Stem cell research has been hailed for the potential to revolutionize the future of medicine with the ability to regenerate damaged and diseased organs. On the other hand, stem cell research has been highly controversial due to the ethical issues concerned with the culture and use of stem cells derived from human embryos. This article presents an overview of what stem cells are, what roles they play in normal processes such as development and cancer, and how stem cells could have the potential to treat incurable diseases. Ethical issues are not the subject of this review.
In addition to offering unprecedented hope in treating many debilitating diseases, stem cells have advanced our understanding of basic biological processes. This review looks at two major aspects of stem cells:
I. Three processes in which stem cells play a central role in an organism, development, repair of damaged tissue, and cancer resulting from stem cell division going awry.
II. Research and clinical applications of cultured stem cells: this includes the types of stem cells used, their characteristics, and the uses of stem cells in studying biological processes, drug development and stem cell therapy; heart disease, diabetes and Parkinson's disease are used as examples.
What are stem cells?
Stem cells are unspecialized cells that have two defining properties: the ability to differentiate into other cells and the ability to self-regenerate.
The ability to differentiate is the potential to develop into other cell types. A totipotent stem cell (e.g. fertilized egg) can develop into all cell types including the embryonic membranes. A pleuripotent stem cell can develop into cells from all three germinal layers (e.g cells from the inner cell mass). Other cells can be oligopotent, bipotent or unipotent depending on their ability to develop into few, two or one other cell type(s).
Self-regeneration is the ability of stem cells to divide and produce more stem cells. During early development, the cell division is symmetrical i.e. each cell divides to gives rise to daughter cells each with the same potential. Later in development, the cell divides asymmetrically with one of the daughter cells produced also a stem cell and the other a more differentiated cell.
| Differentiation Potential | Number of cell types | Example of stem cell | Cell types resulting from differentiation | Source |
| Totipotential | All | Zygote (fertilized egg), blastomere | All cell types | [m1] |
| Pleuripotential | All except cells of the embryonic membranes | Cultured human ES cells | Cells from all three germ layers | [m2] |
| Multipotential | Many | Hematopoietic cells | skeletal muscle,cardiac muscle, liver cells, all blood cells | [m3] |
| Oligopotential | Few | Myeloid precursor | 5 types of blood cells (Monocytes, macrophages, eosinophils, neutrophils, erythrocytes) | [m4] |
| Quadripotential | 4 | Mesenchymal progenitor cell | Cartilage cells, fat cells, stromal cells, bone-forming cells | [m5] |
| Tripotential | 3 | Glial-restricted precursor | 2 types of astrocytes, oligodendrocytes | [m6] |
| Bipotential | 2 | Bipotential precursor from murine fetal liver | B cells, macrophages | [m7] |
| Unipotential | 1 | Mast cell precursor | Mast cells | [m8] |
| Nullipotential | None | Terminally differentiated cell e.g. Red blood cell | No cell division | |
Table 1: Differential potential ranges from totipotent stem cells to nullipotent cells.
Compiled from information in sources shown
I. Stem cells are central to three processes in an organism: development, repair of adult tissue and cancer.
A. Stem cells in mammalian development
The zygote is the ultimate stem cell. It is totipotent with the ability to produce all the cell types of the species including the trophoblast and the embryonic membranes. Development begins when the zygote undergoes several successive cell divisions, each resulting in a doubling of the cell number and a reduction in the cell size. At the 32- to 64-cell stage each cell is called a blastomere. The blastomeres stick together to form a tight ball of cells called a morula. Each of these cells retains totipotential. The next stage is the blastocyst which consists of a hollow ball of cells; trophoblast cells along the periphery develop into the embryonic membranes and placenta while the inner cell mass develops into the fetus. Beyond the blastocyst stage, development is characterized by cell migration in addition to cell division. The gastrula is composed of three germ layers: the ectoderm, mesoderm and endoderm. The outer layer or ectoderm gives rise to the future nervous system and the epidermis (skin and associated organs such as hair and nails). The middle layer or mesoderm gives rise to the connective tissue, muscles, bones and blood, and the endoderm (inner layer) forms the gastrointestinal tract of the future mammal.
Early in embryogenesis, some cells migrate to the primitive gonad or genital ridge. These are the precursors to the gonad of the organism and are called germinal cells. These cells are not derived from any of the three germ layers but appear to be set aside earlier.
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Stem cells in late development
As development proceeds, there is a loss of potential and a gain of specialization, a process called determination. The cells of the germ layers are more specialized than the fertilized egg or the blastomere. The germ layer stem cells give rise to progenitor cells (also known as progenitors or precursor cells). For example, a cell in the endoderm gives rise to a primitive gut cell (progenitor) which can further divide to produce a liver cell (a terminally differentiated cell).
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| Hierarchy of stem cells during differentiation.2at each stage, differential potential decreases and specialization increases. |
Embryonal stem cell(pleuripotent)Role of Progenitor Cells in Development
While there is consensus in the literature that a progenitor is a partially specialized type of stem cell, there are differences in how progenitor cell division is described. For instance, according to one source,3 when a stem cell divides at least one of the daughter cells it produces is also a stem cell; when a progenitor cell undergoes cell division it produces two specialized cells. A different source,2 however, explains that a progenitor cell undergoes asymmetrical cell division, while a stem cell undergoes symmetrical cell division.
The apparent inconsistency of these two versions illustrates the diversity and complexity of progenitor cells and their role in differentiation. This diversity is reflected in the nomenclature as well; progenitor cells are also called Transit-amplifying cells, Precursor cells, Progenitors, Lineage stem cells, and Tissue-determined stem cells.
The table below shows these complex stages:
| Early in development: |
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| Late in development: type 1 |
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| Late in development: type 2 |
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Table 2: Summarized from information in references 6 and 7.
The number of stem cells present in an adult is far fewer than the number seen in early development because most of the stem cells have differentiated and multiplied. This makes it extremely difficult to isolate stem cells from an adult organism, which is why scientists hope to use embryonic stem cells for therapy because embryonic stem cells are much easier to obtain.
B. The role of adult stem cells in tissue repair
During development, stem cells divide and produce more specialized cells. Stem cells are also present in the adult in far lesser numbers. The role of adult stem cells (also called somatic stem cells) is believed to be replacement of damaged and injured tissue. Observed in continually-replenished cells such as blood cells and skin cells, stem cells have recently been found in other tissue, such as neural tissue.
II. Stem cells used in research and clinical applications
Rao and colleagues postulate that all stem cells, regardless of their origin, share common properties.9 These researchers have reviewed the literature for candidate "stemness" genes. They conclude that there are a set of candidate genes that are present in all stem cells and can serve as universal markers for stem cells. These code for proteins are involved in self-renewal and differentiation. In addition they predict some differences in gene expression between different populations of stem cells.
A. Types and characteristics of stem cells for culture:
Embryonic stem (ES) cells are obtained from the inner cell mass and cultured as illustrated:
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ES cells from mouse embryos have been cultured since the 1980s by various groups of researchers working independently.10 These pioneers established murine embryonic stem cells lines that could differentiate into several different cell types.11 ES cell lines have been established from other mammals (hamsters, rats, pigs, and cows). Thompson and colleagues at the
ES cells are the best characterized of all the cultured stem cells. Properties of ES cells:13
(i) ES cells are pleuripotent, i.e. they have the ability to differentiate into cells derived from all three germ layers, but not the embryonic membranes.
(ii) ES cells are immortal i.e. cells proliferate in culture and have been maintained in culture for several hundred doublings. The advantage of maintaining stem cells in culture is that they are a source of a large number of cells in the undifferentiated state. So far other adult stem cells have not been maintained indefinitely.
(iii) ES cells maintain a normal karyotype (there are no major structural changes in the chromosomes)
(iv) ES cells display Oct-4 protein and other unique markers on the cell surface.
Generally, ES cells are maintained in culture on feeder cells (mouse fibroblast cells) There have been recent reports of ES cultured on feeder cell-free medium.14
ES cells can be induced to differentiate in vitro by culturing in suspension to form three-dimensional cell aggregates called embryoid bodies (EBs).15 The cells spontaneously differentiate into various cell types, e.g. neurons, cardiomyocytes, and pancreatic beta cells. The addition of growth factors to the culture directs differentiation to specific cell types. However, it is still challenging to isolate pure differentiated cell types.
Following injection of ES cells into immunodeficient mice, teratomas develop with derivatives of all three germ layers. This is a major disadvantage of using ES cells for cell therapy since any contaminating undifferentiated cells could give rise to cancer.
Embryonic germ cells Gearhart and colleagues originally derived stem cells from primordial germ cells.16 Cells cultured from the genital ridge of the human embryo have been isolated and cultured. These cells have a lesser capacity of proliferation than ES cells but have an advantage in that they are not tumorigenic, unlike ES cells.17
Embryonal carcinoma cells Embryonal carcinoma cell lines were first developed in 1967 by Ephrussi and colleagues from mouse teratomas, followed in 1975 by Fogh and
Adult or somatic stem cells The existence of hematopoietic stem cells was discovered in the 1960s, followed by the discovery of stromal cells (also called mesenchymal cells). Only in the 1990s did scientists confirm the reports of neural stem cells in mammalian brains. Since then stem cells have been found in the epidermis, liver and several other tissues.19
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| Figure 4: Hematopoietic and Stromal stem cell differentiation |
Adult stem cells offer hope for cell therapy to treat diseases in the future because ethical issues do not impede their use. In addition, if the patient's own cells are used, immunological compatibility is not an issue. However, ES cells have been found to be superior for both differentiation potential and ability to divide in culture.
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| Hierarchy of stem cells during differentiation.2at each stage, differential potential decreases and specialization increases. |
Role of Progenitor Cells in Development
While there is consensus in the literature that a progenitor is a partially specialized type of stem cell, there are differences in how progenitor cell division is described. For instance, according to one source,3 when a stem cell divides at least one of the daughter cells it produces is also a stem cell; when a progenitor cell undergoes cell division it produces two specialized cells. A different source,2 however, explains that a progenitor cell undergoes asymmetrical cell division, while a stem cell undergoes symmetrical cell division.
The apparent inconsistency of these two versions illustrates the diversity and complexity of progenitor cells and their role in differentiation. This diversity is reflected in the nomenclature as well; progenitor cells are also called Transit-amplifying cells, Precursor cells, Progenitors, Lineage stem cells, and Tissue-determined stem cells.
The table below shows these complex stages:
| Early in development: |
|
|
| Late in development: type 1 |
|
|
| Late in development: type 2 |
|
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Table 2: Summarized from information in references 6 and 7.
The number of stem cells present in an adult is far fewer than the number seen in early development because most of the stem cells have differentiated and multiplied. This makes it extremely difficult to isolate stem cells from an adult organism, which is why scientists hope to use embryonic stem cells for therapy because embryonic stem cells are much easier to obtain.
B. The role of adult stem cells in tissue repair
During development, stem cells divide and produce more specialized cells. Stem cells are also present in the adult in far lesser numbers. The role of adult stem cells (also called somatic stem cells) is believed to be replacement of damaged and injured tissue. Observed in continually-replenished cells such as blood cells and skin cells, stem cells have recently been found in other tissue, such as neural tissue.
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