Induced Pluripotent Stem Cells as a Novel Tool in Psychiatric Research

Abstract

Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) provides a valuable opportunity to study neurodevelopmental and neurodegenerative psychiatric diseases by offering an unlimited source for patient-specific neuronal and glial cells. The present review focuses on the recent advancements in modeling psychiatric disorders such as Phelan-McDermid syndrome, Timothy syndrome, Rett syndrome, schizophrenia, bipolar disorder, and dementia. The treatment effects identified in studies on iPSCs using known therapeutic compounds are also summarized in this review. Here we discuss validation of cellular models and explore iPSCs as a novel drug screening tool. Although there are several limitations associated with the current methods used to study mental disorders, using iPSCs as a model system provides the advantage of rewinding and reviewing the development and degeneration of human neural cells.

The ups and downs of cellular stress: the “MAM hypothesis” for Bipolar disorder pathophysiology

“…Furthermore, activation of the immune system has been consistently reported in BD [120,121] and in the last few years, evidence has been emerged implying activation of the NLRP3 inflammasome in BD pathophysiology [17]. Altered levels of inflammatory cytokines were shown in the brain and periphery of patients with BD, suggesting that activation of the inflammatory system may play a role in the pathophysiology of BD [120].…”

“…In fact, increased ROS production in result of inhibition of complex I of the mitochondrial respiratory chain led to increased levels of inflammatory factors such as IL-1, caspase 1, and NF-B and was recently linked to activation of an inflammatory redox sensor, the NLRP3. Post-mortem analysis of frontal cortex from BD patients showed lower levels of complex I and NDUFS7, a subunit of complex I, concomitantly with higher levels of mitochondrial NLRP3 and ASC and increased levels of caspase 1, IL-1β, IL-6, TNFα and IL-10 [17], suggesting that brain immune-activation in patients with BD is associated with mitochondrial dysfunction and NLRP3-inflammasome activation. Because inflammasome activation is recognized as a regulatory function associated with the specific membranous ER-mitochondria microdomains [122] a link between interorganelle miscommunication and NLRP3 activation in BD can be anticipated.…”

“…Cellular modeling in BD using lymphoblastoid cell lines, fibroblasts, olfactory neuronal epithelium and neurons reprogrammed from induced pluripotent stem cells (iPSCs) [16][17][18], has proven useful to understand its biological basis, and potential pathways have been identified, especially in cellular resilience-related mechanisms. The most replicated findings that show consistency with genome-wide association studies (GWAS), brain-imaging and post-mortem brain expression include abnormalities in endoplasmic reticulum (ER)-related stress responses, mitochondrial function and Ca 2+ signaling, which are often reversed in vitro with lithium.…”

“…These alterations can explain several clinical features such as the progressive shortening of inter-episode interval with each recurrence occurring in consort with reduced probability of treatment response as the illness progresses. This hypothesis is supported by recent genetic studies in postmortem prefrontal cortex samples, which identified the EGR3 regulatory unit (regulon) that translates environmental stimuli into long-term changes in the brain to be robustly repressed in BD patients [15], further suggesting that an impaired response to stress influences BD risk.Cellular modeling in BD using lymphoblastoid cell lines, fibroblasts, olfactory neuronal epithelium and neurons reprogrammed from induced pluripotent stem cells (iPSCs) [16][17][18], has proven useful to understand its biological basis, and potential pathways have been identified, especially in cellular resilience-related mechanisms. The most replicated findings that show consistency with genome-wide association studies (GWAS), brain-imaging and post-mortem brain expression include abnormalities in endoplasmic reticulum (ER)-related stress responses, mitochondrial function and Ca 2+ signaling, which are often reversed in vitro with lithium.…”

Genetic Expression of Metabotropic Glutamate Receptor 7 in Schizophrenic Patients Using Human Induced Pluripotent Stem Cells

“…However, in animal models, there are species-specific differences between the human and animal brain and the lack of translatable animal models, particularly for the disorders in which higher function is involved. In order to overcome these limitations, the generation of a new study model was necessary for developing the knowledge of the neurobiology of human psychiatric diseases (8) . This was achieved through modeling of neuropsychiatric disorders through human induced pleuripotent stem cells (hIPSc) which depended on reprogramming of somatic cells into hIPSc then differentiating it into human neurons and glial cells.…”