STEM CELL: A REVOLUTION IN THE MODERN BIOLOGY

                                  Bijayalaxmi Pradhan and Rajesh Kumar Mohapatra

                                     Utkal University, Bhubaneswar, Odisha-751004

INTRODUCTION

            Stem cells are one of the most fascinating areas of biology today. But like many expanding fields of scientific inquiry, research on stem cells raises scientific questions as rapidly as it generates new discoveries.

            Human development begins when a sperm fertilizes an ovum and forms a single celled zygote that has the potential to form an entire organism. Thus, the fertilized ovum is totipotent. In the first few hours, this cell divides into identical totipotent cells. After four days of fertilization and after several cycles of cell division, these totipotent cells begin to specialize, forming a hollow sphere of cells, called blastocyst. The blastocyst has an outer layer of cells and an inner cell mass. The inner mass of cells is pluripotent, i.e., they can give rise to many types of cells necessary for foetal development. The pluripotent stem cells undergo further specialization into stem cells that are committed to give rise to cells that have a particular function.

Research on stem cells is advancing knowledge about how an organism develops from a single cell and how healthy cells replace damaged cells in adult organisms. This promising area of science is also leading scientists to investigate the possibility of cell-based therapies to treat disease, which is often referred to as regenerative or reparative medicine.

WHAT ARE STEM CELLS, AND WHY THEY ARE IMPORTANT?

            Stem cells are undifferentiated cells which have the remarkable potential to divide for indefinite periods in culture and give rise to many different cell types on differentiation. In addition, in many tissues they serve as a sort of internal repair system, dividing essentially without limit to replenish other cells as long as the person or animal is still alive. When a stem cell divides, each new cell has the potential either to remain a stem cell (symmetrical cell division) or become another type of cell with a more specialized function (asymmetrical cell division).

            Stem cells are important for living organisms for many reasons. In the 3- to 5- day-old embryo, called a blastocyst, the inner cells give rise to the entire body of the organism, including all of the many specialized cell types and organs such as the heart, lung, skin, sperm, eggs and other tissues. In some adult tissues, such as bone marrow, muscle and brain, adult stem cells generate replacements for cells that are lost through normal wear and tear, injury, or disease.

            Because of their unique regenerative abilities, stem cells offer new potentials for treating diseases such as diabetes, and heart disease. However, much work remains to be done in the laboratory and the clinic to understand how to use these cells for cell-based therapies to treat disease, which is also referred to as regenerative or reparative medicine.

WHAT ARE THE UNIQUE PROPERTIES OF STEM CELLS?

Stem cells differ from other types of cells in the body. All stem cell, regardless of their source; have three general properties: 1) they are capable of dividing and renewing themselves for long periods; 2) they are unspecialized; and 3) they can give rise to specialized cell types.

1)      Stem cells are capable of dividing and renewing themselves for long periods

Unlike muscle cells, blood cells, or nerve cells, which do not normally replicate themselves, stem cells may replicate many times. When cells replicate themselves many times over, it is called proliferation. A starting population of stem cells that proliferates for many months in the laboratory can yield millions of cells. If the resulting cells continue to be specialized, like the parent stem cells, the cells are said to be capable of long-term self-renewal.

2)      Stem cells are unspecialized

One of the fundamental properties of a stem cell is that it does not have any tissue-specific structures that allow it to perform specialized functions. However, unspecialized stem cells can give rise to specialized cells, including heart muscle cells, blood cells, or nerve cells.

3)      Stem cells can give rise to specialized cells

When unspecialized stem cells give rise to specialized cells, the process is called differentiation. Scientists are just beginning to understand the signals inside and outside cells that trigger stem cell differentiation. The internal signals are controlled by a cell's genes while the external signals for cell differentiation include chemicals secreted by other cells, physical contact with neighboring cells and certain molecules in the microenvironment.

KINDS OF STEM CELLS

                  Scientists primarily work with two kinds of stem cells from animals and humans: embryonic stem cells and non-embryonic "somatic" or "adult" stem cells.

                  Scientists discovered ways to obtain stem cells from early mouse embryos more than 30 years ago in 1981. Many years of detailed study of the biology of mouse stem cells led to the discovery, in 1998, of how to isolate stem cells from human embryos and grow the cells in the laboratory. These are called human embryonic stem cells. In 2006, researchers made another breakthrough by identifying conditions that would allow some specialized adult cells to be "reprogrammed" genetically to assume a stem cell- like state. This new type of stem cell, called induced pluripotent stem cells ( iPSCs).

1) Embryonic stem cells

Embryonic stem cells, as their name suggests, are derived from embryos that develop from eggs that have been fertilized in vitro. The embryos from which human embryonic stem cells derived are four- or five-day-old and are a hollow microscopic ball of cells called the blastocyst. The blastocyst includes the trophoblst, the blastocoel and the inner cell mass. The inner cell mass is the source of embryonic stem cells-totipotent cells. When extracting embryonic stem cells, the blastocyst stage signals when to isolate stem cells by placing the "inner cell mass" of the blastocyst into a culture dish containing a nutrient-rich broth. Lacking the necessary stimulation to differentiate, they begin to divide and replicate while maintaining their ability to become any cell type in the human body. Eventually, these undifferentiated cells can be stimulated to create specialized cells.

2)  Adult stem cells

An adult or somatic stem cell is an undifferentiated cell, found among differentiated cells in a tissue or organ that can renew itself and can differentiate to yield some or all of the major specialized cell types of the tissue or organ. The primary roles of adult stem cells in a living organism are to maintain and repair the tissue in which they are found. Unlike embryonic stem cells, which are defined by their origin, the origin of adult stem cells in mature tissues is still under investigation.

Research on adult stem cells has recently generated a great deal of excitement. Scientists have found adult stem cells in many more tissues than they once thought to possible.

One important point to understand about adult stem cells is that there are a very small number of stem cells in each tissue, and once removed from the body; their capacity to divide is limited, making generation of large quantities of stem cells difficult. Scientists in many laboratories, therefore, are trying to find better ways to grow large quantities of adult stem cells in cell culture and to manipulate them to generate specific cell types so that they can be used to treat injury or disease.

Adult stem cells have been identified in many organs and tissues, including brain, bone marrow, peripheral blood, blood vessels, skeletal muscle, skin, teeth, heart, gut, liver, ovarian epithelium, and testis.

3) Induced pluripotent stem cells (iPSCs)

These are adult cells that have been genetically reprogrammed to an embryonic stem cell-like state by being forced to express genes and factors important for maintaining the defining properties of embryonic stem cells. Although these cells meet the defining criteria for pluripotent stem cells, it is not known if iPSCs and embryonic stem cells differ in clinically significant ways.

What are the similarities and differences between embryonic and adult stem cells?

                        Both adult and embryonic stem cells differ in the number and type of differentiated cell types they can become. Embryonic stem cells can become all cell types of the body because they are pluripotent. Adult stem cells are generally limited to differentiating into different cell types of their tissue of origin. However, some evidences suggest that adult stem cell plasticity may exist, increasing the number of cell types. Large number of embryonic stem cells can easily be grown in culture, while adult stem cells are rare in mature tissues and methods for expanding their numbers in cell culture have not yet been worked out.

WHAT ARE THE POTENTIAL USES OF HUMAN STEM CELLS?

            There are many ways in which stem cells can be used. However, there are many technical hurdles between the promise of stem cells and the realization of these uses, which only be overcome by continued intensive stem cell research. The important applications of human stem cells are as follows:

Use in basic research

Pluripotent stem cells could help us to understand the complex events that occur during human development. The functions of genes, the factors affecting their ‘on' and ‘off' activity, will come to light. A better understanding of normal cell processes will help us to understand abnormal cell specialization and cell division in neoplasia, congenital birth defects, etc.

Drug development

Human pluripotent stem cells could be used to develop drugs and test them for safety. For example, new drugs would be initially tested using human stem cell lines and thus streamline the process of drug development.

Cell-based therapy

Perhaps the most important potential application of human stem cells is the generation of cells and tissues that could be used for cell-based therapies. Today, donated organs and tissues are often used to replace ailing or destroyed tissue, but the need for transplantable tissues and organs far outweighs the available supply. Stem cells, directed to differentiate into specific cell types, offer the possibility of a renewable source of replacement cells and tissues to treat diseases including Parkinson's disease and Alzheimer's disease, spinal cord injury, stroke, burns, heart disease, diabetes, rheumatoid arthritis etc.

LIMITATIONS/ OBSTACLES

            Any cell used in transplantation would need to be autologous, immunologically masked, and have homogenous cell phenotypes. Pure populations of cell types would be a pre-requisite, since the introduction of contaminating pluripotent stem cells during transplantation might give rise to teratomas. In transplantation, prevention of rejection is one of the most important issues. There are many regimes utilized to immunosuppressant hosts prior to transplantation to facilitate graft acceptance.

            Embryonic stem cell technology together with cloning can be useful in planned human tissue therapy. People could provide their own cells, and by using them to replace the nuclei of their own or donor eggs, obtain cells in culture and then induce differentiation to provide individually tailored tissues for replacements without any rejection problems, offering life long treatment.

ETHICAL ASPECTS

            The embryonic stem cells are usually obtained after destruction of the embryo, to which ethical and regulatory objections are raised. Many countries in the world have recently come up with regulations to restrict the stem cell research only to a few laboratories, to prevent unwarranted genetic manipulations.

            For many years, experience has been gained on embryo and gamete manipulation in livestock animals. Currently, it is attempted to isolate stem cells from embryos derived from unfertilized eggs (parthenogenesis), so that ethical problems surrounding the use of normal, competent embryos are avoided.

            Utilization of adult stem cells in cell based therapy; however, is not a compromise but one of the most prospective ways to treat a variety of serious diseases, and also to overcome some of the methodical and ethical issues associated with embryonic stem cell research.

FUTURE OF STEM CELL RESEARCH

            Recent breakthrough in the understanding of the intrinsic and extrinsic regulators of stem cell proliferation and factors controlling cell lineage determination have made possible to culture human stem cells. The clinical applications of the cultured stem cells are limited by the lack of suitable markers needed for the identification and selection of cells within proliferating population of precursor cells. The methodology to manipulate potential specification of stem cells undergoing differentiations not fully understood. The assessment of long term results of cultured stem cells originating from transdifferentiation or nuclear transplantation procedures in a clinical setting, and their safety following transplantation has only begun to be addressed. Since the human genome has already been analyzed, the manipulation of the culprit genes in different diseases using cultured stem cells will be a novel treatment modality to alleviate human suffering. The use of genetically modified stem cells that have been pass aged in tissue cultures for long periods of time, could have genetic mutations for which the quality control measures and screening procedures are yet to be developed.

CONCLUSION

             The stem cell technology has revolutionized modern biology. It has helped us to understand normal morphogenesis and mechanisms that lead to pathological conditions. The development of human embryonic and adult stem cell is a major breakthrough and is hoped that human stem cells could be genetically modified and specific cell types isolated. The use of stem cells in transplantation therapies may become a reality. However, a lot of systematic and comprehensive research is needed before in vitro differentiated and genetically modified human stem cells could be used therapeutically.