August 2001
Pluripotent, embryonic stem cells originate as inner mass cells within a blastocyst. Source: Mike Jones, Wikimedia Commons.
This article aims to describe the recent progress in stem cell research and the likely future therapeutic applications.
The world of stem cells
We are aware that different types of cells make up our body (e.g., blood cells, skin cells, cervical cells) but usually forget to appreciate that all of these different cell types arose from a single cell, the fertilised egg. Developmental biologists study the awesome events that occur between the fertilised egg and the formation of a new individual.
- The first steps simply involve cell division: one cell becomes two cells; two cells become four cells, etc.
- Each of these individual cells of early development is not specialized (undifferentiated), that is it does not have a specific body function, and has the capability to contribute to all of the organs in an individual and thus are called totipotent.
- These cells are embryonic stem (ES) cells and have both the capacity to self-renew, thus maintaining a continuous supply of stem cells and the ability to give rise to specialized (differentiated) cell types, such as liver cells or brain cells.
- It is believed that once differentiated, cells remain so and usually lose their ability to divide.
Stem cells also exist in adults and allow specific tissues to regenerate throughout life. They also have the ability for self-renewal and multi-lineage differentiation. In fact, the list for identifying adult stem cells and lineage specific progenitor cells (with limited self-renewal ability) is growing.
Sources of stem cells
The main clinical application of stem cells is as a source of donor cells to be used to replace cells in transplantation therapy. Stem cells can be obtained from several sources:
Spare embryos: stem cells can come from leftover embryos stored at fertility clinics that were not used by couples to have children.
Special purpose embryos: embryos are created in vitro fertilization (artificially in the lab) for the sole purpose of extracting their stem cells.
Cloned embryos: embryos are cloned in labs using somatic nuclear transfer method in order to harvest their stem cells.
Aborted fetuses: stem cells are taken from fetuses in early development that have been aborted.
Umbilical cords: this after-childbirth tissue holds potential for research.
Adult tissue or organs: stem cells are obtained from the tissue or organs of living adults during surgery.
Cadavers: isolation and survival of neural progenitor cells from human post-mortem tissues (up to 20 hours after death) has been reported and provides an additional source of human stem cells.1
Embryonic stem cells must be obtained when an embryo is in early development, that is, when the fertilised egg has divided to form about 1000 cells. These cells are separated and maintained in a cell culture dish, thereby halting embryonic development towards creating an individual. This is why embryonic stem cell research is the subject of ethical debates. Utilization of adult stem cells pose less of an ethical dilemma: however, adult stem cells may not have the same potential as those derived from embryos for medical therapeutics.
Comparing embryonic and adult stem cells
Embryonic stem cells have advantages and disadvantages for therapy.
Advantages: They are
- Flexible: They have the potential to make any body cell.
- Immortal: One cell line can potentially supply endless amounts of cells with carefully defined characteristics.
- Easily available: human embryos can be obtained from fertility clinics.
Disadvantages: They could be
- Difficult to control: The method for inducing the cell type needed to treat a particular disease must be defined and optimized .
- At odds with a patient’s immune system: It is possible that transplanted cells would differ in their immune profile from that of the recipient and so would be rejected.
- Ethically controversial: Those who believe life begins at conception say that doing research on human embryos is unethical even if donors give their consent.
Adult stem cells also have good and difficult characteristics for therapy.
Advantages: They are
- Already somewhat specialized: Inducement may be simpler.
- Immune hardy: Recipients who receive the products of their own stem cells will not experience immune rejection.
- Flexible: Adult stem cells may be used to form other tissue types.
- Mixed degree of availability: Some adult stem cells are easy to harvest and others, such as neural (brain) stem cells, can be dangerous to the donor.
Disadvantages: They could be
- Minimal quantity: They are difficult to obtain in large quantities.
- Finite: They don’t live as long in a culture as embryonic stem cells.
- Genetically unsuitable: The harvested stem cells may carry genetic mutations for disease or become defective during experimentation.
The surprising property of adult stem cells: transdifferentiation
Adult stem cells were thought to be restricted to produce differentiated cells, which were specific to the organ from which they were isolated. Recently, several examples have been reported which demonstrate that these stem cells, under certain conditions, can be induced to form other cell types (transdifferentiation). For example:
- neural stem cells (NSC) can give rise to blood and skeletal muscle
- bone marrow cells can give rise to muscle, liver cells, and astrocytes
When NSCs were used to form muscle, no inducers were needed other than co-culturing them with muscle progenitor cells (myoblasts) or injecting them into muscle.2 This holds promise for cell transplantation therapies in that the experiment suggests that host tissue can instruct transplanted cells to a desired result. Scientists, then, can consider whether it is best for stem cells to be differentiated in vitro (artificially) prior to transplantation or by transplanting them directly into the defective tissue. Some experiments have shown that naturally transplanted stem cells were able to migrate to regions where cells had died due to stroke (called ischaemia).
Stem cell therapies
Stem cells offer the opportunity of transplanting a live source for self-regeneration. Bone marrow transplants (BMT) are a well known clinical application of stem cell transplantation. BMT can repopulate the marrow and restore all the different cell types of the blood after high doses of chemotherapy and/or radiotherapy, our main defence used to eliminate endogenous cancer cells. The isolation of additional stem and progenitors cells is now being developed for many other clinical applications. Several are described below.
Skin replacement
The knowledge of stem cells has made it possible for scientists to grow skin from a patient’s plucked hair. Skin (keratinocyte) stem cells reside in the hair follicle and can be removed when a hair is plucked.3 These cells can be cultured to form an epidermal equivalent of the patients own skin and provides tissue for an autologous graft, bypassing the problem of rejection. It is presently being studied in clinical trials as an alternative to surgical grafts used for venous ulcers and burn victims.
Brain cell transplantation
Neural stem cells were only until recently thought to be strictly embryonic. Many findings have proved this incorrect. The identification and localisation of neural stem cells, both embryonic and adult, has been a major focus of current research. Potential targets of neural stem cell transplants include stroke, spinal cord injury, and neurodegenerative diseases such as Parkinson’s Disease.
Parkinson’s Disease involves the loss of cells which produce the neurotransmitter dopamine. The first double-blind study of fetal cell transplants for Parkinson’s Disease reported survival and release of dopamine from the transplanted cells and a functional improvement of clinical symptoms.4 However, some patients developed side effects, which suggested that there was an oversensitization to or too much dopamine. Although the unwanted side effects were not anticipated, the success of the experiment at the cellular level is significant. Again, further studies are needed and ongoing. Over 250 patients have already been transplanted with human fetal tissue.
Several biotechnology companies are developing different strategies of stem cell therapies.
Diacrin has been developing xenotransplants using fetal pig cells. Clinical trials for chronic stroke patients have begun. Presently, stroke patients require treatment within 24 hours after stroke for effective therapeutic results. Many patients do not receive treatment in time because the symptoms are not initially obvious. Diacrin’s therapy could be applied weeks to months after the initial trauma.
NeuroNova’s strategy is to culture adult human cells from donors, differentiate them in culture to produce the cell type (dopaminergic neurons) which is lost in Parkinson Disease, and to transplant them into the brain of patients.
Neurotech is using genetically altered brain endothelial cells (engineered to produce human Interleukin-2) as immunotherapy for gliomas. Results from experiments in rats showed that these cells “mopped up” the tumour cells and as a result a clinical study has commenced.
Treatment for diabetes
Diabetes affects 16 million people in the U.S. and is caused by the abnormal metabolism of insulin. Normally, insulin is produced and secreted by the cellular structures called the islets of Langerhans in the pancreas. Recently, insulin expressing cells from mouse stem cells have been generated.5 In addition, the cells self assemble to form structures, which closely resemble normal pancreatic islets and produce insulin. Future research will need to investigate how to optimise conditions for insulin production with the aim of providing a stem cell-based therapy to treat diabetes to replace the constant need for insulin injections.
Future directions
The generation of new neurons in the adult brain is limited. However, self-repair of neuronal cell death has been recently demonstrated in the mouse and suggests that stem cells which normally reside in the brain may someday be able to be stimulated by inducers in a manner similar to how we induce our immune system by vaccination.6 This would bypass the need for cell transplantation. Intensive research needs to be pursued into the cell mechanisms involved.
The potential of embryonic stem cells to provide other differentiated cell types needs to be investigated. The production of cardiac muscle cells, which have thus far been evasive, would hold tremendous promise for the number one killer: heart disease.
Scientists and stem cell research
Scientists believe that stem-cell research could lead to cures for a myriad of diseases afflicting humans. Anti-abortion groups, some religious groups, and conservative citizens say that using cells from embryos is immoral because it destroys life. However, a recent ABCNews/Beliefnet poll has shown that Americans support stem cell research by a 2-1 margin and say that it should be funded by the federal government, despite controversy over the use of human embryos.7
Most scientists Do Not support applications for human reproductive cloning (that is, they do not want any embryos altered during stem cell research to develop past a defined stage). They agree with governments and concerned citizens that it should be banned worldwide. However, they Do want the opportunity to continue stem cell research for clinical applications under appropriate regulation and legislation with the hope of alleviating human suffering.
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