Stem Cells and the Breast

Edward P. Buchanan

Victor W. Wong

Geoffrey C. Gurtner

Introduction

Stem cells are a special population of cells that have the unique ability to both self-renew and differentiate into functional end-organ cells, such as cartilage or skin cells. Stem cells are critical components for tissue regeneration through which every tissue and organ system in the human body is made and maintained. Recently, several stem cell populations (such as adipose-derived stem cells) have generated clinical excitement for their applications in both cosmetic and reconstructive surgery. Moreover, stem cells have been identified and isolated in the human breast and may serve both physiologic and pathologic functions. Given the increasing awareness of the importance of stem cells in the normal function, pathology, and postsurgical healing of the breast, it is necessary for plastic surgeons to become acquainted with the fundamentals of stem and progenitor cell biology.

The Spectrum of Human Stem Cells

Stem cells are unique because of two fundamental properties. Like cancer cells, they can self-renew indefinitely and are immortal. Unlike cancer cells, stem cells can differentiate into daughter cells than can perform all of the different functions essential for human life. While undergoing self-renewal, stem cells remain in an undifferentiated state and are able to undergo numerous cycles of cell division. However, to become functional daughter cells (such as cartilage or skin cells) the stem cells must differentiate. “Potency” refers to a given stem cell’s ability to become specialized cell types.

Totipotent cells are those that have the greatest ability to produce all the cells types in both embryonic and extraembryonic (placental) tissues. These types of cells are rare and are most commonly created by the fusion of an egg and a sperm and include the cells that are present after the first few divisions of the zygote. They are not used clinically. Stem cells that do not have the ability to make extraembryonic tissue but can make every other tissue in the human body are known as pluripotent stem cells. The best known of these are embryonic stem cells, which are formed from the inner cell mass of the developing embryo and are capable of differentiating into all the tissues of the human body. Finally, stem cells that can only form cells from one germ layer (endoderm, mesoderm, and ectoderm) are known as multipotent stem cells. Most stem cells that are currently being used in clinical trials are multipotent stem cells. These include bone marrow–derived stem cells, hematopoietic stem cells, and adipose-derived stem cells. All of these maintain the ability to differentiate into cell types derived from a single germ layer (1).

Although the terms progenitor cell and stem cell are often used interchangeably, they are not the same. Progenitor cells maintain the ability to differentiate into different cell types but cannot self-renew indefinitely and are not immortal (unlike true stem cells). In general, progenitor cells are usually multipotent and exhibit potency capacities somewhere between undifferentiated stem cells (embryonic stem cells) and fully differentiated adult cell populations. As such, they can replace failing cells from a single lineage (e.g., bone, cartilage, fat) but would not be useful to replace cells from a different linage (i.e., neurons). However, progenitor cells are incredibly important as the body’s repair system and are found in nearly all mature organs (2).

Embryonic Stem Cells

Over the last 10 years, considerable excitement has been generated by the discovery of embryonic stem cells (ESCs) that are capable of forming all the cells present in the human body. Embryonic stem cells are first formed during the earliest stages of embryonic development. After fertilization, the zygote begins to undergo rapid mitotic divisions to develop into a cluster of cells. Once this division has produced more than 100 cells, the embryo becomes known as a blastula. This further divides into a cell sphere at 4 to 5 days postconception, known as the blastocyst. A mass of cells on the inside of the blastocyst is formed called the inner cell mass (Fig. 80.1).

Embryonic stem cells are derived directly from the epiblast layer of the blastocyst. They can be cultured in vitro and provide a robust source of regenerative cells. These are true pluripotent cells and, if given the necessary signals, can differentiate into the more than 200 different cell types in the human body. It is the hope that these embryonic stem cells may eventually be used clinically for the regeneration of every major organ system. However, the exact mechanism and pathways for differentiation are not well understood, and it is likely that allogeneic grafts will induce an immune response. For this reason, ESCs will need to be matched to the recipient in the way that liver or kidney transplants are currently matched. One very recent advance is the development of induced pluripotent cells (iPS), which can be derived from a patient’s skin fibroblasts and have the same capacity for regeneration as ESCs. The only potential human clinical use for either iPS or ESCs is an industry-sponsored trial to examine the use of ESCs to reverse spinal cord injury.

Adult Stem Cells

In contrast, thousands of patients have already been treated with nonembryonic adult stem cells in a variety of different settings. Adult cells are found throughout every major tissue and organ system in the human body and are involved in the continual renewal of tissues with rapid turnover such as skin and gut mucosa (Fig. 80.2). Like their more primitive embryonic counterparts, these cells have the ability to not only self-renew, but also to create differentiated daughter cells specific to the organ system that they inhabit (2). Clinical applications are

based on exploiting the ability of these cells to differentiate into specialized tissues required for regeneration (3).

Figure 80.1. Blastocyst and embryonic stem cells. During the early stages of embryogenesis, the blastocyst is formed after multiple cell divisions of the zygote. The inner cell mass contains cells that are truly pluripotent.

Figure 80.2. Adult stem cell populations in the human body. Embryonic stem cells are different than adult stem cells because embryonic cells can differentiate into any tissue type in the human body. Adult cells are found throughout every major tissue and organ system in the human body and are involved in the continual renewal of the tissues that they inhabit.

Most adult stem cell populations are multipotent and are referred to according to their tissue of origin. They populate a very small percentage of the total number of cells in a given tissue type (e.g., 1:10,000). The adult stem cell niches being studied include skin, skeletal muscle, brain, breast, bone marrow, pancreas, blood, gastrointestinal system, ocular system, and dental pulp (2). Most adult stem cell populations are found within specialized niches of the specific tissue types into which they differentiate. These cells usually remain dormant until they are activated by various signals to begin differentiation.

A related but distinct group of adult stem cells are found in bone marrow and are known as hematopoietic and mesenchymal stem cells. It is believed that these cells are able to leave the bone marrow and move or “traffic” to sites of injury, where they can differentiate into needed cell types. This is different from most adult stem cells, which are restricted to the physical location and tissue type of the organ in which they reside.

Hematopoietic Stem Cells

Hematopoietic stem cells (HSCs) are found in bone marrow. These cells are multipotent and give rise to cell types in the myeloid and lymphoid cell lineages. Cells produced from the myeloid lineage include erythrocytes, macrophages, neutrophils, eosinophils, and basophils, whereas lymphoid cells include those specific for the immune system, such as B cells, NK cells, and T cells. HSCs are thought to comprise about 1/10,000 of the cells in the bone marrow. Because of the ability for small populations of HSCs to rapidly expand into larger populations, bone marrow transplantation has been used as a therapeutic intervention to reconstitute the hematopoietic system.

HSC transplantation (more commonly known as bone marrow transplantation) is used to treat hematopoietic cancers and genetic defects resulting in defective stem cells, such as severe combined immunodeficiency or congenital neutropenia. Graft types can be either autogenous or allogeneic. Autogenous grafts involves the extraction of the patient’s HSCs, which are then treated with chemotherapy and/or radiotherapy in order to eradicate the patient’s malignant cell population. Once this has occurred, the treated HSCs are returned to the patient’s body for repopulation of the hematopoietic system. Allogenic transplantation involves the transfer of blood stem cells from a healthy donor and to the recipient, or patient. The donor must possess the same tissue type (determined through matching human leukocyte antigen or HLA surface markers on blood cells) as the patient to minimize an immune response after transplantation.

Sources of HSCs include bone marrow, peripheral blood, and umbilical cord blood. Stem cell growth factors GM-CSF (granulocyte macrophage–colony stimulating factor) and G-CSF (granulocyte–colony stimulating factor), which increase the number of circulating stem cells, have made it possible to obtain HSCs for transplantation from peripheral blood. The ability of HSCs to pass through the bone marrow barrier and travel to other areas is well established and has led to the investigation of HSCs in the treatment of nonhematopoietic diseases. These cells have been extensively examined following myocardial infarction, where the clinical efficacy has been disappointing. Thus, their long-term usefulness for tissue regeneration remains unclear.

Mesenchymal Stem Cells

Another adult stem cell population derived from the bone marrow is that of the mesenchymal stem cells (MSC). These cells are derived from the bone marrow stroma and are distinct from the hematopoietic stem cells discussed in the previous section. MSCs have the ability to produce a multitude of tissue types that are all derived from a single germ layer (e.g., fat, cartilage, bone) and are multipotent. MSCs can produce cells specific to the reticular, osteoblastic, adipocytic, myoblastic, and fibroblastic lineages (4). Friedenstein et al. provided the first evidence for a single population of cells capable of multilineage mesodermal differentiation (5). Their studies demonstrated that MSCs could differentiate into cartilage, bone, myelosuppressive stroma, adipocytes, and fibrous connective tissue (5). It is believed that MSCs can both differentiate into committed cells and leave their bone marrow niche and travel to sites of injury to provide regenerative capabilities.

For the last 30 years MSCs have been isolated by bone marrow aspiration, cultured on tissue-grade plastic, and then expanded in vitro. These cells are heterogeneous and demonstrate different capacities for differentiation. In the ideal setting, a homogeneous population of MSCs would be isolated and thus be predisposed toward a specific cell lineage. This type of analysis is not currently possible due to the lack of stage-specific markers for these cells. However, analysis of specific surface antibody markers has identified subpopulations of cells that retain the ability to separate into cartilage, bone, and fat. The antibodies include STRO-1, HOP-26, and SB-10 (4). With the use of gene expression microarrays, pinpointing new cell surface expression markers for MSCs may be possible.

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