Astrocytes are the most prominent type of cells found in the human brain. Despite this fact, until recently, studies on neurons have always overshadowed those on astrocytes. Previously, it was considered that astrocytes only function as structural support to neurons. However, it has now become evident that they are an enormously heterogeneous group of cells with diverse functions and roles to match.
Research on astrocytes and their introduction to neurological disease modeling are turning out to be more and more vital since their effect on neurons and surrounding cell types can be crucial. When neurons are cultured with astrocytes, there is an improvement in neuronal survival, neuronal maturation, and synaptogenesis. Yet, astrocytes that contain genetic mutations could have a detrimental effect on co-cultured, but previously healthy, neurons.
A general review of the function, development, and role of astrocytes in various diseases has been discussed earlier. This article offers a comprehensive description of the role played by astrocytes in Rett Syndrome.
Rett Syndrome, a neurodevelopmental disorder, affects around 1 in 12,000 girls. It is characterized by a period of normal development and symptoms start appearing only after 6 to 18 months. The symptoms include cardiac and breathing problems, seizures, communication difficulties, and repetitive hand movements. Although a normal lifespan can be expected by patients, they have to rely on 24-hour care. At present, there is no cure for this disease.
Mutations in the MeCP2 gene located on the X chromosome lead to this disease. At developmental stages, one X chromosome from each somatic cell is inactivated randomly, causing a mosaic expression of both healthy and mutant MeCP2 alleles. This is the reason for the lethal nature of MeCP2 mutations in boys since they do not have a compensatory healthy MeCP2 gene.
How Does MeCP2 Affect Development in Rett Syndrome?
MeCP2 has the potential to bind to chromatin and recruit factors like HDACs that remodel it into an inactive state. During normal development, neurogenesis takes place first and the changeover to astrogenesis is strictly regulated. While neurogenesis occurs, MeCP2 attaches to methylated portions of astrocyte-specific gene promoters, like GFAP (see Figure 1). With the advance in development, there is a reduction in this methylation and MeCP2 no longer attaches to the promoter, making way for gene transcription.
Figure 1. MeCP2 binds to methylated portions of genes, indicated by the red wavy line. It then recruits chromatin remodelers that remodel chromatin into an inactive state, preventing astrocyte-specific genes from being transcribed during neurogenesis. During neurogenesis, this methylation decreases, therefore MeCP2 cannot bind and the chromatin remodels into an active state. This allows transcription of astrocyte-specific genes, and the commencement of astrogenesis.
This controlled timing leads to the generation of the correct number of neurons and astrocytes. However, in Rett Syndrome, the changeover to astrogenesis takes place very rapidly since MeCP2 is mutated and does not have the ability to remodel the chromatin of the promoters into an inactive state. Hence, there are chances of a very early transcription of astrocyte genes.
Fascinatingly, it is observed that iPSCs in Rett Syndrome patients differentiate more readily into GFAP-positive cells when compared to controls, which can be further confirmed by a rise in GFAP staining in Rett Syndrome brains.
What are Astrocytes Doing? Or What are They Not Doing?
When compared to healthy astrocytes, astrocytes collected from female heterozygous MeCP2-/+ mice exhibited a considerable decrease in the secretion of inflammatory markers IL-6 and IL-1β upon treatment with the immunostimulant lipopolysaccharide (LPS). Moreover, it was found that the MAPK pathway in the MeCP2-/+ mice is hyperphosphorylated, indicating that the pathway was partially activated though there was a lack of external stimulation.
As a result, this could have led to a minimal response to LPS than the healthy astrocytes. The dampened response of pro-inflammatory signaling might indicate that astrocytes in Rett Syndrome are not so potent at initiating a suitable immune response when required, having an effect on the ability of the brains to detect harmful stimuli.
Under control conditions, dendritic growth is boosted by healthy astrocytes upon being co-cultured with healthy neurons. Yet, co-cultures in which astrocytes from the MeCP2-/+ mice and healthy hippocampal neurons are involved led to shorter dendrites and somas. In addition, it was observed that siRNAs targeted against MeCP2 in healthy astrocytes also led to a decrease in dendritic outgrowth, confirming that this impact is because of the MeCP2 deficiency in astrocytes.
A decrease in glutamate clearance was observed in MeCP2-deficient murine astrocytes from another research. This could have a further effect on the neurons since excess glutamate in the synaptic cleft can lead to excitotoxicity in the postsynaptic neuron.
The morphology of healthy iPSC-derived interneurons is detrimentally affected by human iPSC-derived astrocytes produced from Rett Syndrome donors, leading to a decrease in soma size and shorter dendrites. Functionally, this caused a reduction in the frequency of miniature excitatory postsynaptic currents (mEPSCs) but did not have an impact on the amplitude. A decrease in dendritic length and soma size recapitulates what has been noticed in Rett Syndrome animal models. The mechanism underlying the decreased frequency on mEPSCs is not completely understood.
On the whole, it has been found that MeCP2 affects glutamate clearance, cytokine production, electrical signaling, and neuronal morphology, all of which contribute to abnormalities in neurodevelopment.
Can These Phenotypes be Rescued in Models of Rett Syndrome?
The morphology of WT iPSC-derived interneurons was detrimentally affected by human iPSC-derived astrocytes from Rett Syndrome patients; however, in comparison to cultures with Rett Syndrome astrocytes, healthy iPSC-derived astrocytes had a positive effect on Rett Syndrome iPSC-derived interneurons. This further underscores the effect astrocytes can have on neurons in disease.
Reintroducing MeCP2 particularly into astrocytes leads to amelioration of symptoms in MeCP2 null mice. Moreover, astrocyte-conditioned media was found to have an advantageous effect on MeCP2-/- murine neurons, enhancing their dendritic length.
This demonstrates that by targeting astrocytes, some of the negative impacts in Rett Syndrome models can be minimized. When combined with other therapies, treatments that target astrocytes might lead to a positive effect.
This article has demonstrated that astrocytes play a vital role in Rett Syndrome and their function in this disease is worth analyzing. To produce the most translational data possible, it is crucial to take multiple cell types into account while analyzing neurological disease.
Induced pluripotent stem cells offer the capability to produce enormous amounts of different human cells, which would have been highly difficult to obtain earlier. This suggests that cell-based models of neurological diseases can be created without the need for using animal cells or the limited supply of primary human brain cells. Human iPSC-derived cells provide translational models with increased consistency and low variability, offering the potential to help find out innovative treatments and deepen the understanding of Rett Syndrome and other neurological diseases.
About AXOL Biosciences
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