Human iPSC-Derived Astrocytes in Neurological Disorders

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This entry is adapted from the peer-reviewed paper 10.3390/biom12030344

Astrocytes, the most-abundant non-neuronal cell population in the central nervous system, play a vital role in these processes. They are involved in various functions in the brain, such as the regulation of synapse formation, neuroinflammation, and lactate and glutamate levels. The development of human-induced pluripotent stem cells (iPSCs) reformed the research in neurodegenerative disorders allowing for the generation of disease-relevant neuronal and non-neuronal cell types that can help in disease modeling, drug screening, and, possibly, cell transplantation strategies.

human-induced pluripotent stem cells neurodegenerative disease iPSC-derived astrocytes disease modeling

1. Introduction

Neurodegenerative diseases involve chronic and progressive damage to neurons, resulting in various complications such as cognitive impairment, memory deficits, changes in perception and mood, and loss of sensitivity and motor abilities ^[1]. Most neurodegenerative diseases share common pathological pathways such as the over-accumulation of toxic-aggregated proteins, mitochondrial dysfunction, axonal transport defects, excitotoxicity, and chronic inflammation, which lead to neurodegeneration ^[2]. The increasing incidence of neurodegenerative disorders such as Alzheimer’s disease (AD) ^[3], amyotrophic lateral sclerosis (ALS) ^[4], multiple sclerosis (MS) ^[5], and Parkinson’s disease (PD) ^[6] represents a significant impact on global health because of the severity of their symptoms and the lack of effective therapies ^[7].

Due to the complexity of the pathological disease mechanisms and the challenge of accessing human samples, human modeling of neurodegenerative diseases has always been a difficult task. Animal models have commonly been used, due to the intrinsic features of in vivo preclinical experimentation and the possibility to establish ex vivo mechanistic studies. However, animal model studies usually require many animals and take a long time, thus limiting the number of experimental conditions tested ^[8]. The development of induced pluripotent stem cell (iPSC) allowed the creation of a new scenario, complementing animal disease models of neurodegenerative diseases.

In 2007, Yamanaka and colleagues paved the way for this achievement by describing iPSC technology implemented in mice ^[9]. They generate iPSCs from embryonic fibroblasts and adult tail-tip fibroblasts of mice using four transcription factors: Octamer-binding transcription factor 3/4 (Oct3/4), sex-determining region Y (Sox2), the master regulator of cell cycle entry and proliferative metabolism (c-Myc), and Krüppel-like factor 4 (Klf4). This protocol took almost 30 days to generate rodent iPSCs and a further 30 days to differentiate them ^[9]. Subsequent studies showed that human iPSCs could also differentiate into any cell type in the human body; thus, well-established models of human disease, including both developmental and adult-onset diseases, often use iPSCs from patients ^[10]^[11]. Due to the rapid growth of discoveries, it is now possible to differentiate iPSCs from patients and healthy donors in almost all neural cells, allowing human neurodegenerative disease modeling with intrinsic advantages over in-vivo models. Advances in iPSC technology are fundamental to adapt astrocyte research to translational studies since human astrocytes derived from fibroblasts of patients match phenotypes of various neurodegenerative diseases such as AD ^[12]^[13], ALS ^[14]^[15], HD ^[16], and fragile X syndrome ^[17]. Nevertheless, establishing iPSC-derived astrocytes as bona fide models of human astrocytes and individual heterogeneity of in vivo astrocytes should be approached with caution since these cells may modify the phenotype according to the culture conditions ^[18].

2. Astrocytes Phenotypes and Functions

Astrocytes, the most abundant glial cell type in the central nervous system (CNS), play an essential role in neuronal development and function and are very specialized and heterogeneous throughout the CNS. They help maintain synaptogenesis, synaptic plasticity, the extracellular ion concentration, the blood–brain barrier (BBB), promote myelination in the white matter, and support neurons ^[19]. Apart from their fundamental physiological functions, it is generally agreed that astrocytes play a role in toxic/pathological events and that their dysfunction can generate neurological disorders such as neurodegenerative diseases, neurodevelopmental diseases, epilepsy, and astrogliomas ^[20]. In classical taxonomy, protoplasmic and fibrous astrocytes are two prominent gray and white matter classes, respectively ^[21]. Astrocytes form large homologous networks linked by gap junctions and heterologous networks with oligodendrocytes in different brain regions ^[22]^[23]. Recent studies showed that astrocytes change their morphology and function depending on age and their location in the brain ^[24]^[25]^[26]^[27].

Reactive gliosis is defined as changes in the neuroglia morphology, representing an actual reaction rather than a simple indicator of noxious influences on the CNS. Accordingly, the terms “reactive astrogliosis” and “astrocyte reactivity” define a pathological event that determines morphological, biochemical, and metabolic remodeling other than transcriptional regulation, which translates into the gain or loss of homeostatic functions ^[28]. Thus, morphology does not represent the only way to depict the role of astrocytes in neuropathologies since it does not correlate with functional phenotypes or their ability to impact the biology of other cells. Overall, the impact of reactive astrocytes varies and is complex and may depend on the pathological condition, which can be beneficial in one disease and detrimental in another ^[29]. The scenario is even more complex due to the presence of reactive microglia. Microglia can shift astrocyte signaling from a physiological to pathological status by increasing the production of factors such as tumor necrosis factor α (TNFα), which in turn has been reported to alter synaptic functions and behavior ^[30].

Specific molecular profiles and functions characterize the reactivity of astrocytes and their distinct impact on diseases and produce astrocyte phenotypes, representing the unique outcome of a given state. Notably, astrocyte reactivity characterizes pathological contexts while astrocyte activation represents physiological conditions ^[31]. Astrocyte reactivity is secondary to extrinsic signals and may evolve differently, exhibiting pathological modification and etiological features with a remarkable impact on disease progression ^[32].

In recent decades, scientists dramatically accelerated their research and deepened the roles of astrocytes, thanks to new interdisciplinary approaches combining omics with physiology and genetics. In this context, transcriptomics and proteomics have shown that in the healthy brain, following embryonic patterning programs or local neuronal cues, astrocytes are specialized to perform specific tasks in distinct CNS circuits ^[33]. The advent of genetic engineering opened a new research phase based on astrocyte-targeted manipulation, thus extending studies on detrimental astrocyte phenotypes. These studies identified other functional alterations in reactive astrocytes involving neurotransmitter and ion buffering, gap junctions, phagocytic activity, metabolic coupling, and most importantly, increased neuronal death due to the release of toxic factors and not merely the loss of trophic or antioxidant support from astrocytes ^[30].

This evolution generated the need to unify the nomenclature and refine the concepts that precisely define astrocyte heterogeneity by using a systematic approach to contextualize the contribution of astrocytes to CNS disorders. Recent studies have proposed that mouse astrocytes have two discrete pathological conditions: The A1 neurotoxic phenotype when exposed to specific cytokines secreted by activated microglia and the A2 neuroprotective phenotype when exposed to an experimental paradigm mimicking ischemic stroke ^[34]^[35]. However, this binary polarization should be approached cautiously since more recent studies recommend moving beyond the A1–A2 classification ^[30]. Indeed, only a subset of mixed A1 and A2 or pan-reactive transcripts are up-regulated in astrocytes of human patients or mouse models of chronic diseases or acute CNS injuries ^[36]^[37]^[38]^[39]. Moreover, advanced multidimensional data and the co-clustering statistical approach revealed that the A1 and A2 transcriptomes represent only two of the many potential astrocyte transcriptomes. As transcriptomic data are a fundamental tool used to characterize the functional diversity of reactive astrocytes, a multidimensional analysis should be applied to establish the uniqueness of astrocyte phenotypes ^[40].

3. Human iPSC-Derived Astrocytes in Neurological Disorders

The classical drug discovery and validation method has some drawbacks, such as time-consuming procedures, the need for many animals for experiments, and the testing of a limited number of compounds under limited experimental conditions. Recent advancements in the available techniques led to high-throughput screenings, which can test hundreds or even thousands of compounds in less time and with lower relative costs. Although these procedures are more efficient than previous ones, they have poor validation rates due to the rare biological relevance of the screening platforms when related to the disease to treat and the use of non-human derivatives, which may not be related to specific human biology. The great advantage of using iPSC technology in developing treatments for human disease is evident.

3.1. Alzheimer’s Disease

AD is an age-related neurodegenerative disease that mainly affects memory and executive functions, which induce behavioral and neuropsychiatric changes. AD is characterized by the accumulation of amyloid-beta (Aβ) plaques and TAU-laden neurofibrillary tangles ^[41]. Almost 40 million people worldwide have dementia, most of them older than 60 years. This number is rapidly increasing and is estimated to double by at least 2050 ^[42], overtaking cancer as the second leading cause of death after cardiovascular diseases ^[43]. There is no treatment to stop the disease progression; therefore, identifying the exact cause and mechanism is most important.

Astrocytes play an essential role in the pathology of AD. They are reported to be involved in various brain functions and are known to become reactive in different disease pathologies, changing their gene expression profile and metabolism ^[44]. Astrocytes maintain neuronal excitability and synaptic transmission by regulating ion concentrations. Astrocytes also constitute a significant source of cholesterol and other lipids critical for many cellular functions, as well as lipoproteins such as APOE, which are essential regulators of brain Aβ clearance and degradation ^[45]. Astrocytes of AD patients have shown increased GFAP expression and gamma-aminobutyric acid (GABA) production and release ^[46]. Furthermore, Aβ accumulates in AD astrocytes.

3.2. Parkinson’s Disease

PD affects 7 to 10 million people worldwide, making it the second-most prevalent neurodegenerative disease after AD. Most PD cases are sporadic (85%), and only 15% of patients show familial mutations ^[47]. There are several hypotheses behind PD pathogenesis, including neuroinflammation, mitochondrial dysfunction, dysfunctional protein degradation, and alpha-synuclein (α-synuclein) pathology, but the exact cause is still unknown ^[48]^[49]^[50]. PD is mainly characterized by the loss of ventral midbrain dopaminergic neurons in the substantia nigra pars compacta and the presence of Lewy bodies in the brain. These pathological changes are considered responsible for the typical motor symptoms (bradykinesia, rigidity, rest tremor, and postural instability) seen in PD ^[51]^[52]. There is no proper cure for PD, and most interventions are aimed at relieving the motor symptoms with either dopamine replacement therapy or surgery ^[53].

In the early 1980s, researchers used fetal DA neural cells of human origin in a PD rat model for therapeutic purposes. They demonstrated that PD rats successfully restored functional activity after transplantation ^[54]. Ten years later, another group found a way to translate this approach to patients. They successfully transplanted human fetal DA neurons in a severe PD case, which engrafted and improved motor functions ^[55]. With the precedence of previous research, transplantation of iPSC-derived DA neurons is becoming a therapeutic opportunity for PD patients ^[56]. Some preclinical and clinical studies have used iPSC-derived DA neurons in PD rats and human models, demonstrating that neurons successfully improved motor functions and survival rate for at least two years ^[57]^[58]. In 2018, the so-called “Kyoto clinical trial” was started. The authors efficiently induced dopaminergic neurons from human iPSCs and purified dopaminergic progenitor cells by sorting. After in vivo preclinical studies in rats and monkeys, cell-based therapy for PD was started in humans ^[59]. At present, seven patients have been recruited, and the recruitment is now closed.

Apart from DA neurons, the contribution of glial cells to the pathogenesis of PD has been considered. A study compared the functionality of iPSC-derived astrocytes and dopaminergic neurons obtained from PD patients with the p.Gly2019Ser mutation and healthy controls. They found that astrocytes from PD patients secreted α-synuclein, which exerted a neurotoxic function on surrounding dopaminergic neurons, resulting in neuronal dysfunction. They also found dysfunctional chaperone-mediated autophagy and progressive α-synuclein accumulation in the PD iPSC-derived astrocytes ^[53].

Transplantation is a growing field in PD involving iPSC-derived dopaminergic neurons. Further, the knowledge of the role of astrocytes is increasing. This occurrence can be essential in identifying pathological astrocytic phenotypes in human stem cell models of familial and sporadic PD.

3.3. Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of cortical and spinal cord motor neurons, causing muscle weakness, atrophy, and paralysis, with the death of patients by respiratory failure within 3–5 years after diagnosis ^[60]. ALS is a rare disease, affecting about 2–3 in 100,000 individuals, and approximately 90% of ALS cases are sporadic (sALS) due to multiple genetic, epigenetic, and environmental factors, while about 10% are familial (fALS), which is clinically indistinguishable from sALS ^[61]. Mutations in more than 20 genes are associated with fALS, the most important being mutations in the chromosome 9 open reading frame 72 protein (C9orf72), superoxide dismutase type 1 enzyme (SOD1), 43 kDa transactive response-DNA binding protein (TARDBP, TDP43), and fused in sarcoma/translocated in liposarcoma protein (FUS/TLS) ^[62]^[63]. ALS is a complex disease due to its multiple causes, also involving non-neuronal cells ^[64]^[65]. In particular, astrocytes have a detrimental role in ALS progression ^[66]^[67] with several mechanisms, including excitotoxicity, altered astrocyte metabolism, inflammation, and oxidative stress ^[68]^[69]^[70]^[71].

ALS is a multi-factorial and multi-cellular disease where many genes play a decisive role, thus highlighting the limitations of animal models, each characterized by a specific gene mutation. Having access to samples from patients with different genetic signatures or sporadic is a significant advantage for the knowledge of pathology and stratifying the results based on individual patients.

3.4. Huntington’s Disease

HD is a hereditary, neurodegenerative disease caused by cytosine–adenine–guanine (CAG) repeat expansion in the huntingtin (HTT) gene, which codes for glutamine ^[72]^[73]. CAG repeats result in a polyglutamine tract, leading to progressive involuntary motor movements, cognitive disturbances, and dementia ^[74]^[75]. HD affects about 12 per 100,000 individuals in the European population ^[76]. The disease can occur from childhood to old age, with a mean age at onset of 45 years ^[77], and CAG extension strongly correlates with disease onset ^[78]. The HTT gene has critical roles in cellular homeostasis processes such as transcription, protein-protein interactions, transport, mitochondrial functions, cellular stress responses, and vesicular trafficking ^[79]. However, in pathological conditions, a mutation in the HTT gene by CAG expansion in exon 1 results in the expansion of polyglutamine residue at the N-terminus of the HTT protein ^[72]. A previous study also reported the formation of small oligomeric fragments and protein accumulation in the nucleus, leading to the death of medium spiny neurons (MSNs) in the striatum and other regions ^[79].

While neuron degeneration plays a critical role in the pathology of HD, glial cells are also involved. Dysfunctional astrocytes in the striatum lead to alteration of astrocytes structure and abnormalities of electrical properties, thereby maintaining ion homeostasis and neuronal signaling through the release of glutamate and adenosine triphosphate ^[80] and increasing pro-inflammatory and reducing anti-inflammatory cytokine production, as well as the brain-derived neurotrophic factor (BDNF) and Ccl5/RANTES chemokine ^[81].

From the studies in the literature, it appears that patient-derived astrocytes present apparent pathological features of the disease. Thus, iPSCs-derived astrocytes show promise as a valuable tool for HD modeling and emerge with great potential in approaches to cell replacement therapy.

3.5. Multiple Sclerosis

MS, a chronic, auto-immune, demyelinating CNS disease, is the leading cause of neurological disability in young adults ^[82]^[83]. The symptoms start with acute episodes of neurological dysfunction, followed by a relapsing-remitting course (RRMS) ^[84]. Later, approximately 80% of patients develop secondary progressive MS leading to permanent disability, including limb weakness, sensory loss, vision disturbances, pain, and muscle spasms. The remaining patients directly reach the progressive phase, referred to as primary progressive MS ^[84]^[85]. The pathology of MS remains mostly unexplained; however, shreds of evidence suggest that activated immune cells from the periphery migrate to the CNS, forming lesions characterized by primary demyelination and relative preservation of axons ^[82]. Currently, available disease-modifying treatments are proven to suppress the inflammatory components in RRMS; however, these drugs are practically ineffective in progressive forms ^[83].

Reactive astrocytes are instrumental in forming MS plaques from the early stages of the disease, recruiting lymphocytes and damaging tissue, confining inflammation, and promoting lesion repair ^[82]^[86]. Reactive astrocytes contribute to the various neuroinflammatory responses, including the production of and reactivity to soluble mediators (e.g., cytokines and chemokines), but they also regulate oxidative stress and maintain BBB integrity and function ^[87]. Moreover, various studies suggest that reactive astrocytes are associated with a detrimental effect by exacerbating inflammation and inhibiting regeneration; meanwhile, they can also contribute to neuroprotection ^[82]^[86]^[87]^[88]. These results highlight the complex and dual role of astrocyte-mediated regulation during disease progression.

iPSC-derived astrocytes represent an attractive approach to enhancing the knowledge of astrocyte dysfunction contributing to MS etiology ^[18]^[82]^[89]. However, at present, only two studies have been conducted on iPSC-derived astrocytes assessing the risk variants leading to MS susceptibility, with contradictory conclusions ^[18]^[89].

Astrocytes can have different roles in MS pathology depending on the pathological stage, the damage mechanisms considered, and the patient. Studies in the literature have not yet elucidated the mechanisms that give astrocytes this dual role. Therefore, the iPSC-derived astrocyte model is a robust platform that can help evaluate these aspects and highligh therapeutic targets capable of modifying the harmful elements of astrocytes in MS or enhancing the positive ones.

3.6. Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is an autonomous hereditary disease characterized by a loss of motor neurons leading to muscle atrophy, respiratory failure, and death ^[90]^[91]^[92]. SMA is a rare disorder with a frequency of 1:11,000 individuals; however, it is the leading cause of infant death ^[90]^[91]^[92]. SMA is mainly caused by deletion or mutations of the survival motor neuron 1 (SMN1) gene on chromosome 5q, which codes for the SMN protein, found in neuronal and non-neuronal cells, including astrocytes ^[92]^[93]. This protein is essential for normal development and functional homeostasis in all species. Humans carry a second, closely related gene, called SMN2, an SMN1 homolog that can also produce the SMN protein. The greater the number of copies of this gene, the milder the SMA ^[94]. Currently, there are only four approved drugs for SMA: Nusinersen, onasemnogene, abeparvovec, and risdiplam; however, their long-term benefits remain to be assessed ^[95].

Astrocytes are crucial components contributing to MN damage and loss in SMA ^[90]^[92]^[96]. Restoring SMN selectively in astrocytes using scAAV-SMNgfap viral delivery, Rindt and colleagues ^[92] observed improved neuromuscular circuitry and an increase in the number and lifespan of neuromuscular junctions. They also hypothesized that astrocyte functions are disrupted in SMA, measured by the increased number of GFAP-positive cells and elevated production of pro-inflammatory cytokines. This increased expression of inflammatory cytokines was partially normalized in treated mice, suggesting that astrocytes contribute to the pathogenesis of SMA ^[92].

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Marco Milanese

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