Stem cells as role models for reprogramming and repair.

Stem cells are a promising source for cellular therapies across many diseases and tissues. Their inherent ability to differentiate into other cell types has been the focus of investigation over decades. This ability is currently being exploited for therapies using strategies to repair or replace damaged tissues and cells or to alleviate immune rejection. Exploring stem cell function has enabled direct reprogramming approaches, for example, through the production of induced pluripotent stem cells and the generation of tissue-specific stem cells. Understanding stem cell function has emerged as an important strategy for repopulating stem cell pools or generating differentiated cells for therapy. Here, we review general principles of mammalian stem cell biology and cellular reprogramming approaches and their use for current and future therapeutic purposes. Editor's summary: Stem cells have long held promise for cellular therapeutics. Recently, advances in the understanding of stem cell biology have led to an increased number of stem cell–based therapies in the clinic and in clinical trials. Götz and Torres-Padilla reviewed recent insights into the basic biology of mammalian stem cells and current and future prospects for stem cell use in regenerative medicine and other therapies. —Stella M. Hurtley BACKGROUND: Stem cells can generate many different cell types, which makes them useful for understanding developmental mechanisms and as a source to replace cells in disease conditions. Developing stem cell therapies takes time, but there are now many clinical trials in progress. Stem cells start everything off from the very beginning of development as totipotent cells that can generate a complete new being. Later in development, pluripotent stem cells (PSCs) that can generate all cells of the body are produced. During further development, tissue-specific stem cells arise and generate progeny that form tissues and organs. The process of differentiation is governed by the surrounding environment (the niche) and the action of specific transcription factors, which are typically lineage restricted. In the adult organism, some tissues and organs are endowed with adult stem cells, which ensure the natural cycles of tissue turnover and homeostasis seen, e.g., in the skin, intestine, and the hematopoietic system. Such adult stem cells can become activated for tissue repair upon injury or degenerative diseases. However, some adult organs do not have a readily available stem cell pool or the pool changes or becomes exhausted during aging. These organs are typically difficult to repair, but using cellular reprogramming inspired by mechanisms of stem cell differentiation can provide a solution. ADVANCES: Stem cells inspired direct cellular reprogramming because this approach relies on activating developmental fate determinants from tissue-specific stem cells such as those in the muscle or brain or from PSCs. These potent transcription factors are used to instruct cell fate conversion, and this has arisen as a powerful method to generate cells for repair or disease modeling. A foundational discovery in this area is the reversion of somatic cells into a pluripotent state by the so-called Yamanaka transcription factors, which allow the generation of induced PSCs (iPSCs). This discovery has enabled differentiated somatic cells from patients to be reprogrammed to a pluripotent state. In organs without stem cells, natural dedifferentiation or fate conversion can occur, which can be exploited for cellular replacement approaches. Recently, a plethora of reprogramming paradigms have emerged as approaches to repair, and these are now being used to convert cells across germ layers and cell types across a multitude of organs. These experiments have elucidated the mechanisms of cell fate acquisition, conversion, and maintenance and are an advance toward replacing cells in disease conditions. In addition, direct reprogramming has opened entirely unexpected avenues, such as organismal rejuvenation upon transient expression of some of the pluripotency factors in vivo. OUTLOOK: The number of clinical trials with stem cells or their derivates has increased tremendously in recent years, with many using iPSCs. These approches can enable the use of the patient's own cells as therapeutics. Remarkable progress has been made in bringing stem cell–based methods and stem cell–inspired reprogramming toward clinical testing with promising outcomes, e.g., in diabetes, macular degeneration, epilepsy, and Parkinson's disease. However, therapeutic approaches have also followed unexpected avenues, such as aiming to reprogram cancer cells into antigen-presenting immune cells. Leveraging the knowledge acquired through decades of basic research on the features and functions that characterize stem cells is now enabling the design of unexpected treatment options. These findings, emerging primarily through our understanding of the developmental trajectories that stem cells follow, have guided the choice of strategies deployed in the use and manipulation of isolated stem cells. We anticipate that reprogramming strategies for repair will open new avenues to generate cell types that have not been accessible or replaceable in disease until now. The inspiration from stem cells will hopefully continue to take us into a bright future to foster understanding and discovery of approaches for treatment. Uses of stem cells in research.: Shown are the properties and uses of stem cells during natural development and tissue turnover and in applied and clinical research. [ABSTRACT FROM AUTHOR]