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STEM CELLS AND ITS APPLICATION
IN THE FUTURE
Ahmad Aulia Jusuf, MD, AHK, PhD
Depart of Histology, Faculty of Medicine, University of Indonesia
2009
INTRODUCTION
In the last decade the interests and researches about stem cell has been establishing well.
It has correlation with the efforts of the people in treating the diseases that are untreated with the
conservative or surgical treatment.
Nowadays many scientists have been investigating the potency of stem cells in the
treatment of untreatable diseases such as degenerative diseases and other abnormalities due to the
trauma, cancer, etc. Stem cells are also used in the researches to get the new drugs in the
laboratory level and to study the pathogenesis of the diseases. The interests in researching the
stem cell is also correlates with its potency in business when the stem cells has been used widely
in treatment of the untreated diseases or when the new drug has been recovered.
This manuscript will explain the definition of stem cells, its characteristic, types and
sources of stem cells, its potencies and its application in the medicine and the ethical problem of
using stem cells in research and treatment.
DEFINITION
Stem cells1,2 are unspecialized cells that have the ability to differentiate into many various
types of specific cells to generate the various tissues in the body.
CHARACTERISTIC AND TYPES OF STEM CELLS
Stem cells have 2 specific properties:
1. The ability to differentiate is the potential to develop into other cell types. Stem cells
have the capacity to differentiate to become nerve cells, cardiac cells, skeletal muscle
cells, pancreatic cells etc
2. Self regenerate / self renew 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
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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.
Figure-1 Differentiation and Self Regenerate of Stem Cells
Based on the ability to differentiate, the Stem cells are grouped into 3 groups1,2,3
1. Totipotent stem cell
Totipotent stem cells are produced from the fusion of an egg and sperm cell. Cell
produced by the first few divisions of the fertilized egg, known as Morula, are also
totipotent. These cells can differentiate into embryonic and extraembryonic cell types
such as placenta and umbilical cord.
2. Pluripotent stem cell
Pluripotent stem cells are the descendants of totipotent cells and can differentiate into
cells derived from any of the three germ layers (ectoderm, mesoderm and endoderm), but
not the placenta and umbilical cord. The example of pluripotent stem cell is embryonic
stem cells. Embryonic stem (ES) cells are the cells obtained from the inner cell mass of
blastocyst.
Figure-2 Totipotent and Pluripotent
3. Multipotent stem cell
Multipotent stem cell can produce only cells of a closely related family of cells. For
example hematopoietic stem cells differentiate into red blood cells, white blood cells,
platelets, etc. Neural stem cells has the ability to differentiate into nerve cells (neuron)
and glial cells.
4. Unipotent stem cell
Unipotent stem cell can produce only one cell type, but have the property of self
renewal which distinguishes them from non-stem cells Erythroid progenitor cell is
the example of unipotent stem cell that can only differentiate into erythrocytes.
According to its source1,3,4, stem cells are classified as
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1. Zygote is the ultimate stem cell produced from the fusion of an egg and sperm cell.
2. Embryonic stem cells (ES cells) are the cells obtained from the inner cell mass of
blastocyst. A blastocyst is an early stage embryo approximately four to five days
old in humans and consisting of 50–150 cells. ES cells are the best characterized of
all the cultured stem cells. Properties of ES cells are pluripotent (i.e. they have the ability
to differentiate into cells derived from all three germ layers, but not the embryonic
membranes) and immortal (i.e. cells proliferate in culture and have been maintained in
Figure-3. Multipotent and Unipoten stem cells in the bone marrow
Figure-4. Embryonic Stem (ES) Cells
culture for several hundred doublings). ES cells are obtained commonly from the retained
of unused embryos from IVF (invitro fertilization) procedures. Using of ES cells in
research and treatment is still controversial due to the ethical issues.
3. Fetus, usually obtained from abortion clinic
4. Stem cell from umbilical cord blood is obtained from the blood of umbilical cord and
placenta just after birth. Stem cells from umbilical cord blood is hematopoietic stem cells,
even some of scientists classify it as adult stem cell. Until now there are 2 types of stem
cells found in the umbilical cord blood hematopoietic stem cells and mesenchymal stem
cells. Except of those cells, umbilical cord blood also contains another types of stem cells
for example neuron like stem cells, but it still needs many researches5. Umbilical cord
blood has low immunogenecity6, no needs invasive procedures and no needs 100%
matched of HLA (human leucocyte antigen)7
Figure-5 Umbilical cord blood
5. Adult stem cells refers to any cell which is found in a developed organism that has two
properties: the ability to divide and create another cell like itself and also divide and
create a cell more differentiated than itself. Adult stem cells obtained from
a. Bone marrow
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There are two types of stem cells in the bone marrow : the hematopoeitic stem
cells that will develop into various types of blood cells and stromal stem cells or
mesenchymal stem cells.
b. Other adult tissues such as central nervous tissue, adipose tissue, skeletal muscle,
pancreas etc.
Figure-6 Adult Stem Cells
Figure-7 Plasticity of adult stem cells
Adult stem cell has ability to differentiate into multiple cell types known as plasticity or
transdifferentiation. For example hematopoietic stem cells may differentiate into three
major types of brain cells (neurons, oligodendrocytes, and astrocytes); skeletal muscle
cells; cardiac muscle cells; and liver cells. Bone marrow stromal cells may differentiate
into: cardiac muscle cells and skeletal muscle cells. Brain stem cells may differentiate
into: blood cells and skeletal muscle cells.
Figure-9 Types of Stem cells
APPLICATION OF CULTURED STEM CELLS
The most prominent of application of cultured stem cells is cell therapy for treating
conditions such as spinal cord injuries and for curing disease. Stem cells are also used to
investigate questions to further basic and clinical research
1. Gen therapy.
Stem cells specially the hematopoetic stem cells can be used to carry the transgene into the
patient body. The successful of stem cells to express the transgene then can be determined.
There is a possibility of administration of transgene containing stem cells into the body is
only one times, because the stem cells has the property of self renewing. In the other hand the
hematopoietic stem cells can differentiate into many various blood cells implicating that the
transgene may present in many cell types.
2. Studies of biological processes.
The study about the developmental process of organism and cancer are facilitated by
the ability to trace stem cell fate
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3. Research to discover and to develop the new drugs, especially to investigate the effect
of drugs on the tissues
4. Cell based therapy
Stem cells can be cultured and manipulated in the laboratory, followed by transplantation
them into the patient in treatment of the diseases without disturbing the function of the body
Figure-10 The useful of cultured stem cells.
THE APPLICATION OF USING STEM CELLS IN THE TREATMENT OF THE
DISEASES
Nowadays the researchers are performing many researchs by using stem cells in
treatment of various diseases. The using of stem cells in the treatment of the diseases known as
Cell based therapy. The principle of this therapy is to do the transplantation of stem cells in the
target organ. The aims of stem cell transplantation are
1. to achieve the development and the growing of new healthy cells in the tissue or organ of the
patient.
2. to replace the impaired specific cells due to the diseases or trauma with the new transplant
cells.
Embryonic stem cells has a good plasticity and has the ability to be developed to become
many various tissues such as nerve cells (neuron), cardiomyocytes, osteoblast, fibroblast, and
blood cells, so it can be used to replace the impaired tissues. Adult stem cell also can be used to
treat the degenerative diseases, but its plasticity has been decreased. The advantage of using
adult stem cells in research and therapy is less from the ethical issues.
Nowadays the stem cells are used widely in the therapy of degenerative diseases because the
stem cell from umbilical cord blood is easy to be obtained, has low immunogenecity, no needs the
invasive procedures and no needs the 100% matched of HLA (human leucocyte antigen)7.
By using the suitable nutrient stem cells proliferate itself in the laboratory without
undergoing differentiation. Thus the daughter cells have the same genetic material as its parents.
The following stem cell characteristics make them good candidates for cell-based therapies
1. Potential to be harvested from patients, so it can avoid the possibility of rejection
reaction in the recipient
2. High capacity of cell proliferation in culture to obtain large number of cells from a
limited source
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3. Ease of manipulation to replace existing non functional genes via gene transfer
methods
4. Ability to migrate to host's target tissues, e.g. the brain
5. Ability to integrate into host tissue and interact with surrounding tissue
The advantages of using stem cell transplants in the therapy of the diseases are
1. It does not need the matching of tissue properties between donor and recipient
2. Autologous transplantation is better to be used.
3. To avoid the rejection reaction of the recipient the Somatic Cell Nuclear Transfer
(SCNT) or therapeutic cloning method can be used. SCNT is the method in transferring
the stem cells to the recipient without rejection reaction. In this method the patient's DNA
is injected into an enucleated unfertilized egg and used to generate ES cells which are
4.
Figure-11 Somatic Cell Nuclear Transfer (SCNT)
then cultured and allowed to differentiate, followed by transplantation into the patient. The
stem cells in the desired organ or tissue then differentiate into the specific cells such as beta
cell of pancreas, heart muscle etc. This technique is called therapeutic cloning. The use of
such cells may bypass the ethical objections and immunological issues of using ES cells and
is the future of stem-cell clinical application.
Figure-12 Embryonic Stem (ES) cells
In the past it was thought that embryonic stem (ES) cell may proliferate in the unlimited
number. However, now it has already known that the proliferation of stem cells is limited due to
the mutation in their genes, stimulated by the nutrient broth in culture media.
The advantages of using of ES cells in Cell based therapy in the therapy of diseases are
1. Ease to be obtained from the fertilization clinic
2. It is pluripotent stem cell
3. It is immortal cell that can proliferate in hundred times.
4. Low rejection reaction
The disadvantages of using ES cells in the therapy of diseases are
1. It has the possibility to become cancer (tumorigenic)
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2. It is allogenic transplants that has an implication in the rejection reaction due to
immunological process
3. It is still a controversy in the ethical issues
The advantages of using adult stem cells in the therapy of diseases are
1. It can be isolated from the tissue of patient itself, so it can avoid the rejection reaction
2. The limited capacity to differentiate into another cells
3. It does not have the controversy in ethical aspect.
The disadvantages of using adult stem cells in the therapy of diseases are
1. the number in very small in the mature tissue
2. the limited of lifespan
3. it is a multipotent stem cells
Nowadays stem cells which are isolated from umbilical cord blood (cord blood stem cells) is
believed to be a new hope in the cell based therapy. The advantages of using cord blood stem in
the therapy of diseases are
1. It is ease to be obtained from the umbilical cord blood bank
2. It is ready to use because it has been screened, tested and freeze.
3. It has minimal viral contamination than bone marrow stem cells
4. The procedure is very simple
5. The risk of Graft Versus Host Disease (GVHD) is lower than bone marrow stem cells.
The disadvantages of using cord blood stem are
1. the risk of genetic diseases
2. it is impossible to obtain sufficient numbers of stem cells from most cord blood
collections to engraft an adult of average weight.
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 and Alzheimer's diseases, spinal cord injury, stroke, burns, heart disease, diabetes,
osteoarthritis, and rheumatoid arthritis.
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APPLICATION OF STEM CELLS IN THE THERAPY OF CEREBRO
VASCULAR DISEASE
In the past there is a dogma from Cajal, a famous scientist in neurology that the impairment
of nerve cells in the brain was permanent and the nerve cells had no capacity to regenerate.
Nowadays this dogma has been change after the scientists know that the nerve cells in the brain
have plasticity and the stem cells has been discovered in the brain.
Research of using cord blood stem cells in the therapy of cerebrovascular disease9,10gave the
good result. In this research the cord blood stem was injected into the mouse in which its media
cerebri artery had been occlusion. The function of the brain increased to 70% in the group that
received the cord blood stem cells. Intravenous injection of mesenchymal stem cells (MSC)11
isolated from bone marrow into the brain of 30 patient with cerebrovascular diseases increased
the function of the brain according to the Barthel Index and modified Rankin Scale.
In this research the mesenchymal stem cells was obtained from bone marrow aspiration
12
. After peripheral injection, MSC passes the blood brain barrier in the damage area of
the brain13. Administration of MSC intravenous decreased the risk of apoptosis and
induced the proliferation of endogenous cells after stroke14,15.
Figure- 13. The increasing of brain function in the stroke patient that received the MSC
transplants, evaluated with the parameters of Barthel index and modified
Rankin Scale10
APPLICATION OF STEM CELLS IN MYOCARD INFARC
In the acute myocard infarct the circulating bone marrow stem cells and stem cells in the
heart moved to the damage area, but the number is not enough to overcome the abnormality.
These stem cells make the heart muscle and perform the neovascularization. The additional
exogenous stem cells from bone marrow or other resource such as cord blood stem cells are
needed to repair the damage area.
Bartinek16 had done the intracoronary infusion of bone marrow stem cells (autolog) on
the 22 patients with acute myocard infarct and got the good result.
There is the evidence that embryonic and adult stem cells can replace the damage heart
muscle and gives neovascularization. Strauer et al.17 inserts the mononuclear bone marrow
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(autolog) into the occlusion artery when doing the percutaneus transcoronary angioplasty 6 days
after myocard infarct. Ten patient that received the stem cells has the smaller infarct area and
smaller index of stroke volume than patient without insertion of stem cells. The left ventricular
end systolic volume, the contractility of heart muscle in the infarct area and mocard perfusion are
increased compared to the control group.
APPLICATION OF STEM CELLS IN SKIN REPLACEMENT4
The knowledge of stem cells permit the scientists to make the epidermis from keratinocytes
isolated from hair follicles This discovery permits the epidermal transplantation from its own
patient and avoids the rejection reaction. The usage of skin replacement is useful in the therapy of
wide skin wound and traumatic burn.
BIOETHICAL ASPECT IN THE RESEARCH OF STEM CELL AND USING OF
STEM CELLS IN THE TREATMENT OF HUMAN DISEASES
Using of stem cells especially embryonic stem (ES) cell in the research and treatment
of the human diseases may implicate in the arising of ethical problems. Several ethical
issues that have to be thought are
1. Is the use of embryo in the research that implicates in the death of embryo itself
violates the human right?
2.
Is the use of excessive embryos from the IVF procedures for research permitted
ethically?
3. Is the research to make embryos in which their body parts are used for treatment
of human diseases ethically permitted?
The main issue in the using of stem cell is the resource of stem cell itself. Embryonic
stem (ES) cells are obtained commonly from several resource such as abortion, the
excessive embryo from IVF procedure and cloning process. Cloning of human embryos
in order to get the stem cells is the controversial issue. It has correlation with the issue of
“the beginning of life” and the respect of life itself. Cloning of human embryo is
prohibited by all of the religions.
The procedures in harvesting the stem cells from human embryos will destroy the
embryo and make the embryo to be death. There is the argument that the status of human
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embryo is same with the human itself. Thus all of the procedures in collecting the stem
cells from human embryo are not permitted by the religion.
The status of human embryo is still debatable. Does the human embryo has to be
appreciated as the human because it has a potency to be the human or it is a part of
human life? Furthermore Is it true that the developing human embryo is an organism?
Using of embryos obtained from the excessive human embryo in the IVF procedure
are still controversy. There is a moderate argument that states that it is better to use those
embryos in research and therapy of human diseases rather throw them away. But it is also
an argument that those embryos have to keep alive until they die naturally.
REFFERENCES
1. The Stem cells-stem cell information-the official National Institute of Health
Resource for Stem cell Research
2. Anatomy
101:
Stem
Cells-Reeeve
Irvine
Research
Center-
http://www.reeve.uci.edu/anatomy /stemcells.php
3. Stem Cells-Wikipdia- http://en.wikipedia.org/wiki/stem cell
4. Stem Cells for Cell Based Therapies, Lauren Pecorino- American Institute of
Biological Science
5. Jurga M, et al. Neurogenic potential of human umbilical cord blood: neural like
stem cells depend on previous long term culture condition . J. Neurosci Res 2006:
83: 627-37
6. Ryan JM et al. Mesenchymal stem cells avoid allogenic rejection. J Inflammation
2005: 2:8-18
7. Bradley MB, Cairo MS. Cord blood immunology and stem cells transplantation.
Human Immunol. 2005: 66: 431-46
8. Therapeutic use of cell nuclear replacement: Therapeutic cloning-Research in
focus- MRC (Medical Research Council)
9. Intravenous administration og human umbilical cord blood reduces behavioral
deficits after stroke in Rats. Stroke 2001: 32-2682
10. Umbilical cord blood derived stem cells given intravenously reduce stroke
damage. www.medicalnewstoday.com
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11. Autologous mesenchymal stem cell transplantation in stroke patients. Annu.
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