Special issue on stem cell and tissue engineering in development, disease, and repair

Abstract

Recent advances in cellular reprogramming approaches have revolutionized the field of developmental biology and changed the ways we study human development and disorders. As such, the discovery of induced pluripotent stem cells (iPSCs) and direct fate conversion has provided powerful experimental tools for generating inaccessible human cells and probing the cellular and molecular mechanisms of human tissue development. The ability to generate a homogeneous population of human somatic cells and organized tissue from iPSCs has also provided unprecedented opportunities for regenerative medicine and drug discovery. Progress in the stem cell field has been paralleled by the development of versatile and easy-to-use genome editing technologies, allowing one to directly assess the impacts of diseaseassociated mutations on the development and function of human cells and correct mutations in inherited disorders, which has unleashed additional progress in the field. Thus, this special issue of Developmental Dynamics is devoted to the discussion of recent progress, issues, and opportunities associated with the use of stem cells and reprogramming tools for modeling the normal and pathological development of the nervous system. One of the fundamental, groundbreaking discoveries in developmental biology has been the discovery by Shinya Yamanaka and co-workers demonstrating that terminally differentiated fibroblasts can be reprogrammed into pluripotent stem cells, termed induced pluripotent stem cells (iPSCs), using a combination of embryonic stem cell-enriched transcription factors (Sox2, Oct3/4, c-Myc, and Klf4) delivered through retroviruses (Takahashi and Yamanaka, 2006; Takahashi et al., 2007). Given the pluripotent nature of iPSCs, many researchers have invested efforts in improving the efficiency of reprogramming, developing novel and efficient differentiation protocols for obtaining different cell and tissue types, and devising novel combinations of genetic factors to directly convert iPSCs or differentiated somatic cells to other cell types for modeling human-specific aspects of development and disorders (Fig. 1). It has been demonstrated that iPSCs can be efficiently produced using the identified transcription factors delivered through lentior sendi viruses, episomal vectors, or mRNAs (Chang et al., 2009; Fusaki et al., 2009; Warren et al., 2010; Okita et al., 2011). The use of sendi viruses and episomal vectors are the most common techniques that are currently used due to the improved efficiency of reprogramming and lack of genomic integration of the transgenes, thereby avoiding novel genetic modifications into the reprogrammed cells. There are also many protocols available for cellular differentiation from iPSCs that are constantly modified and refined to improve the differentiation efficiency and enrichment of differentiated cells. For example, the early protocols for generating midbrain dopaminergic neurons had a yield of less than 5% (Nguyen et al., 2011). By contrast, the most updated protocols, which take into consideration the molecular signaling cascades activated during midbrain development, result in the generation of almost a pure population of dopaminergic neurons (Kirkeby et al., 2017), a technical feat that advances the potential of cell replacement-based therapeutic approaches for Parkinson’s disease. Indeed, recently, several clinical trials have been initiated for treating Parkinson’s disease patients with iPSC-derived dopaminergic neurons transplanted in the brains of patients (Barker et al., 2017). Overall, the rapid progress in developing differentiation protocols for iPSCs has indicated the potential of deriving any cell type from iPSCs. This progress has been largely fueled by the lessons learned from studying development in various model organisms. The current special issue contains reviews that examine the developmental aspects of microglial cells (Anderson and Vetter, 2019), as well as cellular interactions and molecular pathways that mediate differentiation of skull cells (Yang and Ornitz, 2019), cell types that have been difficult to generate from iPSCs, with protocols only recently being established for generating human iPSC-derived microglia (Muffat et al., 2016; Abud et al., 2017). In addition, Eun-Jung and coworkers discuss differentiation of iPSCs into dental cells (Kim et al., 2019). iPSC-derived cells have also been widely used for modeling genetic disorders and drug screening. Over the years, diseaserelated phenotypes and potential treatments have been detected in association with several complex developmental disorders including Rett, Timothy, and Phelan-McDermid syndromes (Marchetto et al., 2010; Paşca et al., 2011; Shcheglovitov et al., 2013). In contrast, the late-onset disorders have been difficult to model using iPSC-derived cells due to the alteration of cellular age inherent iPSC. To overcome this limitation, different combinations of genetic factors have been used to allow direct fate conversion of human fibroblast to neurons and production of neurons that maintain age-associated epigenetic marks (Huh et al., 2016). Lineage reprogramming has been used for the generation of striatal Funding for A. Shcheglovitov: Brain and Behavior Research Foundation; US Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health 1R01MH113670-A101; National Institute of Neurological Disorders and Stroke NS104963-01A1; Whitehall Foundation 20150886. Funding for A. Yoo: the Andrew B and Virginia C. Craig Faculty Fellowship Endowment, Cure Alzheimer’s Fund (CAF), Mallinckrodt Scholar Award, NIA (RF1AG056296), and NINDH (1R01NS107488). *Correspondence to: Alex Shcheglovitov, Department of Neurobiology & Anatomy, University of Utah, BPRB 408C, 20 South 2030 East, Salt Lake City, UT 84112. E-mail: [email protected] Article is online at: http://onlinelibrary.wiley.com/doi/10.1002/dvdy. 3/abstract © 2018 Wiley Periodicals, Inc.