Stem Cells A New Lease on Life

offspring, including the germ cell compartment. To During embryogenesis, a single fertilized oocyte gives maintain cultured ES cells in their relatively undifferentirise to a multicellular organism whose cells and tissues ated, pluripotent state, they must both express the inhave adopted differentiated characteristics or fates to trinsic transcription factor Oct4, and constitutively reperform the specified functions of each organ of the ceive the extrinsic signal from the cytokine leukemia body. As embryos develop, cells that have acquired their inhibitory factor (LIF) (Nichols et al., 1998; Niwa et al., particular fate proliferate, enabling tissues and organs 1998 and references therein). to grow. Even after an animal is fully grown, however, Upon LIF withdrawal, cultured ES cells spontaneously many tissues and organs maintain a process known as aggregate into embryo-like bodies, where they differenhomeostasis, where as cells die, either by natural death tiate and spawn many cell lineages, including beating or by injury, they are replenished. This remarkable feature heart muscle cells, blood islands, neurons, pigmented has ancient origins, dating back to the most primitive cells, macrophages, epithelia, and fat-producing adipoanimals, such as sponges and hydrozoans. Throughout cytes (Figure 1; for review, see Bradley, 1990). Similarly, evolution, nature has exerted considerable fun and fancy when ES cells are injected into nude mice, they differenin elaborating on this theme. Some amphibians, for intiate into multicellular masses, called teratocarcinomas. stance, can regenerate a limb or tail when severed, and Although the programs of gene expression in these the neurons of bird brains can readily regenerate. While structures often bear strong resemblance to the differmammals seem to have lost at least some of this wonentiation pathways typical of developing animals, the derful plasticity, their liver can partially regenerate protriggering of these programs is chaotic, yielding a jumviding that the injury is not too severe, and the epidermis bled grab bag of tissue types. These examples graphiand hair of their skin can readily repair when wounded cally illustrate the importance of intercellular interactions or cut. Additionally, the epidermis, hair, small intestine, and cellular organization in orchestrating development and hematopoietic system are all examples of adult tisand embryo shape. sues that are naturally in a state of dynamic flux: even During development, intercellular cross-talk results in in the absence of injury, these structures continually give the generation and transmission of specific signals from rise to new cells, able to transiently divide, terminally a cell to its neighbor, altering in some key way the subsedifferentiate and die. quent behavior of the neighbor. Of prime importance is The fabulous ability of an embryo to diversify and of sifting through the galaxy of environmental signals to certain adult tissues to regenerate throughout life is a determine which constellations of cues can selectively direct result of stem cells, nature’s gift to multicellular coax ES cells down a specific cell lineage pathway at organisms. Stem cells have both the capacity to selfthe expense of all others. To this end, Brüstle et al. renew, that is, to divide and create additional stem cells, (1999) were recently able to obtain pure populations of and also to differentiate along a specified molecular multipotent progenitor cells expressing glial precursor pathway. Embryonic stem cells are very nearly totipomarkers. They achieved this goal by taking aggregates tent, reserving the elite privileges of choosing among of cultured mouse ES cells and propagating them semost if not all of the differentiation pathways that specify quentially in medium containing first fibroblast growth the animal. In contrast, stem cells that reside within an factor (FGF) 2 alone, then a mixture of FGF2 and epideradult organ or tissue have more restricted options, often mal growth factor (EGF), and finally a mix of FGF2 and able to select a differentiation program from only a few platelet-derived growth factor (PDGF). Bathed in this possible pathways. Or so it seemed, until very recently. last broth of growth factors, these pluripotent cells could In the last year, some spectacular fireworks have exbe maintained for many generations in culture. Upon ploded many long-standing dogmas in the stem cell growth factor withdrawal, they subsequently differentiworld, giving adult stem cells a new lease on life, and enated into either of two specific lineages, oligodendroabling them to be what researchers previously thought cytes or astrocytes (Brüstle et al., 1999). they were not. Illustrating the enormous potential of this type of research for clinical application, McKay and coworkers Embryonic Stem Cells transplanted these cloned glial precursor cells into the Emanating from the pioneering mouse research of Marventricle of myelin-deficient rats. Myelin sheaths formed tin Evans in the 1970s and culminating with the recent around host axons in various brain regions, including cortex, hippocampus, and hypothalamus (Figure 2; Brüstle et al., 1999). No signs of nonneuronal tissue were * To whom correspondence should be addressed (e-mail: liptack@