Neuropsychiatric Illness in the Age of Stem Cell Research

Psychiatric illness is a leading cause of disability worldwide with approximately one in five people affected in any given year [1]. A high incidence of treatment resistance across disorders, undesirable pharmacological side effects, and substantial rates of treatment drop out indicate that a significant unmet medical need remains. The way that we think about and treat mental illness has evolved over centuries, beginning with practices such as trephination and bloodletting in ancient times to more behavioral, surgical, and pharmacological approaches in modern times [2]. Without a doubt, treatment of mentally ill patients has a controversial history and modern approaches may seem just as controversial in some ways. Throughout history, common themes and challenges have been recurrent including the fundamental need for accurate diagnosis and improved biological understanding. Psychiatric conditions involve complex higher order processes including motivation, cognition, mood, and social interactions and as such are associated with a high degree of heterogeneity in the genetics and psychopathology, complicating accurate diagnosis and treatment efficacy. In addition, shared symptoms across disorders further challenge accurate diagnosis. Toward improved understanding of cross-disorder similarity and differences, shared genetic architecture was recently demonstrated across 8 mental illnesses, in which 23 single nucleotide polymorphisms were found common to 4 or more of these conditions, potentially helping explain overlapping symptomology [3]. Driven by advances in genetics and neuroscience and motivated to reframe mental illness as dysregulation of normal processes, in 2009, the National Institute of Mental Health (NIMH) launched the Research and Domain Criteria (RDoC) project to advance precision medicine of psychiatric illness by providing a framework for implementing a multidimensional matrix that integrates among other constructs genetic, cellular, neural circuitry, and behavioral units of analysis [4]. Progress in understanding neurodevelopment and research using animal and human models under the RDoC framework holds significant potential for improving clinical translation of basic research studies.

At its core, the basis for advancing biomedical research to treat mental illness is the belief that these conditions have biological etiology that can be investigated such that knowledge of underlying cellular mechanisms and neural circuitry can be translated for therapeutic value [5]. Toward this aim, it is essential that we develop accurate model systems that allow us to test specific hypothesis and observe emergent behavior. Limited by the ethical and tissue resource constraints of experimenting on human subjects and brain matter as well as other pragmatic considerations, murine animal models have been the dominant empirical system for preclinical mental illness research. Although these models have generated a wealth of knowledge and understanding of psychiatric illnesses, there are some limitations in directly translating to patients. Recent advances in cellular reprogramming technology to generate induced pluripotent stem cells (iPSCs) and improvements in directed-differentiation protocols enable researchers to create patient-based in vitro or ex vivo cellular models that can be used to model disease. Human iPSC-based models are beneficial for satisfying species similarity, matched biological context on cell type, and maintaining the patient's genetic background [6]. Although important and necessary, patient-based cellular models have challenges to overcome and inherent limitations. Meeting sufficient neuroanatomical sophistication to faithfully capture detailed processes such as neurogenesis is a daunting hurdle; in practice, both derivation of disease-relevant cell types and recapitulating functional phenotypes remain significant, although surmountable endeavors. Patient-derived stem cell-based models will be invaluable for their high throughput scalability in pharmacological drug screening. Thus, both animal models and patient-derived stem cell-based disease models are complementary systems holding great promise to increase our understanding of neuropsychiatric illness for improving risk prediction, diagnostics, and drug discovery.

In this special issue, we have assembled a collection of concise reviews and original research articles that highlight the latest advances in the use of stem cells to study psychiatric illnesses. In their original research, Bame et al. (in this issue) underscore the complexity of bipolar disorder by identifying microRNAs that are differentially expressed in iPSCs-derived neurons from bipolar patients compared with iPSCs-derived neurons from healthy controls and are involved in key biological processes such as cell migration, axon guidance, and dendrite and synapse development. In complement to this, Louhivouri et al. (in this issue) provide a detailed mechanistic understanding of effectors of neuronal migration and mediation of bipolar to multipolar transition in neocortical cells. In this issue, we are also presenting a collection of four concise reviews that thoroughly detail the usefulness of different stem cell models to understanding disease mechanisms and developing novel treatments. To begin, Donegan and Lodge (in this issue) thoroughly discuss the scalability of neural progenitor cells and the application of more advanced 3D organoid models for improving our understanding of neurodevelopmental disorders such as schizophrenia and autism. Pernia et al. (in this issue) provide a thorough overview of stem cell-based disease modeling to understand neurological disorders, including limitations, and illustrate the potential of iPSC models to generate significant scientific contributions. De Los Angeles and Tunbridge (in this issue) provide a compelling example of using iPSC models to elucidate the molecular impact on neuronal function from mutations in psychiatric illness-associated gene, NRXN1. Rodrigues et al. (in this issue) critically examine the alteration of neural stem cells in brain pathology and their potential as regenerative vessels for treating mental illness and addiction. Taken together, the articles in this special issue illustrate the importance of using stem cell biology and technology to advance our understanding of psychiatric illness and highlight their enormous potential for future studies.

In closing, we express our sincerest thanks to the Editor-in-Chief, Graham Parker, PhD, and the editorial board of the Stem Cells and Development. We strongly appreciate the reviewers for their time and contributions to supporting the peer-review process and are grateful to the authors for their submissions. We are hopeful that this special issue will advance the scientific community's understanding of stem cell research's unique application to improve our understanding of mental illness and increase support for science as a whole.