart P. Atkinson

Oligodendrocytes precursor cells (OPCs) differentiate into oligodendrocytes with remyelination capabilities which, in the adult central nervous system (CNS), restores conduction, prevents axonal degradation and promotes functional recovery. Reduction in this capacity in aging (Sim et al) leads to demyelinated neurons and axonal degeneration, which is understood to be mediated in part by environmental signals (Hinks and Franklin). This suggests that exogenous factors may be able to reverse this age-associated decline in function, which has now been addressed in an article (Ruckh and Zhao et al) in Cell Stem Cell by researchers in the laboratory of Amy J. Wagers (Howard Hughes Medical Institute) and Robin J.M. Franklin (MRC Centre for Stem Cell Biology and Regenerative Medicine).

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