Application of EGF was insufficient and inhibition of EGFR signaling prevented MG activation as well as cell cycle re-entry upon retinal explant culture. This data is in agreement with previous studies in mice and rats in and ex vivo (Close et al. 2006; Karl et al. 2008; Löffler et al. 2015; Todd et al. 2015; Ueki and Reh 2013). In contrast, stimulation of EGFR signaling has been shown to be sufficient and necessary to induce MG proliferation in undamaged zebrafish retina (Wan et al. 2012). Thus, differential regulation of MG quiescence and cell cycle states might exist. Cellular quiescence is generally incompletely understood, but recent data demonstrated the role of multiple activation states upon tissue injury (Cheung and Rando 2013; …show more content…
Various receptor activations might interact via downstream signaling mechanisms, including MAPK, which have been shown to regulate MG reactive gliosis or regenerative response upon retinal injury (Fischer 2005; Goldman 2014; Gorsuch and Hyde 2014; Hollborn et al. 2005; Lenkowski and Raymond 2014). The MAPK-ERK1/2 pathway is a well-known downstream target of EGFR. Recent studies showed that ERK1/2 has an essential function in the regulation of cell cycle re-entry and ERK activation could underlie differences in regenerative competence between mammals and salamanders (Yun et al. 2014). In the retina explant system we observed that P-ERK1/2 rapidly accumulates in MG similar to previous reports in vivo (Groeger et al. 2012). The number of activated MG, indicated by P-ERK1/2, correlates with the level of neuronal cell death. Inhibition of EGFR reduced P-ERK1/2 and proliferation of MG, but not overall cell death. This further supports the notion that cell death dependent signals prime MG to become responsive to EGFR-ERK1/2 mediated proliferation.
Understanding how neuronal injury and disease differentially determine glia responses may have major implications for disease progression, outcome of a given therapy, the identification of novel therapeutic targets and development of regenerative therapies in the future. Here, we provide evidences suggesting that the
After a retinal molecule absorbs light, the normally 11-cis form of the bound retinal molecule straightens to become the 11-trans from. This change activated the opsin molecule. Opsin activates transducin which is a G protein. This G protein then activates phosphodiesterase. Phosphodiesterase is an enzyme that breaks down cyclic-GMP. The break-down of cyclic-GMP removes them from the gated sodium channels and makes the gated sodium channels inactive. Because of this, sodium ion entry into the cytoplasm decreases.
2010). The neuroinflammation is an early, non-specific immune reaction to tissue damage or pathogen invasion (Lee et al. 2010). Inflammation of the central nervous system (CNS) is characterized by increased glial activation, pro-inflammatory cytokine concentration, blood-brain-barrier permeability, and leukocyte invasion (Lee et al. 2010). Microglia are cells that support and protect neuronal functions (Lee at al. 2010). They act as the first and main form of active immune defense that orchestrate the endogenous immune response of the Central Nervous System. The microglia play a central role in the cellular response to pathological lesions such as Aβ. Aβ can attract and activate microglia, leading to clustering of microglia around Aβ deposits sites in the brain (Lee et al. 2010). Even though microglia have neuroprotective functions, neurotoxic mechanisms which involves continuous activation of microglia and toxic factors are released by microglia, which may lead to neuroinflammation (Lee et al. 2010). Astrocytes (star-shaped glial cells) are the most abundant cells in the brain and are located in the brain and spinal. Astrocytes have various functions such as: biochemical support of endothelial cells of the BBB, supplying nutrients to the nervous tissue, maintenance of extracellular ion balance, and healing the brain and spinal cord following traumatic injury (Lee et al., 2010). Chemokines are released by astrocytes which attract microglia and they further express proinflammatory products, thus increasing neuronal damage in the pathogenesis of AD (Lee et al., 2010). Astrocytes play a critical role in Aß clearance and degradation, and they also provide trophic support to neurons forming a protective barrier between Aß deposits and neurons (Wyss-Coray et al., 2003). Neurons contribute to the production of
In most cases of X-linked retinitis pigmentosa RPGR has been observed to be dysfunctional, approximately 60 to 80% of X-linked retinitis pigmentosa are attributed to dysfunctional RPGR (Haddad et al., 2016; Pawlyk et al., 2016). Unfortunately, as of now, there is no therapeutic cure for any of the genetically inheritable forms of retinitis pigmentosa, but research is being conducted into the gene therapies, stem cell therapies. Currently the only method of treatment is to slow degradation of the photoreceptor cells of the retina, but this only mitigates the damage and does not stop or repair any of the damage that
Age-related macular degeneration (AMD) is the leading cause of blindness for people 60 years of age and older in the developed world. Vision loss is caused by the destruction of the cone photoreceptors, located in the macula, that are responsible for color/central vision. The underlying cause of AMD is the loss of the monolayer of pigmented epithelial cells located just below the photoreceptors, known as the retinal pigmentum epithelium (RPE). The main role of the RPE is to maintain the function of the photoreceptor layer by secreting nutrients, absorbing stray light, and recycling debris used during the visual cycle. As a person ages the efficiency of the RPE layer is diminished causing a build up of toxic by-products. These toxic build-ups, known as drusens, result in the separation and death of the photoreceptor and RPE layers. AMD is speculated to result from as many as 20 different genetic mutations and as a result there is no known cure for the disease (CITE), but recent advances in stem cell therapy is a hopeful step in the right direction.
“...neurons of the peripheral nervous system have a greater ability to regenerate. However...this is often both incomplete and inadequate.” (Kulraj et al, 2016)
Firstly, many forms of glaucoma are related to genetic mutations. For example, elevated IOP and glaucoma in DBA/2J mice is caused by recessive mutations in the genes Tyrp1 and Gpnmb, and the human genes MYOC and GLC1A are associated with human autosomal dominant recessive glaucoma and with human adult-onset glaucoma (Jakobs, Libby, Ben, John, & Masland, 2005). Gene therapy for people with the glaucomatous mutations should be explored as a possible preventative measure for future generations. Secondly, the changes in morphology of RGCs in glaucomatous eyes may be explored. Although several structural changes have already been observed, such as higher-order dendrite disappearance and overall shrinkage of RGCs, the effect of these changes in morphology on physiology has not yet been documented. Moreover, it is still unknown whether living RGCs in glaucomatous eyes adapt to the widespread cell loss and change in structure. Finally, stem cell therapy should be explored as a possible regenerative treatment for glaucoma patients. Although RGCs do not undergo mitosis, it may be possible for stem cells to develop and emulate their morphology and physiology. It may equally be possible for stem cells to help regenerate the damaged optic nerve. The many studies on the neural impact of glaucoma have reached a stage where, with the advances in cellular research and biotechnology, novel treatment options may be explored on this extremely common neurodegenerative
Generally, two surface molecules including complement receptor type 3 (CR3) and galactose-specific lectin MAC-2 are involved in Wallerian degeneration process and consequently the peripheral nerve regeneration. However, injury to CNS is not followed by extensive regeneration. It is limited by the inhibitory influences of the glial and extracellular environment. The environment within the CNS, especially following trauma, counteracts the repair of myelin and neurons. Growth factors are not expressed or re-expressed; for instance, the extracellular matrix is free of laminin, so glial scars rapidly form and produce factors that inhibit re-myelination and axon repair. The axons themselves also lose the potential for growth with age due to a decrease in the expression of
was to assess and determine the importance of the extracellular signal-regulated kinase (ERK) pathway in melanoma development in gray horses.4 They hypothesized that in the absence of certain somatic cancer causing mutations, such as BRAF, RAS, GNAQ, GNA11 and KIT genes, the ERK pathway is activated in gray horse melanocytic tumors and melanoma cells. The association between the absence of the somatic cancer mutations and ERK pathway activation is linked to activating the ERK pathway in certain human tumors caused by
Diabetic retinopathy is the leading cause of blindness globally and in the U.S. adults younger than age 60. It is more common in individual with type 2 diabetes compared to those with type 1 due to long-standing hyperglycemia before diagnosis. Most people with diabetes eventually develops some degree of retinopathy and they are more likely to develop cataracts and glaucoma. The prevalence and severity of retinopathy are strongly related to individual’s age, the duration of diabetes, and the extent of glycemic control. Three stages of the retinopathy leads to vision loss; stage I – non-proliferative is characterized by thickening of the retinal capillary basement membrane and increased retinal capillary permeability, vein dilation, micro-aneurysm formation, and hemorrhages. Stage II – pre-proliferative there is progression of retinal ischemia with areas of inadequate perfusion that result in infarcts. Stage III – proliferative involves neovascularization (angiogenesis) and fibrous tissue formation within
Steiner et al, 1997,(30) found that an immunophilin ligand, GPI-1046, caused regeneration of nerve axons and myelin, and also protected nerve fibres in vitro and in vivo in rat studies, providing evidence that there is potential with regard to immunophilins and neuroprotection. Another paper by Poulter et al, 2004(31) also suggested that immunophilin ligands derived from FK506 are effective in preventing neuronal degeneration in animal studies, however in clinical trials these effects were debatable, which may be rectified by carrying out a trial for a longer period of time. The authors commented that the inconsistent results show that the action of these ligands is not fully understood.
Integrated motif activity response analysis (ISMARA) - a bioinformatic tool to predict altered transcription factor activity - predicted the E2f family as upregulated in ENT1-/- AF tissue. E2f transcription factors are associated with cell cycle progression from G1 to S phase.14 Indeed, the expression of numerous E2f transcription factors was significantly upregulated in ENT1-/- AF tissue. We will further investigate the role of E2f factors in ENT1-/- AF tissues using a combination of RT-qPCR, immunohistochemistry and western blotting to examine tissue specific changes in the IVD and their association with markers of cell proliferation (i.e. Ki-67, PCNA). Further, we will use established protocols for AF cell isolation and culture to assess whether changes observed in vivo are recapitulated in vitro. Additionally, shRNA knockdown in WT AF cells will be used to identify specific E2f members responsible for increased cell proliferation, and genes downstream of altered E2f
More than forty percent of the mice tested gained the ability to see light clearly. This was a new medical advancement for the science community as no one has ever before been successful in transplanting stem cells that have the ability to sense light. Retinal degeneration is extremely complex to treat until now. Cells need to have the ability to make connections with the host’s nervous system and send signals to the brain. Regardless, many unsolved answers exist. Researchers are still trying to find a way to increase the number of connections between a degenerated retina and the transplant. This would allow the hosts to not only see light but large-scale figures and movement. This is extremely important as retinal degeneration that affects approximately around 170 million people worldwide can led to total blindness. Nevertheless, this advancement comes with many unanswered questions. Researchers are concerned whether this treatment could actually be applied to humans as many risk factors exist. The experiments do not provide information on recovery time in humans nor how the transplanted retinas would respond to the same procedure. Moreover, Scientists contend whether human eyes have different environments from mice. The only way researchers could test human retinal transplants would be from human conducted trails which remain a controversial
To address some identified gaps, several lines of investigation have been proposed. These include the determination of adipocyte contribution to regeneration, investigation of later-stage calcium ion signaling and its potential implications in positional memory, and allografts of cells from zebrafish cancer models into the regenerating fin as a method of locally perturbing the signaling landscape. These novel studies would add valuable information to the knowledgebase of zebrafish fin regeneration that may be translatable to other species, and ultimately, hopefully, able to be applied to enable robust human
In severe diffuse reactive astrogliosis, the astrocytes undergo proliferation, which results in overlapping processes that effect neighbouring cells, their functions and individual domains. Most of the astrocytes express GFAP and other genes. As a result, these changes cause the reorganization
Astrocytes are the most abundant type of glial cells and their organization in the brain is quite complex. Each astrocyte has its own domain and has the ability to reach more than 100 thousand neuronal synapses at once (Halassa, et al. 2007). In fact, the size of astrocytes increase as the brain functionality become more complex that implies that astrocytes are evolutionary old (Kimelberg and Nedergaard 2010). For a long time, it was believed that astrocytes are only function as a structural support. Indeed, astrocytes are contributing to network activity of neurons. They have and important role in neuronal metabolism, providing neurons with necessary nutrients via vasculature and act as a storage of glycogens to sustain