Stem cells are characterized by their ability to self-renew and differentiate into multiple adult cell types. Although substantial progress has been made over the last decade in understanding stem cell biology, recent technological advances in molecular and systems biology may hold the key to unraveling the mystery behind stem cell self-renewal and plasticity. The most notable of these advances is the ability to generate induced pluripotent cells from somatic cells. In this review, we discuss our current understanding of molecular similarities and differences among various stem cell types. Moreover, we survey the current state of systems biology and forecast future needs and direction in the stem cell field.

Introduction

Stem cells have the remarkable ability to self-renew, as well as to differentiate into multiple cells types in response to extra-cellular signals. Thus, they are not only valuable research tools to understand cellular reprogramming and human disease, but hold tremendous promise in regenerative medicine. Since the creation of human embryonic stem cells a decade ago, tremendous progress has been made in the field. Although this technology has yet to yield human therapeutics, earlier this year, the world's first human embryonic stem (ES) cell–based therapy was approved for clinical trial in patients with spinal cord injuries (Geron Corp., Menlo Park, CA, USA). Also, the factors required to create induced pluripotent stem (iPS) cells from terminally differentiated somatic cells have been identified within the past 2 years (1,2,3,4). These iPS cells have the potential to revolutionize patient-specific, cell-based therapy. While the generation of iPS cells is a giant leap for stem cell biology, it highlights some of the basic processes that still remain beyond our understanding. Specifically, while the factors required for reprogramming are now known, the mechanism by which these genes control the process and why these genes alone are sufficient for the production of iPS cells remains unknown.

Therefore, to realize the true potential of stem cells, and in order to safely manipulate cellular signaling, there is a need for unprecedented knowledge of the regulation of these cells. Such knowledge will be derived from the integration of gene expression, protein expression, and epigenetics. Specifically, we need to illuminate the networks that regulate pluripotency and self-renewal. This review examines the current status of stem cell biology with an emphasis on recent progress and emerging molecular technologies that will help address crucial questions as we stand at the threshold of realizing the promise that stem cells hold in the field of regenerative medicine.

Stem cells, pluripotency, and self-renewal

There exist several different types of stem cells, each of which has unique properties and advantages. Comparisons between these stem cells, with varying self-renewal and plasticity, provide insights into the molecular mechanisms controlling these processes.

Adult stem cells are undifferentiated cells, found among differentiated cells within a tissue or organ, which are capable of limited self-renewal and are multipotent (may differentiate to form several types of cells). Hematopoietic stem cells (HSCs) are stem cell progenitors that have contributed to most of our current knowledge about adult stem cells. HSCs are multipotent cells predominantly found in the bone marrow that give rise to the different kinds of blood cells. Owing to vast amounts of research, HSCs have been used in therapeutic transplantation for decades. Bone marrow also harbors mesenchymal stem (MS) cells that are multipotent cells that give rise to chondrocytes, osteocytes, and adipocytes. In addition, adult stem cells are found in most organs of the body, including the brain (neural stem cells), liver, lungs, heart, intestines, skin, and muscles (5). Although adult stem cells cannot be expanded in culture indefinitely, their use lacks the ethical constraints surrounding the use of embryonic stem cells. Moreover, autologous transplantation of these cells (when possible) circumvents the problem of immune rejection, making them a preferred choice for cell-based therapies.

Human umbilical cord blood has been used in transplantation for over two decades now, as it is considered to be a valuable source of cord blood stem cells that comprise both hematopoietic and non-hematopoietic stem cells (6). Cord blood stem cells are of particular interest in cell therapy due to their plasticity, lower immunogenic properties, abundance of progenitors and immature cell types, as well as the ease with which they can be obtained and banked (7). Several disorders (including sickle cell anemia, thalassemia, severe combined immune deficiency, aplastic anemia, Fanconi's anemia, and glycogen storage diseases) are currently treated with transplantation of cord blood. Also, the ability to generate cells of neural lineage from cord blood stem cells holds tremendous promise for treatment of neurodegenerative diseases (8).

Embryonal carcinoma (EC) cells were first derived from human teratocarcinomas in 1977 (9), about two decades after the establishment of mouse EC cells (10). These cells were extensively studied for their potential to differentiate into multiple cells types, but the use of human EC cells is limited by their aneuploid nature. However, this research helped establish culture conditions and provided the framework for derivation of embryonic stem (ES) cells.