Socializing with the Neighbors: Stem Cells and Their Niche
Elaine Fuchs,* Tudorita Tumbar, and Geraldine Guasch Howard Hughes Medical Institute The Rockefeller University New York, New York 10021
The potential of stem cells in regenerative medicine relies upon removing them from their natural habitat, propagating them in culture, and placing them into a foreign tissue environment. To do so, it is essential to understand how stem cells interact with their microenvironment, the so-called stem cell niche, to establish and maintain their properties. In this review, we examine adult stem cell niches and their impact on stem cell biology. The Existence and Importance of Adult Stem Cells and Their Niches The magnificent ability to generate an embryo from a single fertilized oocyte or to regenerate certain tissues, upon injury or natural physiological turnover, is a direct result of stem cells, nature’s gift to multicellular organisms. The gold standard of stem cells is the fertilized egg, which produces an organism replete with a myriad of specialized cell types, including reproductive germ stem cells (GSCs). As the embryo first develops, an outer protective shell of support cells encases an undifferentiated mass of pluripotent embryonic stem cells (ESCs) that will make the animal. As development proceeds, pluripotent embryonic stem cells disappear as more restricted somatic stem cells (SSCs) give rise to the tissues and organs. Although cell diversification is largely complete at or shortly after birth, organs must possess a mechanism to replenish cells as they die, either by natural wear and tear (homeostasis), or by injury. To accomplish this feat in the adult world, many developing tissues set aside life-long reservoirs of somatic stem cells, which retain some of the versatile characteristics of their early ESC counterparts, including the capacity to seemingly endlessly self-renew, i.e., divide and create additional stem cells (Schofield, 1978). Even though the elite privilege of differentiating into most if not all cell types appears to be reserved for the more versatile ESCs, adult SSCs residing within an organ or tissue are nevertheless able to progress to differentiate along at least one (unipotent) and typically multiple (multipotent) lineages. Given the life-long importance of stem cells, they must be tucked safely from harm’s way. The protective niches are composed not only of stem cells but also a diverse gathering of neighboring differentiated cell types which secrete and organize a rich milieu of extracellular matrix and other factors that allow stem cells to manifest their unique intrinsic properties, including the ability to self renew, while keeping their repertoire of differentiation programs on hold. The importance of the niche is perhaps best exempli*Correspondence: firstname.lastname@example.org
fied by experiments in which the fate of ESCs is monitored following their subcutaneous injection into nude mice. ESCs isolated from a blastocyst-stage mouse embryo can be propagated indefinitely in tissue culture without losing their pluripotent potential (Thomson et al., 1998; Shamblott et al., 1998 and references therein). However, when faced with a foreign environment of surrounding in vivo tissue, ESCs unleash a Pandora’s box of differentiation programs, forming ugly multicellular tumor masses, known as teratomas, which contain a multiplicity of cell types. Without the appropriate microenvironment of specific intercellular interactions and cellular organization, the ESC can become an undesirable beast. By contrast, as shown by Beatrice Mintz and Martin Evans in the 1970’s, when injected instead into the center of a recipient mouse blastocyst, analogous to their native niche, ESCs resume normal behavior and contribute to generating all of the tissues of a healthy normal chimeric offspring. Taken together, these findings imply that...