A stem cell is an unspecialized cell that is not terminally differentiated and has the potential to acquire a more specialized function by differentiation. Stem cells may be classified based upon their stage of differentiation or their differentiation lineage. All terminally differentiated cells had their beginning in embryonic stem cell progenitors.

The main types of stem cells, based upon their potential to differentiate, are totipotent, pluripotent and multipotent stem cells. As these cell types have progressively restricted phenotypes in terms of the potential for differentiation, they may also be referred to as checkpoints in stem cell differentiation.

Totipotent Stem Cells.

Totipotency is the potential of a cell to divide and differentiate to become any cell type in the organism, including the potential to become an organism. The cells formed in the very early embryonic stages are an example of totipotent stem cells, as these cells give rise to, not only multiple different cell types serving disparate functions in the body, but also have the ability to develop into complete organism. Cells in all tissues of the organism are derived from these undifferentiated stem cells. This is better understood in the context of the developmental stages of a human embryo.

The zygote, the single cell from which the embryo is derived, is a totipotent cell. The single cell zygote divides and becomes a 4-32 cell mulberry-like cluster called a morula. Until this stage, theoretically, any cell in this cluster has the ability to become a complete organism, though it has been reported that these cells can be regarded as lineage-specific stem cells as early as 4-cell stage. Further divisions lead to the development of an outer cellular layer and an inner cell mass.

The inner cell mass later differentiates into different tissues of the organism where as the outer cell mass, the trophoblast cells, functions to provide nutrients to the embryo and develop to become the placenta. When the embryonic development is past the morula stage, the stem cells can be said to have passed the first checkpoint of development and have become pluripotent stem cells.

Pluripotent Stem Cells or Embryonic Stem Cells - Checkpoint 1

Pluripotent cells are isolated from the inner cell mass of the embryo. As opposed to totipotent stem cells that can differentiate into any cell type in the organism, including the extraembryonic tissue (placenta), a self-renewing pluripotent stem cell may differentiate only into any cell type of the three germ layers: endoderm, mesoderm or ectoderm. Self-renewal is the ability of a cell to proliferate in the same state.

When a stem cell is referred to as embryonic stem cell, the reference is to the pluripotent stem cells derived from the inner cell mass. A pluripotent cell does not have the ability to be cloned into an organism, unless this cell is made to de-differentiate back by some mechanism. Under appropriate conditions, a pluripotent cell differentiates to cells of the heart, kidney, brain, intestine, skin or any other cell type in the organism. A terminally differentiated cell is one that is permanently committed to a certain function, such as a skin cell.

Multipotent Stem Cells - Checkpoint 2

Like any other stem cells, multipotent stem cells have the ability to self-renew, but they can differentiate into only a limited subset of cell types. For example, hematopoietic cells give rise to different types of blood cells, but not fat cells. Mesenchymal stem cells, another type of multipotent cells, can differentiate into a variety of cells such as that of the bone, fat and muscle.

Multipotent cells are derived from fetal tissues that are differentiated past the inner cell mass or from adult tissues. Adult stem cells are often quiescent within the niche. The differentiation lineages of these cells are usually determined by tracing them back to the respective germ layer of origin, for example, neural stem cells originate from the neuroectoderm.

Do these multipotent stem cells interconvert? There are some studies that show they can be converted. It has been found that the stem cell microenvironment can re-direct cell fate allowing crossing of primitive germ layer boundaries. When thymus is believed to be of endodermal origin and skin is of ectodermal origin, a group of researchers were able to convert thymic epithelial cells to hair follicle cells by culturing thymic cells in skin microenvironment. The multipotent cells resident in most body organs function to replenish aging, injured or dead cells throughout the lifespan of the organism, though aging adversely influences their ability to self-renew.

Terminal Differentiation - Checkpoint 3

When a multipotent stem has been differentiated into a terminally differentiated cell type, they cease to differentiate further. This is the third and final checkpoint in the fate a cell. In all probabilities, a neuron remains a neuron. Interestingly, oocytes and sperm are some of the most differentiated cells in our bodies, and these cells generate all cell types after fertilization. It is now possible to artificially convert a terminally differentiated adult somatic cell into a pluripotent cell, by inducing "forced" expression of specific genes. Such cells are called induced pluripotent stem cells (iPSc).

Stem cells may also be categorized into two broad types of cells based upon their origin: embryonic stem cells derived from the inner mass of the blastocyst, and adult stem cells derived from differentiated tissues; though origin of adult stem cells in some mature tissues is still under investigation. Though different stages of differentiation have been called checkpoints in this article, it is not necessary that a cell has to go through each checkpoint in its differentiation journey.

Another interesting area of stem cell biology is forcing differentiation of stem cells across lineage barriers, called trans-differentiation. It is a processby which a cell type committed to a specific developmental lineage switches to a different lineage. Though very interesting, research in this area is in very early stages to make any assumption on its potential impact in translation to patient care. However, considering the great interest and growth of research on induced pluripotent stem cells, we can conclude that at least for the time being trans-differentiation research is not in the mainstream.

Stem cells hold great promise in treating and curing human diseases. However stem cell research is also mired in controversies, mainly due to ethical concerns surrounding the use of embryonic stem cells. With the advent of technology to convert somatic stem cells to induced pluripotent stem cells and in the use of adult stem cells, it is unlikely that stem cell research will hold back. In addition, one great advantage of using adult stem cells or induced pluripotent stem cells is that cells from the same individual can be engineered to treat the disease condition, avoiding immunological rejection, as the cells are autologous. However, the use of engineered autologous stem cells in diseases with genetic basis may have limitations, as these cells may also transform to diseased states following transfer.

During the last 10 years, we have seen great strides in stem cell research. We have also seen some setbacks such as the termination of embryonic stem cell based spinal cord injury treatment by Geron. Hopefully, stem cell based therapies will become a common practice within the next 10 years.

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