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Breast: Stem and Progenitor Cells in Adults
Breast: Stem and Progenitor Cells in Adults
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Breast: Stem and Progenitor Cells in Adults
The mammalian breast is one of the few organs in the female body that undergoes large changes during the life cycle. Puberty, pregnancy, and lactation are some of the physiological processes that dramatically alter the nature and cellular composition of the breast. This article discusses the stem and progenitor cell populations present in the breast that allow for this inherent regenerative capacity in the breast.
The breast has a branched network of ducts and lobules that comprises the glandular tissue responsible for producing milk during lactation. It is also comprised of a layer of myoepithelial cells that have muscle-like contractile ability that can contract to allow for milk extraction from the mammary glands into the ducts that carry the milk. In essence, there are three major cell types in the glands and ducts of the breast. The luminal, or outward-facing alveolar cells, and the layer of myoepithelial cells that form a basal layer below the alveolar cells make up the glandular portion. The ductal cells line the epithelial layer of the ducts. These cells arise from two lineages, the luminal and myoepithelial. The alveolar and ductal cells described above arise from the luminal lineage. These three cell types are thought to originate from a common progenitor stem cell. Several other cell types exist in the breast, including a large amount of adipose cells that make up the fat pads in the breast and stromal cells in the connective tissue of the breast. Stem and progenitor cells in the breast, which are the focus of this article, are predominantly present to the glands where myoepithelial and alveolar cells are present. In particular, the major population of multipotent stem cells discovered in the breast is restricted to the basal layer of the glands.
During puberty, cell growth causes the branching and elongation of the epithelial ducts. After puberty, cycles of both proliferation and differentiation occur, with the estrous cycle accounting for the growth and decay of the alveolar tissue.
During pregnancy, the breast undergoes extensive changes, with a dramatic increase in the glands and ducts to allow for milk production in the lactating period. After lactation, the glands undergo involution as a result of cell death and return to their prepregnant state. The ability of the breast cell types to proliferate, involute, and proliferate again with each pregnancy presented the first clues for the presence of a stem cell type in the breast that can serve as the origin of the epithelial cell types.
Evidence that pointed toward the presence of mammary stem or progenitor cells with regenerative capacity in the breast came from transplantation experiments done in mice as early as the 1960s. Research studies found that serial transplantations (described below) of epithelial cells into empty fat pads of other mice resulted in the regeneration of all the epithelial cell lineages for several successive generations. The presence of stem cells in these studies was indicated by the fact that the transplanted cells satisfied the two important criteria for being stem cells: the ability to differentiate into multiple lineages and the ability to self-renew. The sections below detail the methods of identifying mammary stem cells, the discovery of stem and progenitor cells, and the types of stem cells that have been proposed to give rise to the epithelial cell lineages in the breast.
Methods of Identifying Mammary Stem Cells
Two major techniques have been used to identify mammary stem cells. A single stem cell that can generate complete bi-layered glands with both luminal and basal cells is known as a Mammary Repopulating Unit (MRU), and the number of stem cells identified by any method used is quantified in terms of MRUs.
Transplantation Assays
Transplantation assays to identify the presence of stem or progenitor cells involve first isolating tissue fragments or specific cell populations from the epithelial layer of the breast. While earlier techniques used more heterogeneous populations, newer cell isolation reagents have the ability to isolate and test individual cells or more homogenous populations. These cells are then transplanted to the cleared fat pads of other mice that contain the supporting tissue but no glandular or ductal cells. If the transplanted cells had stem cell capacity, they would generate either one more of the three epithelial cell types depending upon whether they were multipotent or unipotent in nature. Further self-renewal capacity, which is an important characteristic of stem cells, can be tested by obtaining cells from the first transplantation and transferring them again to another recipient animal and observing whether they have the capacity to regenerate all epithelial cell types in the luminal and basal layer. In this method, the accuracy of identifying stem cells depends on the ability to isolate and purify cells that are being transplanted.
Lineage Tracing
Lineage tracing or tracking is a more recent technique that was created with the ability to genetically mark specific cells in the breast with molecular signatures known as reporters. Once marked, these parent cells would be able to transmit the reporter to all the daughter cells that arise through cell proliferation and differentiation. Thus the lineage of individual cells can be tracked through this method, making it easy to identify multipotent stem cells in the breast. Since both the cell type and the timing at which the reporter is activated can be controlled, lineage tracing can identify stem cells with more accuracy. Some of the drawbacks of this technique include technical difficulty in labeling specific cell populations and the off-target expression of the reporter molecule.
Mammary Stem Cells and the Epithelial Differentiation Hierarchy
The search for mammary stem and progenitor cells is based on the understanding of a differentiation hierarchy that is present in the mammary epithelial cells. This differentiation hierarchy gives rise to three adult cell types: the myoepithelial cell, the ductal cell, and the alveolar cell. Currently there are two modes of differentiation that have been proposed to explain the origin of these cells based upon the techniques used. In both cases, the primary cell of origin is a stem cell with self-renewing capacity and multipotency, termed mammary stem cell. In the first model, the stem cell gives rise to a single progenitor that is long lived but not self-renewing, which in turn gives rise to both luminal (ductal, alveolar) and myoepithelial progenitor cells, which are more restricted in their differentiation capacity. These are termed bipotent progenitors. In the second model, proposed based on lineage tracing studies, cell maintenance in the adult breast is proposed to occur from unipotent progenitor cells (which in turn arise from the single progenitor). These cells are capable of producing cells of only a single lineage (luminal, alveolar, or myoepithelial). In both cases, the restricted progenitor cells give rise to the adult cells. The existence of bipotent progenitor cells was initially thought to occur only during development, with a switch to unipotent cells occurring at birth. However, recent studies have shown that bipotent progenitors continue to exist in the adult and may contribute to the long-term maintenance of the breast. This is an active area of study that is currently determining the roles of each of these modes of differentiation in the developing and adult breast.
Identification of Adult Mammary Stem Cells (MaSCs) and Luminal Progenitor Cells
The identification a specific cell that could regenerate the entire epithelial breast lineage with intact morphological features such as ducts and glands occurred in 2006. Researchers