iPSCs in NK Cell Manufacturing and NKEV Development.

Natural killer (NK) cell immunotherapies for cancer can complement existing T cell therapies while benefiting from advancements already made in the immunotherapy field. For NK cell manufacturing, induced pluripotent stem cells (iPSCs) offer advantages including eliminating donor variation and providing an ideal platform for genome engineering. At the same time, extracellular vesicles (EVs) have become a major research interest, and purified NK cell extracellular vesicles (NKEVs) have been shown to reproduce the key functions of their parent NK cells. NKEVs have the potential to be developed into a standalone therapeutic with reduced complexity and immunogenicity compared to cell therapies. This review explores the role iPSC technology can play in both NK cell manufacturing and NKEV development.

iPSC-Derived Natural Killer Cells for Cancer Immunotherapy.

The discovery of human pluripotent stem cells (PSCs) at the turn of the century opened the door to a new generation of regenerative medicine research. Among PSCs, the donors available for induced pluripotent stem cells (iPSCs) are greatest, providing a potentially universal cell source for all types of cell therapies including cancer immunotherapies using natural killer (NK cells). Unlike primary NK cells, those prepared from iPSCs can be prepared with a homogeneous quality and are easily modified to exert a desired response to tumor cells. There already exist several protocols to genetically modify and differentiate iPSCs into NK cells, and each has its own advantages with regards to immunotherapies. In this short review, we detail the benefits of using iPSCs in NK cell immunotherapies and discuss the challenges that must be overcome before this approach becomes mainstream in the clinic.

Making Cardiomyocytes from Pluripotent Stem Cells.

The ability to differentiate pluripotent stem cells to cardiomyocyte lineages (PSC-CMs) has opened the door to new disease models and innovative drug and cell therapies for the heart. Nevertheless, further advances in the differentiation protocols are needed to fulfill the promise of PSC-CMs. Obstacles that remain include deriving PSC-CMs with proper electromechanical properties, coalescing them into functional tissue structures, and manipulating the genome to test the impact mutations have on arrhythmias and other heart disorders. This chapter gives a brief consideration of these challenges and outlines current methodologies that offer partial solutions.

Konnichiwa: Japanese scientists and their struggle to speak English: More research careers in Japan need less English.

Japanese students' seeming low proficiency of English is not caused by lack of efforts to internationalize, but rather changing career preferences.

Human Cell Atlas and cell-type authentication for regenerative medicine.

In modern biology, the correct identification of cell types is required for the developmental study of tissues and organs and the production of functional cells for cell therapies and disease modeling. For decades, cell types have been defined on the basis of morphological and physiological markers and, more recently, immunological markers and molecular properties. Recent advances in single-cell RNA sequencing have opened new doors for the characterization of cells at the individual and spatiotemporal levels on the basis of their RNA profiles, vastly transforming our understanding of cell types. The objective of this review is to survey the current progress in the field of cell-type identification, starting with the Human Cell Atlas project, which aims to sequence every cell in the human body, to molecular marker databases for individual cell types and other sources that address cell-type identification for regenerative medicine based on cell data guidelines.

ALS, a cellular whodunit on motor neuron degeneration.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily targets motor neurons. Motor neurons from ALS patients show cytoplasmic inclusions that are reflective of an altered RNA metabolism and protein degradation. Causal gene mutations are found in all cell types even though patient motor neurons are by far the most susceptible to the degeneration. Using induced pluripotent stem cell (iPSC) technology, researchers have generated motor neurons with the same genotype as the patient including sporadic ones. They have also generated other cell types associated with the disease such as astrocytes, microglia and oligodendrocytes. These cells provide not only new insights on the mechanisms of the disease from the early stage, but also a platform for drug screening that has led to several clinical trials. This review examines the knowledge gained from iPSC studies using patient cells on the gene mutations and cellular networks in ALS and relevant experimental therapies.

Application of induced pluripotent stem cells to primary immunodeficiency diseases.

Primary immunodeficiency diseases (PIDs) are a heterogeneous group of rare immune disorders with genetic causes. Effective treatments using hematopoietic stem cells or pharmaceutical agents have been around for decades. However, for many patients, these treatment options are ineffective, partly because the rarity of these PIDs complicates the diagnosis and therapy. Induced pluripotent stem cells (iPSCs) offer a potential solution to these problems. The proliferative capacity of iPSCs allows for the preparation of a large, stable supply of hematopoietic cells with the same genome as the patient, allowing for new human cell models that can trace cellular abnormalities during the pathogenesis and lead to new drug discovery. PID models using patient iPSCs have been instrumental in identifying deviations in the development or function of several types of immune cells, revealing new molecular targets for experimental therapies. These models are only in their early stages and for the most part have recapitulated results from existing models using animals or primary cells. However, iPSC-based models are being used to study complex diseases of other organs, including those with multigenic causes, suggesting that advances in differentiation processes will expand iPSC-based models to complex PIDs as well.

Induced Pluripotent Stem Cells and Their Use in Human Models of Disease and Development.

The discovery of somatic cell nuclear transfer proved that somatic cells can carry the same genetic code as the zygote, and that activating parts of this code are sufficient to reprogram the cell to an early developmental state. The discovery of induced pluripotent stem cells (iPSCs) nearly half a century later provided a molecular mechanism for the reprogramming. The initial creation of iPSCs was accomplished by the ectopic expression of four specific genes (OCT4, KLF4, SOX2, and c-Myc; OSKM). iPSCs have since been acquired from a wide range of cell types and a wide range of species, suggesting a universal molecular mechanism. Furthermore, cells have been reprogrammed to iPSCs using a myriad of methods, although OSKM remains the gold standard. The sources for iPSCs are abundant compared with those for other pluripotent stem cells; thus the use of iPSCs to model the development of tissues, organs, and other systems of the body is increasing. iPSCs also, through the reprogramming of patient samples, are being used to model diseases. Moreover, in the 10 years since the first report, human iPSCs are already the basis for new cell therapies and drug discovery that have reached clinical application. In this review, we examine the generation of iPSCs and their application to disease and development.

Erratum for DOI: 10.31662/jmaj.2018-0005.

[This corrects the article DOI: 10.31662/jmaj.2018-0005.].

Considerations in hiPSC-derived cartilage for articular cartilage repair.

BACKGROUND: A lack of cell or tissue sources hampers regenerative medicine for articular cartilage damage. MAIN TEXT: We review and discuss the possible use of pluripotent stem cells as a new source for future clinical use. Human induced pluripotent stem cells (hiPSCs) have several advantages over human embryonic stem cells (hESCs). Methods for the generation of chondrocytes and cartilage from hiPSCs have been developed. To reduce the cost of this regenerative medicine, allogeneic transplantation is preferable. hiPSC-derived cartilage shows low immunogenicity like native cartilage, because the cartilage is avascular and chondrocytes are segregated by the extracellular matrix. In addition, we consider our experience with the aberrant deposition of lipofuscin or melanin on cartilage during the chondrogenic differentiation of hiPSCs. SHORT CONCLUSION: Cartilage generated from allogeneic hiPSC-derived cartilage can be used to repair articular cartilage damage.

Bringing Induced Pluripotent Stem Cell Technology to the Bedside.

Induced pluripotent stem cells (iPSCs) describe somatic cells that have been reprogrammed to the pluripotent state. From a scientific perspective, their discovery has provided a molecular roadmap for turning on and off cell identities, effectively allowing any cell type to have its identity changed into any other cell type. They also act as a human model for understanding the development of every cell and organ in the body. In addition, because they can be prepared from patients, iPSCs offer a unique human model for studying disease development, including many diseases that are generally diagnosed at a late stage of their development. These models have provided new insights on the pathogenesis and new targets to prevent or reverse the disease development process. Indeed, clinical studies on compounds based on drug screening hits in human iPSC disease models have begun. Because of their proliferation and differentiation capacity, iPSCs can also be used to prepare cells for transplantations, and related clinical studies using iPSC-based cell therapies are ongoing. The combination of iPSCs with other technologies or therapeutic strategies is expected to expand their medical benefits. In this review, we consider medical accomplishments based on iPSC research and future ones that can be anticipated.

Surface Markers Guide the Journey toward Naive Pluripotency.

Several protocols have managed to reset human primed PSCs to the naive state. In this issue of Cell Stem Cell, Collier et al. (2017) report a set of surface markers that identify which cells are susceptible to resetting and suggest a potential roadmap for the acquisition of naive pluripotency.

RNA-based gene circuits for cell regulation.

A major goal of synthetic biology is to control cell behavior. RNA-mediated genetic switches (RNA switches) are devices that serve this purpose, as they can control gene expressions in response to input signals. In general, RNA switches consist of two domains: an aptamer domain, which binds to an input molecule, and an actuator domain, which controls the gene expression. An input binding to the aptamer can cause the actuator to alter the RNA structure, thus changing access to translation machinery. The assembly of multiple RNA switches has led to complex gene circuits for cell therapies, including the selective killing of pathological cells and purification of cell populations. The inclusion of RNA binding proteins, such as L7Ae, increases the repertoire and precision of the circuit. In this short review, we discuss synthetic RNA switches for gene regulation and their potential therapeutic applications.

Ten years of induced pluripotency: from basic mechanisms to therapeutic applications.

Ten years ago, the discovery that mature somatic cells could be reprogrammed into induced pluripotent stem cells (iPSCs) redefined the stem cell field and brought about a wealth of opportunities for both basic research and clinical applications. To celebrate the tenth anniversary of the discovery, the International Society for Stem Cell Research (ISSCR) and Center for iPS Cell Research and Application (CiRA), Kyoto University, together held the symposium 'Pluripotency: From Basic Science to Therapeutic Applications' in Kyoto, Japan. The three days of lectures examined both the mechanisms and therapeutic applications of iPSC reprogramming. Here we summarize the main findings reported, which are testament to how far the field has come in only a decade, as well as the enormous potential that iPSCs hold for the future.

Reprogramming away from the exhausted T cell state.

Induced pluripotent stem cells (iPSCs) describe somatic cells that have been reprogrammed to the pluripotent state from which they can then be differentiated into any cell type of the body. This ability has tremendous implications on a wide number of medical sciences and applications, including cancer treatments. In many cancer patients, tumor infiltrating lymphocytes (TILs) have reached an exhausted state and are unable to exert effector function despite detecting and localizing at the tumor. Although the isolation, ex vivo expansion and transplantation of TILs is effective in a significant group of patients, too many patients do not respond positively to this treatment, in part because the expanded TIL population does not include a sufficient number of cells with the naïve or memory phenotype. Cell reprogramming using iPSC technologies aims to overcome this problem by returning TILs to the pluripotent state from which they can be differentiated into a heterogeneous population of T cells that are best suited to combat the tumor.