Stem Cells: Self-Renewal, Differentiation, and Heterogeneity

by englishkingship (student)

Project Update #1

Joe Buran, Nick Rotella, Karamveer Birthare

Introduction- Stem cells are biological cells found in all multi-cellular organisms, and have the potential to develop into several different types of cells in the body during their early life and throughout growth. They also play a major role in the regeneration of many tissues, as they continue to divide almost without limit as long as the organism is still alive. After a stem cell divides, it can either remain a stem cell or continue to grow, or it can differentiate into a more specific cell with a specialized function.

Heterogeneity of Stem Cells- The classical definition of a stem cell requires that it possesses two properties, or metastable cell states. The first property, self-renewal, means that they have the ability to go through numerous cycles of cell division while maintaining the undifferentiated state. Secondly, they must possess potency. This is the ability under certain physiological conditions to become, or differentiate, into tissue or organ-specific cells with defined tissues. However, in other areas and tissues of the body, stem cells may only divide under special biological conditions. The ability of a stem cell to maintain both metastable cell states is referred to as stem cell heterogeneity. Various groups of scientists have identified specific transcription factors that maintain a stem cell's self-renewal abilities. Expression of these transcription factors fluctuate in response to extracellular stimuli, thus directing which metastable cell state the stem cell is currently in. For example, the transcription factor Nanog pertains to a stem cell's self-renewal ability. Expression of Nanog is shown in two forms, positive and negative. Positive Nanog shows a higher propensity for self-renewal and negative Nanog shows a higher propensity for differentiation. Nanog expression can be controlled using extracellular stimuli and shifted between positive and negative expression types. This ability of the stem cell to be shifted between both expression types depending on extracellular stimuli therefore proves the existence of heterogeneity in stem cells. Along with Nanog, other important transcription factors that help maintain a stem cell’s self-renewal ability include Oct4, Klf4, and Sox2.

There are 3 major types of stem cells scientists use today – embryonic, ‘somatic’ or ‘adult’ stem cells, and induced pluripotent stem cells (iPSC’s). The uniqueness of stem cells and their self-renewal and regenerative abilities provide incredible potential for advancements in the field of regenerative medicine. However, a lot of work still remains to be performed and studied in order to fully understand these unique cells and reach the full potential of their use. Researchers hope that one day stem cells can be used to treat various diseases such as diabetes and heart disease.

Self-Renewal of Stem Cells- ...

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Self-Renewal of Stem Cells- A stem cell must be able to renew itself indefinitely, and also produce cell progeny which mature into organ specific cells with a specific function. In order to do this, the stem cell needs to divide continuously. To ensure that a stem cell population is maintained, two mechanisms exist. The first is obligatory asymmetric replication, in which a stem cell divides into one ‘father’ cell that is identical to the original stem cell, in addition to another daughter cell that is differentiated. Stochastic differentiation also occurs, which means that when one stem cell develops into two differentiated daughter cells, another stem cell undergoes mitosis and produces two stem cells identical to the original.

Scientists are still a long way from understanding this mechanism. For example, researchers have tried to grow human hematopoietic stem cells in culture without much success, as the cells fail to maintain stem cell characteristics, even when the numbers of cells are increased dramatically. Embryonic stem cells are currently the only stem cells that can be propagated and amplified in culture without losing their stem cell characteristics, and are therefore a primary subject of stem cell research. Research is ongoing to understand everything there is to know behind the asymmetric divisions of stem cells, to unravel the molecular pathway behind self-renewal, and analyzing global gene expression patterns in various types of stem cells. A great understanding of these pathways is vital to scientists as they try to grow the very small number of stem cells they obtain from patients for therapeutic purposes.

As we have discussed stem cells can give way to several different types of specialized cells. The process through which non-specialized cells acquires functional characteristics to form highly specific cells such as, muscle cells, heart cells etc. is called as differentiation.

Differentiation is affected and partly controlled by interaction of physical and chemical condition prevalent outside the cell with genes within a cell. These interactions usually take place through internal and external signaling through proteins embedded on the cell surface. These signals control changes in cell structures and functions, which could be chemical or physical in nature. Cells undergo through various step in order to become very specifically specialized when they undergo differentiation.

Differentiation is a really important aspect of stem cells that allow us to potentially generate large no of cells with specific characteristics. Directed differentiation is a process where stem culture conditions are manipulated in order to induce differentiation for specific characteristics.

Modeling of Stem Cells- Stem cells when modeled towards our need for a specific type of cell through controlled differentiation, opens possibilities for variety of cell therapies that could help replacement of tissues in the body, generate a lost limb and could possibly treat variety of diseases such as heart diseases, Parkinson’s disease, Alzheimer’s disease, diabetes etc.

The heterogeneity of stem cells is extremely unique, separating stem cells as one of the most fascinating areas of biology. Scientific questions regarding stem cell self-renewal and differentiation continue to be explored and answered. However, with nearly every new discovery, new questions arise. Some of these questions may be answered through the use of computer modeling, with the hope of speeding up the scientific discovery process so we many someday fully understand every aspect of stem cell properties and capabilities.

References –

Graf, T., and M. Stadtfield. "Heterogeneity of Embryonic and Adult Stem Cells." ScienceDirect.com. Cell Stem Cell, Nov. 2008. Web. Feb. 2012. <http://www.cell.com/cell-stem-cell/retrieve/pii/S1934590908005304>.
Kaderei, S. "Stem Cells and Self-Renewal." International Society for Stem Cell Research. Web. Feb. 2012. <http://www.isscr.org/public/SC_self-renewal.pdf>.