Trophic Support Research Articles

The Role of Metals in the Neuroregenerative Action of BDNF, GDNF, NGF and Other Neurotrophic Factors.

Mature neurotrophic factors and their propeptides play key roles ranging from the regulation of neuronal growth and differentiation to prominent participation in neuronal survival and recovery after injury. Their signaling pathways sculpture neuronal circuits during brain development and regulate adaptive neuroplasticity. In addition, neurotrophic factors provide trophic support for damaged neurons, giving them a greater capacity to survive and maintain their potential to regenerate their axons. Therefore, the modulation of these factors can be a valuable target for treating or preventing neurologic disorders and age-dependent cognitive decline. Neuroregenerative medicine can take great advantage by the deepening of our knowledge on the molecular mechanisms underlying the properties of neurotrophic factors. It is indeed an intriguing topic that a significant interplay between neurotrophic factors and various metals can modulate the outcome of neuronal recovery. This review is particularly focused on the roles of GDNF, BDNF and NGF in motoneuron survival and recovery from injuries and evaluates the therapeutic potential of various neurotrophic factors in neuronal regeneration. The key role of metal homeostasis/dyshomeostasis and metal interaction with neurotrophic factors on neuronal pathophysiology is also highlighted as a novel mechanism and potential target for neuronal recovery. The progress in mechanistic studies in the field of neurotrophic factor-mediated neuroprotection and neural regeneration, aiming at a complete understanding of integrated pathways, offers possibilities for the development of novel neuroregenerative therapeutic approaches.

Can a Scaffold Enriched with Mesenchymal Stem Cells Be a Good Treatment for Spinal Cord Injury?

Spinal cord injury (SCI) is a worldwide highly crippling disease that can lead to the loss of motor and sensory neurons. Among the most promising therapies, there are new techniques of tissue engineering based on stem cells that promote neuronal regeneration. Among the different types of stem cells, mesenchymal stem cells (MSCs) seem the most promising. Indeed, MSCs are able to release trophic factors and to differentiate into the cell types that can be found in the spinal cord. Currently, the most common procedure to insert cells in the lesion site is infusion. However, this causes a low rate of survival and engraftment in the lesion site. For these reasons, tissue engineering is focusing on bioresorbable scaffolds to help the cells to stay in situ. Scaffolds do not only have a passive role but become fundamental for the trophic support of cells and the promotion of neuroregeneration. More and more types of materials are being studied as scaffolds to decrease inflammation and increase the engraftment as well as the survival of the cells. Our review aims to highlight how the use of scaffolds made from biomaterials enriched with MSCs gives positive results in in vivo SCI models as well as the first evidence obtained in clinical trials.

Development of myelinating glia: An overview.

Myelin is essential to nervous system function, playing roles in saltatory conduction and trophic support. Oligodendrocytes (OLs) and Schwann cells (SCs) form myelin in the central and peripheral nervous systems respectively and follow different developmental paths. OLs are neural stem-cell derived and follow an intrinsic developmental program resulting in a largely irreversible differentiation state. During embryonic development, OL precursor cells (OPCs) are produced in distinct waves originating from different locations in the central nervous system, with a subset developing into myelinating OLs. OPCs remain evenly distributed throughout life, providing a population of responsive, multifunctional cells with the capacity to remyelinate after injury. SCs derive from the neural crest, are highly dependent on extrinsic signals, and have plastic differentiation states. SC precursors (SCPs) are produced in early embryonic nerve structures and differentiate into multipotent immature SCs (iSCs), which initiate radial sorting and differentiate into myelinating and non-myelinating SCs. Differentiated SCs retain the capacity to radically change phenotypes in response to external signals, including becoming repair SCs, which drive peripheral regeneration. While several transcription factors and myelin components are common between OLs and SCs, their differentiation mechanisms are highly distinct, owing to their unique lineages and their respective environments. In addition, both OLs and SCs respond to neuronal activity and regulate nervous system output in reciprocal manners, possibly through different pathways. Here, we outline their basic developmental programs, mechanisms regulating their differentiation, and recent advances in the field.

Stable isotope mixing models demonstrate the role of an invasive plant in wetland songbird food webs.

PremiseInvasive plants in wetlands are often ecosystem engineers, mediating changes in ecosystem functions like trophic support. We documented the impacts of Lepidium latifolium, an invasive plant, on the food web of omnivorous birds (Suisun song sparrows, Melospiza melodia maxillaris) in a tidal wetland of northern California, USA.MethodsWe used analysis of natural abundance stable isotopes of 13C and 15N in song sparrow blood, invertebrate food sources, L. latifolium seeds, and other marsh plant seeds to inform Bayesian, concentration‐dependent mixing models that predicted average song sparrow diets.ResultsSeason and plant phenology influenced food source incorporation and isotopic signatures. Song sparrows showed higher isotopic variability in the summer. The observed changes in song sparrow diets were driven by altered invertebrate communities related to seasonal L. latifolium presence and by shifts from seeds to consumption of invertebrate food sources during the breeding season in the spring and summer.DiscussionThis study used stable isotope tools and modeling to demonstrate two mechanisms of isotopic influence by L. latifolium on omnivorous song sparrows. This study can inform site‐ and species‐specific management strategies by demonstrating how changes to the plant community can impact entire trophic systems.

Effects of ethanol and deferoxamine on rat primary glial cell cultures, in regard with ischemia induced by traumatic spinal cord injury

Although they have been regarded, in the past, as passive support cells, many experimental data have shown that glial cells play a critical role in the development and functioning of the nervous system. Despite the advances that have been made in understanding astrocytes' role in the nervous system's development and function, our knowledge of their interactions with other cells is still limited, albeit neurons are dependent on the trophic support provided by astrocytes release. Materials and Methods. The use of the McCarthy and de Vellis methods for isolating glial cells has been regarded as an essential tool for studying their function. This study aims to evaluate the effects of ethanol and deferoxamine on primary rat glial cell cultures and try to explain, as far as possible, the relevance of such effects for patients with chronic alcoholism and traumatic spinal cord injuries. Discussion. Because glial cells are very important in the functioning of the central nervous system and experiments cannot be performed on human primary nerve cell cultures, we performed an experiment on glial cells harvested from the newborn rat, analyzing the dynamics of IL-6 and TNF alpha on models of suffering in spinal cord injury (hypoxia and thermally stress). Conclusion. Inhibition of TNF alpha synthesis was more important at 7 days posttraumatic in cells with prolonged ethanolic exposure, even if protein levels of IL-6 were elevated (under similar experimental conditions). Thus, we can say that long-term exposure to ethanol of nerve cells can ensure a favorable evolution of medical recovery (by increasing TNF alpha), even if the inflammatory process remains active (shown by elevated IL-6 values). Keywords: ethyl alcohol, deferoxamine, primary glial cells cultures, traumatic Spinal Cord Injury

Synthetic cannabinoids reduce the inflammatory activity of microglia and subsequently improve neuronal survival in vitro

Microglia are resident immune cells of the brain that survey the microenvironment, provide trophic support to neurons, and clear debris to maintain homeostasis and healthy brain function. Microglia are also drivers of neuroinflammation in several neurodegenerative diseases. Microglia produce endocannabinoids and express both cannabinoid receptor subtypes suggesting that this system is a target to suppress neuroinflammation. We tested whether cannabinoid type 1 (CB1) or type 2 (CB2) receptors could be targeted selectively or in combination to dampen the pro-inflammatory behavior of microglia, and whether this would have functional relevance to decrease secondary neuronal damage. We determined that components of the endocannabinoid system were altered when microglia are treated with lipopolysaccharide and interferon-gamma and shift to a pro-inflammatory phenotype. Furthermore, pro-inflammatory microglia released cytotoxic factors that induced cell death in cultured STHdhQ7/Q7 neurons. Treatment with synthetic cannabinoids that were selective for CB1 receptors (ACEA) or CB2 receptors (HU-308) dampened the release of nitric oxide (NO) and pro-inflammatory cytokines and decreased levels of mRNA for several pro-inflammatory markers. A nonselective agonist (CP 55,940) exhibited similar influence over NO release but to a lesser extent relative to ACEA or HU-308. All three classes of synthetic cannabinoids ultimately reduced the secondary damage to the cultured neurons. The mechanism for the observed neuroprotective effects appeared to be related to cannabinoid-mediated suppression of MAPK signaling in microglia. Taken together, the data indicate that activation of CB1 or CB2 receptors interfered with the pro-inflammatory activity of microglia in a manner that also reduced secondary damage to neurons.

Bioactive extracellular vesicles from a subset of endothelial progenitor cells rescue retinal ischemia and neurodegeneration.

Disruption of the neurovascular unit (NVU) underlies the pathophysiology of various CNS diseases. One strategy to repair NVU dysfunction uses stem/progenitor cells to provide trophic support to the NVU’s functionally coupled and interdependent vasculature and surrounding CNS parenchyma. A subset of endothelial progenitor cells, endothelial colony-forming cells (ECFCs) with high expression of the CD44 hyaluronan receptor (CD44hi), provides such neurovasculotrophic support via a paracrine mechanism. Here, we report that bioactive extracellular vesicles from CD44hi ECFCs (EVshi) are paracrine mediators, recapitulating the effects of intact cell therapy in murine models of ischemic/neurodegenerative retinopathy; vesicles from ECFCs with low expression levels of CD44 (EVslo) were ineffective. Small RNA sequencing comparing the microRNA cargo from EVshi and EVslo identified candidate microRNAs that contribute to these effects. EVshi may be used to repair NVU dysfunction through multiple mechanisms to stabilize hypoxic vasculature, promote vascular growth, and support neural cells.

Topography of neurotrophins in the rat neocortex and their role in neuron apoptosis after experimental ischemic stroke

Neuronal loss due to apoptosis after ischemic injury depends on the trophic support of neurons and cytoprotective effects of neurotrophins (NTs). Different NTs may activate both pro- and antiapoptotic factors. Their distribution in the ischemic core (IC) and penumbra (IP) has been poorly studied. The available data on the localization of NTs in the ischemic brain are contradictory and depend to a certain degree on the pathogenetic model used. The distribution of NTs in different layers of the ischemic cortex is also largely unknown hindering our understanding of their exact effects and targets in different zones of the ischemic brain. We examined the immunolocalization of brain-derived neurotrophic factor (BDNF), neurotrophin-3, and glial cell line-derived neurotrophic factor (GDNF) in the parietal cortex using a rat model of ischemic stroke due to permanent occlusion of the middle cerebral artery. The spatial density of immunoreactive (IR) cells varied across the cortical layers and changed with time after ischemic injury. Their distribution in the IC differed considerably from that in the IP. The immunolocalization of neurotrophins in the contralateral hemisphere was similar to that in IP. We also studied the distribution of pro- and anti-apoptotic factors in IC and IP with and without intravenous BDNF administration. In the model without BDNF administration, the proportions of Bcl-2-, p53-, caspase-3-, and Mdm2-IR cells showed different dynamics during the ischemic period. In the model with BDNF administration, Mdm2 immunoreactivity was mainly observed in pyramidal cells of layers V/VI, and Bcl-2, in interneurons of layers II and III. The dynamics of p53 immunoreactivity was opposite to that of caspase-3 throughout the ischemic period. The present results suggest that after ischemic injury, 1) the number of neurotrophin-positive cells increases in the early ischemic period and decreases afterwards; 2) there is a close metabolic relationship between astrocytes and neurons contributing to their adaptation to ischemic conditions; 3) the IP borders undergo constant changes; 4) in the IP, neuronal loss occurs mainly by apoptotic pathway throughout the ischemic period; 5) BDNF may enhance considerably antiapoptotic mechanisms with a predominance of Mdm-2 activity in pyramidal neurons.

STEREOMETRIC ANALYSIS OF GLIAL AND VASCULAR COMPONENTS IN THE MICROSTRUCTURE OF HUMAN NEOCORTEX REGIONS INVOLVED IN VISUAL-SPATIAL PERCEPTION

Visual-spatial perception in children and adolescents is largely determined by age-specific features of the structure and hemodynamics in the associative areas of the cerebral cortex. Aim. The aim of the study was to investigate the quantitative ratios of vascular and glial components in the oculomotor area 8 of the prefrontal cortex and the 37aс subarea of the posterior associative cortex involved in visual-spatial analysis. Methods. We studied 27 left large hemispheres of the brains in male subjects aged 10 to 17 years, grouped in annual intervals. We studied specific volumes of intracortical blood vessels and gliocytes in the external pyramidal layer on paraffin-embedded cortical slices impregnated with silver nitrate according to Peters with Nissl dyeing using a stereometric method. Results. We found that microstructural changes in the adolescent neocortex resulted in a decrease in the relative content of intracortical microvessels and an increase in the specific volume of gliocytes. The structural changes occur heterochronously: in the oculomotor area 8 of the prefrontal cortex, at 11-12 years of age, and in the subarea 37aс, at 12-13 years of age. Conclusion. The data obtained testify to a significant morpho-functional restructuring of trophic support and metabolic processes in the associative areas of the neocortex controlling visual-spatial perception.

Increased Biodiversity Associated With Abandoned Benthic Oyster Farms Highlight Ecosystem Benefits of Both Oyster Reefs and Traditional Aquaculture

Oyster reefs are structurally complex habitats which are increasingly recognized for their importance in estuarine systems. With over 85% of oyster reefs lost to human activities globally, there is increasing interest in aquaculture to not only meet the growing need for food worldwide, but also enhance ecological functions and services. Prime among these services is the provision of habitat for marine biodiversity. We assessed the biodiversity associated with an abandoned benthic oyster farm to investigate the potential ecological benefits of benthic farming techniques used in traditional oyster farms. In addition, we made note of any invasive species which may use these abandoned structures as habitat. The macrobenthic assemblage in the oyster habitat formed by the farm was different from the surrounding mudflats, containing 61 and 26 species, respectively. Density of invertebrates was similar in both habitats (~ 5,777 ± 981 indiv·m−2), but biomass in the oyster farm over ten times greater than the mudflat substrate, which had a fauna dominated by small polychaetes (<5 mm long). Molluscs and crustaceans were especially abundant in the oyster habitat and contributed to 90% of the enhanced biomass associated with oyster habitat (excluding oyster biomass). Only one invasive species was documented, the musselXenostrobus secures, but at densities lower than nearby artificial substrates (e.g., concrete shorelines). Oyster development on this abandoned farm appears to be self-sustaining, provide habitat and trophic support for associated benthic macrofauna. In addition to supporting higher biodiversity and biomass of associated species, traditional oyster aquaculture could improve the restoration potential of oyster reefs by supporting broodstock of native oysters, thus maintaining larval supply.

Abstract B011: P300 histone acetyltransferase mediates glioma stem cell adaptive response to therapeutic stress

Abstract Glioma stem-like and tumor cells exhibit phenotypic plasticity in response to environmental and therapeutic stress leading to tumor recurrence, but the underlying mechanisms remain largely unknown. In this study, we employed single-cell and whole transcriptomic analyses to uncover that radiation-stress induces a dynamic shift in functional states of glioma cells allowing for acquisition of vascular endothelial-like and pericyte-like cell phenotypes. These vascular-like cells provide trophic support to promote proliferation of tumor cells, and their selective depletion results in reduced tumor growth post-treatment in vivo. Mechanistically, the acquisition of vascular-like phenotype is driven by increased chromatin accessibility and H3K27 acetylation in specific vascular gene regions allowing for their increased expression post-treatment. Blocking P300 histone acetyltransferase activity using a small molecule inhibitor C646 or gene knockdown reverses the epigenetic changes induced by radiation, inhibits the adaptive conversion of GSC into vascular-like cells, reduces tumor growth and enhances animal survival. Our findings highlight an important role for P300 in mediating adaptive response of glioma stem cells to therapeutic-stress, and opens a new therapeutic avenue for preventing glioma recurrence. Citation Format: Sree Deepthi Muthukrishnan, Riki Kawaguchi, Pooja Nair, Alvaro Alvarado, Harley Kornblum. P300 histone acetyltransferase mediates glioma stem cell adaptive response to therapeutic stress [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B011.

Castration mediated schwann cell dedifferentiation leads to slower nerve conduction, decreased neuritogenesis, and nitrergic neuron loss

ABSTRACT Introduction/Objectives Low levels of androgens due to androgen deprivation therapy for prostate cancer treatment or due to aging lead to erectile dysfunction (ED). Castration, a preclinical model of low androgens, induces ED due to damage to pelvic nerves and a loss of erectogenic nitrergic nerves. Schwann cells (SC) release neurotrophic factors to promote pelvic nerve growth and survival. It is unknown how testosterone deficiency impacts SC function. This study determines how testosterone deficiency influences SC phenotype and trophic support in neuronal regeneration. We hypothesize testosterone deficiency will decrease myelinated pelvic SC populations, delay penile nerve conduction and reduce pelvic nitrergic neurons. Methods Male Sprague Dawley rats (12 wks) were divided into control (CON) and surgical castration (CAST) groups. All experiments were performed six weeks following castration. Dorsal penile nerves (DPN; 15-16 mm) were excised, placed in a sylgard dish containing oxygenated buffer and conduction velocity of myelinated fast fibers was assessed (n=8 per group). The major pelvic ganglia (MPG) were collected and dissociated into SC or neurons. Dissociated neurons were grown on laminin coated coverslips. To determine whether SCs could provide trophic support, we co-cultured neurons on top of confluent SCs. We assessed the following co-culture groups: CON SC + CON MPG, CON SC + CAST MPG, CAST SC + CON MPG (n=4 per group, cultured in triplicate). After 72 hours, all cultures were fixed and stained with beta tubulin class III, neuronal nitric oxide synthase (nNOS), and tyrosine hydroxylase (TH) to assess neurite length and branching, nitrergic and sympathetic neuron populations, respectively. Dissociated SC were characterized via qPCR for markers of all SC (Sox10), myelinated SC (Krox20), and dedifferentiated SC (glial fibrillary acidic protein; GFAP). Results CAST slows DPN myelinated fast fiber conduction velocity. In dissociated cultured MPG neurons, castration reduces both neurite length and number of branches. Interestingly, CAST MPG neurons co-cultured with CON SC restore neurite length and branching to same level as CON MPG neurons co-cultured with CON SC; however, CAST SC do not impact CON MPG neurite length. CAST MPG neurons co-cultured with CON SC and CON MPG neurons co-cultured with CAST SC both have less nitrergic neurons than CON SC + CON MPG neurons. CAST does not impact the number of TH neurons in single or co-cultured conditions. CAST reduces gene expression of Sox10, myelinated SC, and dedifferentiated SC. Conclusions CAST markedly impairs penile nerve conduction, reduces neurite outgrowth and the proportion of pro-erectile nitrergic neurons. Healthy SC are able to rescue neuritogenesis but not the survival of nitrergic neurons. Additionally, healthy MPG neurons plated on CAST SC have a reduced number of nitrergic neurons. We believe CAST SC are undergoing a phenotypic switch from a myelinated neurotrophic form into dedifferentiated SC promoting neuritogenesis and loss of nitrergic neurons. Preserving the myelinated SC phenotype may prevent impaired nerve damage and subsequent ED in patients with testosterone deficiency. Disclosure Work supported by industry: no.

Single-Cell Analysis of Dorsal Root Ganglia Reveals Metalloproteinase Signaling in Satellite Glial Cells and Pain

Somatosensory stimuli such as touch, temperature and pain are transduced in the periphery and transmitted to the central nervous system by primary sensory neurons, which cell bodies reside in sensory ganglia such as dorsal root ganglia (DRGs). Although DRG are complex tissues with neuronal and non-neuronal cells, diversity of non-neuronal cells and their function in homeostasis and pain are still unclear. Satellite glial cells (SGCs) are among the most abundant non-neuronal cells in DRGs and tightly envelop neurons providing metabolic and trophic support, buffering extracellular ions and neurotransmitters, and enabling neuromodulation. Importantly, it is now clear that SGCs can control neuroinflammation and neuronal excitability contributing to development of pathological pain. Yet our understanding of SGC biology and molecular signaling is still rudimentary. Here, we used single-cell RNA sequencing (scRNA-seq) to study the heterogeneity of non-neuronal cell populations in DRGs and, in particular, to understand SGC biology and molecular signaling in the context of modulation of somatosensory stimuli and pathological pain. We identified a distinct gene expression for non-neuronal cells and heterogeneity of SGCs. In particular, we found an enriched expression of the tissue inhibitor metalloproteinase 3 (TIMP3) and other metalloproteinases in SGCs, and demonstrated using small interfering RNA and neutralizing antibody that TIMP3 controls somatosensory stimuli. TIMP3 expression is decrease after paclitaxel, and its rescue by delivery of a recombinant TIMP3 protein reversed and prevented paclitaxel-induced pain. We also established that paclitaxel directly modulates metalloproteinase signaling in cultured SGCs, which can be used to screen novel drugs for pain. Thus, our findings reveal a metalloproteinase signaling in SGCs for the proper processing of somatosensory stimuli and discovery of new treatment of pain. Grant support from NS113243.

Abstract 223: Modifiable Mesenchymal Stem Cell Defects In Veterans With Diabetes Mellitus

Diabetes Mellitus (DM) affects 34.2 million Americans. DM impairs the body’s reparative machinery leading to early onset chronic illness (peripheral arterial disease (PAD), neuropathy, nephropathy, and retinopathy, the latter being hallmarks of microvascular disease). Patients with DM+PAD have increased risk of major amputation. Mesenchymal stem cells (MSCs) are reparative cells found in all tissues providing paracrine and trophic support for new tissue. This study’s objective was to identify intracellular and epigenetic mechanisms of how DM impairs MSC function and test if these defects are modifiable with culture rejuvenation (CR). MSCs obtained from bone marrow of 13 consecutive, male Veterans undergoing lower limb major amputation were cultured in 10% fetal bovine serum or 5% human platelet lysate (PL) for CR. Groups were DM+PAD (n=8) and PAD no DM (n=5). Intracellular signaling was analyzed with multiplexed ELISA. Epigenetic differences were identified by ATAC-sequencing. DM+PAD MSCs had modifiable AKT signaling defects with PL (Fig 1) and a discrete DNA profile identified in their introns and intergenic regions (Fig 2). MSCs from PAD alone had increased transcription factor binding at Wnt and cGMP-PKG pathways (p=0.04). DM+PAD MSCs had increased binding at MAPK (p=0.01) and Rap1 (p=0.01) pathways. DM is a complex disease disrupting reparative mechanisms and can lead to major complications. MSC dysfunction in DM may have common mechanisms throughout the body. We have identified potentially druggable pathways that may provide therapeutic solutions to relieve chronic illness for endogenous MSCs and to expand MSC donor pool for regenerative medicine strategies.

Autochthony and isotopic niches of benthic fauna at shallow-water hydrothermal vents

The food webs of shallow-water hydrothermal vents are supported by chemosynthetic and photosynthetic autotrophs. However, the relative importance of these two basal resources for benthic consumers and its changes along the physicochemical gradient caused by vent plumes are unknown. We used stable carbon and nitrogen isotopes (i.e., δ13C and δ15N) and Bayesian mixing models to quantify the dietary contribution of basal resources to the benthic fauna at the shallow-water vents around Kueishan Island, Taiwan. Our results indicated that the food chains and consumer production at the shallow-water vents were mainly driven by photoautotrophs (total algal contribution: 26–54%) and zooplankton (19–34%) rather than by chemosynthetic production (total contribution: 14–26%). Intraspecific differences in the trophic support and isotopic niche of the benthic consumers along the physicochemical gradient were also evident. For instance, sea anemone Anthopleura sp. exhibited the greatest reliance on chemosynthetic bacteria (26%) and photoautotrophs (66%) near the vent openings, but zooplankton was its main diet in regions 150–300 m (32–49%) and 300–700 m (32–78%) away from the vent mouths. The vent-induced physicochemical gradient structures not only the community but also the trophic support and isotopic niche of vent consumers.

Stem Cell-based Treatment Strategies for Degenerative Diseases of the Retina.

The main cause of progressive vision impairment in retinal degenerative diseases is the dysfunction of photoreceptors and the underlying retinal pigment epithelial cells. The inadequate regenerative capacity of the neural retina and lack of established therapeutic options demand the development of clinical-grade protocols to halt the degenerative process in the eye or replace the damaged cells by using stem cell-derived products. Recently, stem cell-based regenerative therapies have been at the forefront of clinical investigations for retinal dystrophies. This article will review different stem cell-based therapies currently employed for retinal degenerative diseases, recent clinical trials, and major challenges in the translation of these therapies from bench to bedside. A systematic literature review was conducted to identify potentially relevant articles published in MEDLINE/PubMed, Embase, ClinicalTrials.gov, Drugs@FDA, European Medicines Agency, and World Health Organization International Clinical Trials Registry Platform. Transplantation of healthy cells to replace damaged cells in the outer retina is a clinically relevant concept because the inner retina that communicates with the visual areas of the brain remains functional even after the photoreceptors are completely lost. Various methods have been established for the differentiation of pluripotent stem cells into different retinal cell types that can be used for therapies. Factors released from transplanted somatic stem cells showed trophic support and photoreceptor rescue during the early stages of the disease. Several preclinical and phase I/II clinical studies using terminally differentiated photoreceptor/retinal pigment epithelial cells derived from pluripotent stem cells have shown proof of concept for visual restoration in Age-related Macular Degeneration (AMD), Stargardt disease, and Retinitis Pigmentosa (RP). Cell replacement therapy has great potential for vision restoration. The results obtained from the initial clinical trials are encouraging and indicate its therapeutic benefits. The current status of the therapies suggests that there is a long way to go before these results can be applied to routine clinical practice. Input from the ongoing multicentre clinical trials will give a more refined idea for the future design of clinical-grade protocols to transplant GMP level HLA matched cells.

Metabolic reprogramming in astrocytes results in neuronal dysfunction in intellectual disability.

Astrocyte aerobic glycolysis provides vital trophic support for central nervous system neurons. However, whether and how astrocytic metabolic dysregulation contributes to neuronal dysfunction in intellectual disability (ID) remain unclear. Here, we demonstrate a causal role for an ID-associated SNX27 mutation (R198W) in cognitive deficits involving reshaping astrocytic metabolism. We generated SNX27R196W (equivalent to human R198W) knock-in mice and found that they displayed deficits in synaptic function and learning behaviors. SNX27R196W resulted in attenuated astrocytic glucose uptake via GLUT1, leading to reduced lactate production and a switch from homeostatic to reactive astrocytes. Importantly, lactate supplementation or a ketogenic diet restored neuronal oxidative phosphorylation and reversed cognitive deficits in SNX27R196W mice. In summary, we illustrate a key role for astrocytic SNX27 in maintaining glucose supply and glycolysis and reveal that altered astrocytic metabolism disrupts the astrocyte-neuron interaction, which contributes to ID. Our work also suggests a feasible strategy for treating ID by restoring astrocytic metabolic function.

Contribution of Müller Cells in the Diabetic Retinopathy Development: Focus on Oxidative Stress and Inflammation.

Diabetic retinopathy is a neurovascular complication of diabetes and the main cause of vision loss in adults. Glial cells have a key role in maintenance of central nervous system homeostasis. In the retina, the predominant element is the Müller cell, a specialized cell with radial morphology that spans all retinal layers and influences the function of the entire retinal circuitry. Müller cells provide metabolic support, regulation of extracellular composition, synaptic activity control, structural organization of the blood–retina barrier, antioxidant activity, and trophic support, among other roles. Therefore, impairments of Müller actions lead to retinal malfunctions. Accordingly, increasing evidence indicates that Müller cells are affected in diabetic retinopathy and may contribute to the severity of the disease. Here, we will survey recently described alterations in Müller cell functions and cellular events that contribute to diabetic retinopathy, especially related to oxidative stress and inflammation. This review sheds light on Müller cells as potential therapeutic targets of this disease.

Current Concepts of Neural Stem/Progenitor Cell Therapy for Chronic Spinal Cord Injury.

Chronic spinal cord injury (SCI) is a devastating condition that results in major neurological deficits and social burden. It continues to be managed symptomatically, and no real therapeutic strategies have been devised for its treatment. Neural stem/neural progenitor cells (NSCs/NPCs) being used for the treatment of chronic SCI in experimental SCI models can not only replace the lost cells and remyelinate axons in the injury site but also support their growth and provide neuroprotective factors. Currently, several clinical studies using NSCs/NPCs are underway worldwide. NSCs/NPCs also have the potential to differentiate into all three neuroglial lineages to regenerate neural circuits, demyelinate denuded axons, and provide trophic support to endogenous cells. This article explains the challenging pathophysiology of chronic SCI and discusses key NSC/NPC-based techniques having the greatest potential for translation over the next decade.

Cotransplant With Pancreatic Islet Homogenate Improved Survival and Long-Term Efficacy of Islet Transplant in Streptozotocin-Diabetic Rats.

Pancreatic islet transplant is suggested as a promising treatment option in diabetes, but the number of viable and functional islets and the long-term efficacy of transplanted islets have not been satisfactory. Islet isolation leads to destruction of the extracellular matrix and loss of trophic support of islets, which reduces their survival and function. Reconstruction of islet microenvironment with biomaterials may preserve islet survival and graft efficacy. Accordingly, we investigated the effects of pancreatic islet homogenate on islet quality and graft outcomes in diabetic rats. Islets were isolated from the pancreas of Sprague Dawley rats and were cultured with or without pancreatic islet homogenate. Before transplant, viability, insulin content, and insulin released from cultured islets were assessed. Islets were then transplanted into subcapsular space of diabetic rat kidney. Transplant outcomes were evaluated by plasma glucose and insulin levels, glucose tolerance tests, and stress oxidative markers. Viability and insulin release in the pancreatic islet homogenate-treated islets were significantly higher than that in the control islets. After transplant of islets, recipient rats with pancreatic islet homogenate showed significant decreases in blood glucose and malondialdehyde levels and increases in superoxide dismutase activity and plasma insulin levels. Islet treatment with pancreatic islet homogenate could improve islet survival and transplant function and outcomes. Oxidative stress reduction might be a secondary beneficial effect of improved quality of treated islets.