During development, stem cells give rise to all the various differentiated tissues; in the adult organism, stem cells replace damaged cells and maintain tissue populations as individual cells within them undergo replicative senescence due to attrition of telomeres. There is a homeostatic equilibrium between the replication, self-renewal, and differentiation of stem cells and the death of the mature, fully differentiated cells (Fig. 1). The dynamic relationship between stem cells and terminally differentiated parenchyma is particularly evident in the continuously dividing epithelium of the skin. Thus, stem cells at the basal layer of the epithelium progressively differentiate as they migrate to the upper layers of the epithelium before dying and being shed.

Fig1. Mechanisms regulating cell populations. Cell numbers can be altered by increased or decreased rates of stem cell input, cell death due to apoptosis, or changes in the rates of proliferation or differentiation. (Modified from McCarthy NJ, et al: Apoptosis in the development of the immune system: growth factors, clonal selection and bcl-2. Cancer Metastasis Rev 11:157, 1992.)

Stem cells are characterized by two important properties:

• Self-renewal, which permits stem cells to maintain their numbers.

• Asymmetric division, in which one daughter cell enters a differentiation pathway and gives rise to mature cells, while the other remains undifferentiated and retains its self-renewal capacity.

Although there is a tendency in the scientific literature to partition stem cells into several different subsets, fundamentally there are only two varieties:

• Embryonic stem cells (ES cells) are the most undifferentiated. They are present in the inner cell mass of the blastocyst, have virtually limitless cell renewal capacity, and can give rise to every cell in the body; they are thus said to be totipotent (Fig.2). While ES cells can be maintained for extended periods without differentiating, they can be induced under appropriate culture conditions to form specialized cells of all three germ cell layers, including neurons, cardiac muscle, liver cells, and pancreatic islet cells.

Fig2. Embryonal stem cells. The zygote, formed by the union of sperm and egg, divides to form blastocysts, and the inner cell mass of the blastocyst generates the embryo. The pluripotent cells of the inner cell mass, known as embryonic stem (ES) cells, can be induced to differentiate into cells of multiple lineages. In the embryo, pluripotent stem cells can asymmetrically divide to yield a residual stable pool of ES cells in addition to generating populations that have progressively more restricted developmental capacity, eventually generating stem cells that are committed to just specific lineages. ES cells can be cultured in vitro and be induced to give rise to cells of all three lineages.

• Tissue stem cells (also called adult stem cells) are found in intimate association with the differentiated cells of a given tissue. They are normally protected within specialized tissue microenvironments called stem cell niches. Such niches have been demonstrated in many organs—including the brain, where neural stem cells inhabit the subventricular zone and dentate gyrus. Skin stem cells are found in the bulge region of the hair follicle, and in the cornea they are found at the limbus. Soluble factors and other cells within the niches keep the stem cells quiescent until there is a need for expansion and differentiation of the precursor pool (Fig. 3). Adult stem cells have a limited repertoire of differentiated cells that they can generate. Thus, although adult stem cells can maintain tissues with high (e.g., skin, and gastrointestinal tract) or low (e.g., heart and brain) cell turnover, the adult stem cells in any given tissue can usually only produce cells that are normal constituents of that tissue.

Fig3. Stem cell niches in various tissues. A, Skin stem cells are located in the bulge area of the hair follicle, in sebaceous glands, and in the lower layer of the epidermis. B, Small intestine stem cells are located near the base of the crypt, above Paneth cells. C, Liver stem cells (oval cells) are located in the canals of Hering (thick arrow), structures that connect bile ductules (thin arrow) to parenchymal hepatocytes. Bile duct cells and canals of Hering are stained here with an immunohistochemical stain for cytokeratin 7. (C, Courtesy Tania Roskams, MD, University of Leuven, Belgium).

The most extensively studied of the tissue stem cells are the hematopoietic stem cells that continuously replenish all the cellular elements of the blood as they are consumed. Hematopoietic stem cells may be isolated directly from bone marrow, as well as from the peripheral blood after administration of certain colony stimulating factors (CSF) that induce their release from bone marrow niches. Although rare, hematopoietic stem cells can be purified to virtual homogeneity based on cell surface markers and ability to give rise to blood cell of lineages. Clinically, these stem cells can be used to repopulate marrows depleted after chemotherapy (e.g., for leukemia), or to provide normal precursors to correct various blood cell defects (e.g., sickle cell disease, Chapter 14).

Besides hematopoietic stem cells, the bone marrow (and notably, other tissues such as fat) also contains a population of mesenchymal stem cells. These are multipotent cells that can differentiate into a variety of stromal cells including chondrocytes (cartilage), osteocytes (bone), adipocytes (fat), and myocytes (muscle). Because these cells can be expanded to large numbers, and can also generate a locally immunosuppressive microenvironment (thus potentially evading rejection), they may represent a ready means of manufacturing the stromal cellular scaffolding for tissue regeneration.

Regenerative Medicine

The ability to identify, isolate, expand, and transplant stem cells has given birth to the new field of regenerative medicine. Theoretically, the differentiated progeny of ES or adult stem cells can be used to repopulate damaged tissues, or to construct entire organs for replacement. In particular, there is considerable excitement about the therapeutic opportunities for restoring damaged tissues that have low intrinsic regenerative capacity, such as myocardium after a myocardial infarct or neurons after a stroke. Unfortunately, despite an improving ability to purify and expand stem cell populations, much of the initial enthusiasm has been tempered by difficulties encountered in introducing and functionally integrating the replacement cells into sites of damage.

Another potential problem is the immunogenecity of most stem cells; although mesenchymal stem cells may be weakly immunogenic, most other adult stem cells, as well as ES cells (from fertilized blastocysts), express histocompatibility (HLA) molecules of the sperm and egg donors that provoke immunologic rejection by the host (Chapter 6). Hence, considerable effort has been expended to generate cells that are totipotential like ES cells but are derived from the patient into whom they will be implanted. To accomplish this, a handful of genes have been identified whose products can—remarkably—reprogram somatic cells to achieve the “stem-ness” of ES cells. When such genes are introduced into fully differentiated cells (e.g., fibroblasts), induced pluripotent stem cells (iPS cells) are generated (Fig. 4). Since these cells are derived from the patient, their differentiated progeny (e.g., insulin-secreting β-cells in a patient with diabetes) can be engrafted without eliciting a rejection reaction. Another exciting recent development is genomic editing, a process using a nuclease called Cas9 that was originally identified in prokaryotes that can be used together with guide RNAs called CRISPRs to selectively alter or correct DNA sequences, such as disease- causing mutations. While iPS cells and Cas9 technology hold considerable promise, whether they are the Holy Grail of tissue regeneration remains to be seen.

Fig4. The production of induced pluripotent stem cells (iPS cells). Genes that confer stem cell properties are introduced into a patient’s differentiated cells, giving rise to stem cells that can be induced to differentiate into various lineages. (Modified from Hochedlinger K, Jaenisch R: Nuclear transplantation, embryonic stem cells, and the potential for cell therapy. N Engl J Med 349:275-286, 2003.)

Concluding Remarks. This survey of selected topics in cell biology will serve as a basis for our later discussions of pathology, and we will refer back to it throughout the book. Students should, however, remember that this summary is intentionally brief, and more information about some of the fascinating topics reviewed here can be readily found in textbooks devoted to cell and molecular biology.

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مواضيع ذات صلة

Proliferation and the Cell Cycle

Growth Factors and Receptors

Signal Transduction Pathways

Cell Signaling

Cellular Metabolism and Mitochondrial Function

Waste Disposal: Lysosomes and Proteasomes

Biosynthetic Machinery: Endoplasmic Reticulum and Golgi

Cytoskeleton and Cell-Cell Interactions

Plasma Membrane: Protection and Nutrient Acquisition

Cytoplasmic Structures in Prokaryotic Cell

Eukaryotic Cell Structure

Cell Differentiation