Stem cell biology is a rapidly expanding field that explores the characteristics and possible clinical applications of a variety of stem cells that serve as the progenitors of more differentiated cell types. In addition to potential therapeutic applications (Chap. 67), patient-derived stem cells can also be used as disease models and a means to test drug effectiveness. Stem cells and their niche are becoming a major focus of medical research because they play central roles in tissue and organ homeostasis and repair, which are important aspects of aging and disease.
Identification, Isolation, and Derivation of Stem Cells
The definition of stem cells remains elusive. Stem cells were originally postulated as unspecified or undifferentiated cells that provide a source of renewal of skin, intestine, and blood cells throughout life. These resident stem cells have been identified in a variety of organs (e.g., epithelia of the skin and digestive system, bone marrow, blood vessels, brain, skeletal muscle, liver, testis, and pancreas) based on their specific locations, morphology, and biochemical markers.
Unequivocal identification of stem cells requires their separation and purification, usually based on a combination of specific cell-surface markers. These isolated stem cells [e.g., hematopoietic stem (HS) cells] can be studied in detail and used in clinical applications, such as bone marrow transplantation (Chap. 66). However, the lack of specific cell-surface markers for other types of stem cells has made it difficult to isolate them in large quantities. This challenge has been partially addressed in animal models by genetically marking different cell types with green-fluorescence protein driven by cell-specific promoters. Alternatively, putative stem cells have been isolated from a variety of tissues as side population (SP) cells using fluorescence-activated cell sorting after staining with Hoechst 33342 dye.
It is desirable to culture and expand stem cells in vitro to obtain a sufficient quantity for analysis and potential therapeutic use. Although the derivation of stem cells in vitro has been a major obstacle in stem cell biology, the number and types of cultured stem cells have increased progressively (Table 65–1). Cultured stem cells derived from resident stem cells are often called adult stem cells to distinguish them from embryonic stem (ES) and embryonic germ (EG) cells. However, considering the existence of embryo-derived, tissue-specific stem cells [e.g., trophoblast stem (TS) cells] and the possible derivation of similar cells from an embryo/fetus [e.g., neural stem (NS) cells], it is more appropriate to use the term, tissue stem cells.
Table 65–1 Classification of Cultured Stem Cells
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Table 65–1 Classification of Cultured Stem Cells
|Embryonic stem cells (ES, ESC)||Blastocysts or immuno-surgically isolated inner cell mass (ICM) from blastocysts.||ES cells grow as tightly adherent multicellular colonies with a population doubling time of ~12 h, maintain a stable euploid karyotype even after extensive culture and manipulation, can differentiate into a variety of cell types in vitro, and can contribute to all cell types, including functional sperm and oocytes, when injected into a blastocyst (m). ES cells form relatively flat, compact colonies with a population doubling time of 35–40 h (h).|
|Embryonic germ cells (EG, EGC)||Primordial germ cells (PGCs) from embryos at E8.5–E12.5 (m). Gonadal tissues from 5–11 week post-fertilization embryo/fetus (h).||EG cells show essentially the same pluripotency as ES cells when injected into mouse blastocysts (m). The only known difference is the imprinting status of some genes (e.g., Igf2r): Imprinting is normally erased during germline development, and thus, the imprinting status of EG cells is different from that of ES cells.|
|Trophoblast stem cells (TS, TSC)||Trophectoderm of E3.5 blastocysts, extraembryonic ectoderm of E6.5 embryos, and chorionic ectoderm of E7.5 embryos.||TS cells can differentiate into trophoblast giant cells in vitro (m). TS can contribute exclusively to all trophoblast subtypes when injected into blastocysts (m).|
|Extraembryonic endoderm cells (XEN)||ICM from blastocysts||XEN cells can contribute only to the parietal endoderm lineage when injected into a blastocyst (m).|
|Embryonal carcinoma cells (EC)||Teratocarcinoma—a type of cancer that develops in the testes and ovaries||EC cells rarely show pluripotency in vitro, but they can contribute to nearly all cell types when injected into blastocysts (m). EC cells often have an aneuploid karyotype and other genome alterations (m, h).|
|Mesenchymal stem cells (MS, MSC)||Bone marrow, muscle, adipose tissue, peripheral blood, and umbilical cord blood (m, h)||MS cells can differentiate into mesenchymal cell types, including adipocytes, osteocytes, chondrocytes, and myocytes (m, h).|
|Multipotent adult stem cells (MAPC)||Bone marrow mononuclear cells (m, h); postnatal muscle and brain (m)||MAPCs are very rare cells that are present within MSC cultures from postnatal bone marrow (m, h). MAPCs can be cultured for >120 population doublings, can differentiate into all tissues in vivo when injected into a mouse blastocyst, and can differentiate into various cell lineages of mesodermal, ectodermal, and endodermal origin in vitro (m).|
|Spermatogonial stem cells (SS, SSC)||Newborn testis (m)||SS cells can reconstitute long-term spermatogenesis after transplantation into recipient testes and restore fertility (m).|
|Germline stem cells (GS, GSC)||Neonatal testis (m)||GS cells can differentiate into three germlayers in vitro and contribute to a variety of tissues, including germline, when injected into blastocysts (m).|
|Multipotent adult germline stem cells (maGSC)||Adult testis (m)||maGSC can differentiate into three germlayers in vitro and can contribute to a variety of tissues, including germline, when injected into blastocysts.|
|Neural stem cells (NS, NSC)||Fetal and adult brain (subventricular zone, ventricular zone, and hippocampus)||NS cells can be cultured as a heterogeneous cell population of monolayer or floating cell clusters called neurospheres. NS cells can differentiate into neuron and glia in vivo and in vitro. Recently, the culture of pure population of symmetrically ...|
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