Due to the difficulty of obtaining human brain tissue for experimental studies, scientists have begun using induced pluripotent stem cells (iPSCs) to generate several representative models to study human neurological diseases. iPSCs can be differentiated or reprogrammed to form multiple neuronal or glial cell types that are directly relevant to a particular disease, therefore, they have great potential as cell-replacement therapies for neurological diseases, especially neurodegenerative disorders. iPSC-based stem cell therapy has become a very promising and advanced scientific research topic in neurosciences.
Fig.1 A schematic for iPSC modeling of neurological diseases. (Li, 2018)
AD is a devastating and progressive neurodegenerative disease that mainly affects the aging population. Patients display a progressive loss of cognition and disruption of basic functions, such as swallowing, walking, attention, and memory. Currently, FDA approved treatment for AD mainly target cholinergic and/or glutamatergic neuronal function, which provides modest and transient cognitive benefit, but do not alter disease course or underlying neurodegeneration. In the past decade, countless promising therapeutics have shown efficacy in rodent Alzheimer's disease models, but failed to benefit human patients. Fortunately, iPSC technology has ushered in a new era of AD study.
Several groups have successfully generated AD patient-specific iPSC-derived neuron lines and complex co-culture systems that greatly facilitate neuroscience research. Yagi et al. first generated iPSCs-derived neurons from AD patients carrying presenilin 1 or 2 (PS1, PS2) mutations, which revealed elevated levels of β-amyloid (Aβ), thus confirming the amyloid cascade hypothesis. Furthermore, iPSC-based genome editing tools are critical in understanding the roles of the numerous new genes and mutations found to modify Alzheimer's disease risk in the past decade. In the field of AD drug and toxicity screenings, iPSC derived neuronal cells also play important roles. Both studies have shown the potential that iPSC represents in modeling AD and allow it to investigate the pathogen pathways of this disease, holding considerable promise to push forward efforts to combat AD.
PD is the second most common neurodegenerative disease, behind only to AD, affecting more than 1% of the population over 65 years of age. Patients may display progressive motor dysfunction, including bradykinesia, tremors and muscle rigidity, as well as non-motor symptoms that include intestinal dysfunction, depression, cognitive decline and sleep disturbances. The representative pathological hallmarks are the presence of Lewy bodies composed of alpha-synuclein (α-syn) protein beyond the nigra and the cortex. In the past PD research, researchers mainly use patients' post-mortem tissues, animal models, or immortalized cell lines to dissect cellular pathways, but they failed to faithfully capture key mechanisms at play in the human brain.
The emergence of iPSCs has revolutionized PD research, allowing for the differentiation and growth of human dopaminergic (DA) neurons in vitro, holding immense potential not only for modeling PD, but also for screening promising drugs and identifying novel therapies. Using iPSC-derived neurons, scientists have intensively investigated the connection between PD-associated risk genes, such as LRRK2, PARK2, PINK1, DJ1, SNCA.
HD is an inherited, autosomal dominant neurodegenerative disease characterized by involuntary movements, cognitive decline, and behavioral impairment ending in death. Mutations in the huntingtin gene (HTT) lead to an expansion in the number of CAG repeats, causing psychiatric and physiologic alterations. To date, there is no effective therapy for preventing the onset or progression of this disease.
The development of iPSC technology helps elucidate the etiopathology of HD. In 2010, cells from HD patients were first reprogrammed into iPSC and investigated the alterations in electrophysiology, cell metabolism, adherence and toxicity. Scientists created genetically corrected HD iPSCs lines and further differentiated them into neural stem cells (NSC), which displayed normalized pathogenic TGF-β and cadherin signaling pathways. Moreover, they transplanted these NSCs into a transgenic HD mice model, which populated the striatum after a two-week post-transplantation period. This study uncovered the potential of stem cell replacement therapy in HD.
SMA is an autosomal recessive neurodegenerative disease caused by a genetic defect in the survival motor neuron 1 (SMN1) gene resulting from deletions or other mutations. It is characterized by selective and progressive degeneration of spinal cord motor neurons and muscular atrophy on limbs and trunk.
iPSC as research tools to generate more relevant models of SMA pathophysiology and advance the drug discovery process. It has been documented that iPSCs generated from skin fibroblasts from SMA patients and genetically corrected are proposed to be useful for autologous cell therapy. When transplanted of the corrected motor neurons derived from SMA-iPSCs into an SMA mouse model, they extended the life span of the animals and improved the disease phenotype.
ALS is a heterogeneous motor neurodegenerative disease characterized by progressive degeneration of motor neurons in the cortex, brainstem and bone marrow, leading to paralysis. Although ALS has been studied for many decades, scientists have only partially revealed the pathophysiology and no effective treatment is available.
Using iPSC technology to generate differentiated cells retaining ALS patients' full genetic information, scientists have established various in vitro ALS models. These models help to determine the relationship between cellular phenotype and genotype, facilitate the development of new drugs and/or drug screening, and allow the exploration of novel ALS therapy.
In addition to AD, PD, SMA and ALS, there are a lot of other neurological diseases benefited enormously from iPSC technology, such as Duchenne muscular dystrophy (DMD), familial dysautonomia (FD), autism, epilepsy and so on. Because of their patient specificity and ability to differentiate into a variety of cell types both in vitro and in vivo, iPSCs have been the most suitable among the various types of autologous stem cells with an unlimited cell source. These iPSC-derived neural cells provide valuable tools to study neurological disease mechanisms, develop potential therapies, and deepen our understanding of the nervous system.
With years of experience in stem cell therapy development, Creative Biolabs provides high-quality iPSC reprogramming, differentiation, iPSC pluripotency characterization services to promote customers' research in neurological diseases. Please feel free to contact us for a discussion with our scientists.
Reference
For Research Use Only. Not For Clinical Use.
