អ្វីទៅជាកោសិកា(Stem cell)?
ពាក្យ “ស្ងូត” ក្នុងកោសិកា(Stem cell) សំដៅលើ “ដើម” “ស្ងូត”
និង “កំណើតដើម” មានន័យថា កោសិកា(Stem cell)មានលក្ខណៈដូចដើមឈើ
អាចបង្កើតមែក ស្លឹក ផ្លែផា្ក និង លទ្ធផលដូចគ្នា។
ដូចនេះអ្នកវិទ្យាសាស្ត្របាន កំនត់ន័យបែបនេះ អោយកោសិកា(Stem cell)។
កោសិកា(Stem cell)គឺជាកោសិកាដើមមួយបែបដែលមានសមត្ថភាព
បង្កើតកោសិកាថ្មី និង បំណែងចែកច្រើន
គឺជាកោសិកាដើមមានក្នុងសរីរាង្គស្រាប់។ នៅក្នុងលក្ខខណ្ឌសមស្រប
វាអាចបំលែងជាកោសិកាមានមុខងារច្រើន ឬ ប្រព័ន្ធសរីរាង្គ។
ក្នុងភាសាពេទ្យគេហៅថា “កោសិកាមុខងារមួយម៉ឺន” ។
អ្វីទៅហៅថាវិធីកើតឡើងវិញនៃកោសិកា(Stem cell)?
វិធីកើតឡើងវិញនៃកោសិកា(Stem cell) ជាវិធីចាប់យកកោសិកា(Stem
cell)ពីកំណើតមកប្រើការបណ្តុះ អាចនិយាយថា
អោយតែកនែ្លងណាមានជំងឺគឺបណ្តុះនៅទីនោះ
ហើយឈានដល់ការព្យាបាលជំងឺយ៉ាងមានប្រសិទ្ធិភាព។
មូលន័យនៃការកើតឡើងវិញនៃកោសិកា(Stem cell)
គំនិតបង្កើត វិទ្យាពេទ្យនៃការកើតឡើងវិញ ដុះចេញពី សត្វឈ្លើង
ត្រកួត និង ជីងចក់។
ក្នុងសារពាង្គកាយនៃសត្វទាំងនេះមិនត្រឹមតែមានកោសិកា(Stem
cell)កើតឡើងវិញដ៏ខ្លាំងក្លានោះទេ នៅមានសមាសភាពអាចបញ្ឆេះ និង
ធំធាត់យ៉ាងរហ័ស។ ដូចនេះក្រោយពេលដាច់កន្ទុយ និង អវៈយវៈ
វានឹងកើតថ្មីយ៉ាងឆាប់រហ័ស។
បច្ចេកវិទ្យាកោសិកា(Stem
cell)រាប់ចូលទៅក្នុង “បច្ចេកវិទ្យាព្យាបាលកើតឡើងវិញ” ។
តម្លៃដែលគួរអោយកត់សំគាល់គឺ ឆ្លងកាត់ការបំបែកនៅក្រៅសារពាង្គកាយ
បណ្តុះ និងជំរុញឲ្យវាក្លាយទៅជាកោសិកាដែលយើងចង់បាន -ល-
អាចបណ្តុះចេញកោសិកា សរីរាង្គ និងប្រព័ន្ធ ប្រភេទថ្មីមួយភា្លម
ប្រក្រតី និង កាន់តែថ្មី។ ឆ្លងកាត់វិធី
បណ្តុះដ៏ពិសេសទៅក្នុងសារពាង្គកាយ
មកជំនួសកោសិកាណាបានសា្លប់ដោយប្រក្រតី និង មិនប្រក្រតី។
ដើម្បីកែប្រែការព្យាបាលជំងឺច្រើនយ៉ាងអោយកាន់តែទាន់សម័យ។
ដំណើរការបណ្តុះកោសិកា(Stem cell)នៅមន្ទីរពេទ្យក្វាងចូវទំនើបផ្នែកមហារីក
1.ដកយកខួរឆ្អឹងពីសារពាង្គកាយអ្នកជំងឺ
2.បំបែកកោសិកា(Stem cell)ក្រៅសារពាង្គកាយ សំអាត បង្កើតឡើងទ្វេដង
3. យកកោសិកា(Stem cell)បញ្ចូលតាមសារធាតុរាវទៅថ្លើមឈឺ
4.កោសិកា(Stem cell) នៅក្នុងសាច់ថ្លើម បំលែងជាកោសិកាថ្លើម
៤. លក្ខខណ្ឌសំរេចប្រសិទ្ធិភាពបណ្តុះកោសិកា(Stem cell)
1.លក្ខខណ្ឌគុណភាពកោសិកា(Stem cell)។
វិធីព្យាបាលដោយបំបែកកោសិកា(Stem cell)ឈាមក្រៅ និង កោសិកា(Stem
cell)ខួរឆ្អឹងដោយងាយៗ ទើបបញ្ចូលទៅក្នុងសារពាង្គកាយវិញ
ជាធម្មតាគ្មានផលល្អឡើយ។ កោសិកា(Stem
cell)ដែលយើងប្រើប្រាស់ជាកោសិកាដែលឆ្លងកាត់ការបណ្តុះបំបែកដោយ
បច្ចេកវិទ្យាទំនើបនៅមន្ទីរពេទ្យក្វាងចូវទំនើបផ្នែកមហារីក។
2.
ដំណើរបញ្ចូល។ ពួកយើងប្រើប្រាស់វិធីចាក់បញ្ចូលតាមជីបចរ។
បច្ចុប្បន្ននៅលើឆាកអន្តរជាតិគេប្រើការចាក់បញ្ចួលតាមសសៃ
វិធីបញ្ចូលតាមសសៃ និង បណ្តុះឆ្លុះចូលថ្លើម។
ប៉ុនែ្តយើងយល់ថាជីបចរថ្លើមជាជីបចរមានជីវជាតិជាងគេ
ដូចនេះឆ្លងកាត់ការបញ្ចួលតាមជីបចរជាជំរើសប្រសើរជាងគេ។
3.
រយៈកាលព្យាបាល។ យើងខ្ញុំយល់ថា គួរកំនត់តាមស្ថានភាពអ្នកជំងឺ
ក្នុងការពិចារណាទៅដល់ការធានាប្រសិទ្ធិភាពក្នុងការព្យាបាល និង
កាត់បន្ថយការចំនាយរបស់អ្នកជំងឺដែរ។
ការប្រើប្រាស់ក្នុងផ្នែកវេជ្ជសាស្ត្រ
បច្ចុប្បន្ន
នៅលើឆាកអន្តរជាតិគេប្រើប្រាស់យ៉ាងទូលំទូលាយចំពោះអ្នកជំងឺ
ទឹកនោមផ្អែមប្រភេទទី១ និង ប្រភេទទី២
ទឹកនោមផ្អែមបណ្តាលឲ្យរាលដាលដល់ជើង ជំងឺក្រិនថ្លើម
ជំងឺថ្លើមប្រភេទធ្ងន់ ជំងឺតំរងនោមដែលមានឈ្មោះថាNephrotic syndrome
ជំងឺរលាកតំរងនោមដែលបណ្តាលមកពីSLE ឆ្អឹងត្រគាករលួយស្លាប់
ជំងឺសាច់ដុំគ្មានកំលាំងដែលមានឈ្មោះថាMyasthenia gravis
មុខងារបន្តពូជរបស់មនុស្សប្រុសមិនពេញលេញ និង
ជំងឺនៅជុំវិញសសៃឈាម-ល-។
របៀបព្យាបាលជាធម្មតាមិនអាចព្យាបាលអ្នកជំងឺ
មានរោគច្រើនពិបាកព្យាបាលអាចប្រើការព្យាបាលដោយវះកាត់កោសិកា(Stem
cell)៕
Stem cell research has been hailed for the potential
to revolutionize the future of medicine with the ability to regenerate
damaged and diseased organs. On the other hand, stem cell research
has been highly controversial due to the ethical issues concerned
with the culture and use of stem cells derived from human embryos.
This article presents an overview of what stem cells are, what roles
they play in normal processes such as development and cancer, and
how stem cells could have the potential to treat incurable diseases.
Et
1
hical issues are not the subject of this review.
In addition to offering unprecedented hope in treating many
debilitating diseases, stem cells have advanced our understanding
of basic biological processes. This review looks at two major
aspects of stem cells:
I. Three processes in which stem cells play a central role in an
organism, development, repair of damaged tissue, and cancer resulting
from stem cell division going awry.
II. Research and clinical applications
of cultured stem cells: this includes the types of stem cells
used, their characteristics, and the uses of stem cells in studying
biological processes, drug development and stem cell therapy;
heart disease, diabetes and Parkinson's disease are used as examples.
What are stem cells?
Stem cells are unspecialized cells that have two defining properties: the ability to
differentiate into other cells and the ability to
self-regenerate.
The ability to differentiate is the potential to develop
into other cell types. A
totipotent stem cell (e.g.
fertilized egg) can develop into all cell types including the
embryonic membranes. A
pleuripotent stem cell
can develop into cells from all three germinal layers (e.g cells
from the inner cell mass). Other cells can be oligopotent, bipotent
or unipotent depending on their ability to develop into few, two
or one other cell type(s).
2
Self-regeneration 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 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.
|
Differentiation Potential
|
Number of cell types
|
Example of stem cell
|
Cell types resulting
from differentiation
|
Source
|
|
Totipotential
|
All
|
Zygote (fertilized egg),
blastomere
|
All cell types
|
|
|
Pleuripotential
|
All except cells of the
embryonic membranes
|
Cultured human ES cells
|
Cells from all three germ
layers
|
|
|
Multipotential
|
Many
|
Hematopoietic cells
|
skeletal muscle,cardiac muscle,
liver cells, all blood cells
|
|
|
Oligopotential
|
Few
|
Myeloid precursor
|
5 types of blood cells (Monocytes,
macrophages, eosinophils, neutrophils, erythrocytes)
|
|
|
Quadripotential
|
4
|
Mesenchymal progenitor
cell
|
Cartilage cells, fat cells,
stromal cells, bone-forming cells
|
|
|
Tripotential
|
3
|
Glial-restricted precursor
|
2 types of astrocytes, oligodendrocytes
|
|
|
Bipotential
|
2
|
Bipotential precursor from
murine fetal liver
|
B cells, macrophages
|
|
|
Unipotential
|
1
|
Mast cell precursor
|
Mast cells
|
|
|
Nullipotential
|
None
|
Terminally differentiated
cell e.g. Red blood cell
|
No cell division
|
|
Table 1: Differential potential
ranges from totipotent stem cells to nullipotent cells.
Compiled
from information in sources shown
I. Stem cells are central to three processes in an organism:
development, repair of adult tissue and cancer.
A. Stem cells in mammalian development
The zygote is the ultimate
stem cell. It is totipotent with the ability to produce all the
cell types of the species including the trophoblast and the embryonic
membranes. Development begins when the zygote undergoes several
successive cell divisions, each resulting in a doubling of the
cell number and a reduction in the cell size. At the 32- to 64-cell
stage each cell is called a
blastomere.
2
The blastomeres stick together to form a tight ball of cells called
a
morula. Each of these
cells retains totipotential. The next stage is the
blastocyst which consists
of a hollow ball of cells;
trophoblast cells along
the periphery develop into the embryonic membranes and placenta
while the inner cell mass develops into the fetus. Beyond the
blastocyst stage, development is characterized by
cell migration in addition
to cell division. The gastrula is composed of three
germ layers: the ectoderm,
mesoderm and endoderm. The outer layer or
ectoderm gives rise to
the future nervous system and the epidermis (skin and associated
organs such as hair and nails). The middle layer or
mesoderm gives rise to
the connective tissue, muscles, bones and blood, and the
endoderm (inner layer)
forms the gastrointestinal tract of the future mammal.
Early in embryogenesis, some cells migrate to the primitive gonad or
genital ridge. These are the precursors to the gonad of the organism and
are called
germinal cells. These cells are not derived from any of the three germ layers but appear to be set aside earlier.
Stem cells in late development
As development proceeds, there is a loss of potential and a gain of specialization, a process called
determination.
The cells of the germ layers are more specialized than the fertilized
egg or the blastomere. The germ layer stem cells give rise to
progenitor cells (also known as progenitors or
precursor cells).
For example, a cell in the endoderm gives rise to a primitive gut cell
(progenitor) which can further divide to produce a liver cell (a
terminally differentiated cell).
|
Hierarchy of stem cells during
differentiation.2at each stage, differential potential decreases and specialization increases.
(* These are also called transit-amplifying cells)
|
Role of Progenitor Cells in Development
While there is consensus in the literature that a
progenitor is a partially specialized type of stem cell, there
are differences in how progenitor cell division is described.
For instance, according to one source,
3
when a stem cell divides at least one of the daughter cells it
produces is also a stem cell; when a progenitor cell undergoes
cell division it produces two specialized cells. A different source,
2
however, explains that a progenitor cell undergoes asymmetrical
cell division, while a stem cell undergoes symmetrical cell division.
The apparent inconsistency of these two versions illustrates the
diversity and complexity of progenitor cells and their role in
differentiation. This diversity is reflected in the nomenclature as
well; progenitor cells are also called Transit-amplifying cells,
Precursor cells, Progenitors,
Lineage stem cells, and
Tissue-determined stem cells.
The table below shows these complex stages:
| Early in development:
|
 |
| Late in development: type 1
|
 |
| Late in development: type 2
|
 |
Table 2: Summarized from information in references 6 and 7.
The number of stem cells present in an adult is far fewer than the
number seen in early development because most of the stem cells have
differentiated and multiplied. This makes it extremely difficult to
isolate stem cells from an adult organism, which is why scientists hope
to use embryonic stem cells for therapy because embryonic stem cells are
much easier to obtain.
B. The role of adult stem cells in tissue repair
During development, stem cells divide and produce more specialized
cells. Stem cells are also present in the adult in far lesser numbers.
The role of adult stem cells (also called somatic stem cells) is
believed to be replacement of damaged and injured tissue. Observed in
continually-replenished cells such as blood cells and skin cells, stem
cells have recently been found in other tissue, such as neural tissue.
Organ regeneration has long been believed to be through
organ-specific and tissue-specific stem cells. Hematopoietic stem
cells were believed to replenish blood cells, stem cells of the
gut to replace cells of the gut and so on. Recently, using cell
lineage tracking, stem cells from one organ have been discovered
that divide to form cells of another organ. Hematopoietic stem
cells can give rise to liver, brain and kidney cells. This
plasticity of adult stem
cells has been observed not only under experimental conditions,
but also in people who have received bone marrow transplants.
4
Tissue regeneration is achieved by two mechanisms:
(1) Circulating stem cells divide and differentiate under appropriate signaling by
cytokines
and growth factors, e.g. blood cells; and (2) Differentiated cells
which are capable of division can also self-repair, e.g. hepatocytes,
endothelial cells, smooth muscle cells, keratinocytes and fibroblasts.
These fully differentiated cells are limited to local repair. For more
extensive repair, stem cells are maintained in the quiescent state, and
can then be activated and mobilized to the required site.
5
For wound healing in the skin, epidermal stem cells and bone-marrow
progenitor cells both contribute.
6
Thus it is likely that organ-specific progenitors and hematopoietic
stem cells are involved in repair, even for other organ repair.
Fundamental remaining questions regarding adult stem cells include: Does
one common type of stem cell migrate to different organs and repair
tissue or are there multiple types of stem cells? Does every organ have
stem cells (some of which have not yet been discovered)? Are the stem
cells programmed to divide a finite number of times or do they have
unlimited cell proliferation capacity?
C. Role of stem cells in cancer
Ontogeny (development of an organism) and oncology (cancer development)
share many common features.
From the 1870s the connection between development and cancer has been
reported for various types of cancers. Existence of "cancer stem cells"
with aberrant cell division has also been reported more recently. The
connection between cancer and development is clearly evident in
teratocarcinomas.
As early as 1862, Virchow discovered that the germ cell tumor
teratocarcinoma is made up of embryonic cells. In 1970, Stevens derived
embryonal carcinoma cells from teratocarcinomas. A teratocarcinoma is a
spontaneous tumor of germ cells that resembles development gone awry.
This tumor may contain several types of epithelia: areas of bone,
cartilage, muscle, fat, hair, yolk sac, and placenta. These specialized
tissues are often adjacent to an area of rapidly dividing unspecialized
cells. The teratocarcinomas are able to differentiate into normal mature
cells when transplanted into another animal. This alternation between
developmental and tumor cells status demonstrates how closely
development and cancer are related.
McCulloch explored the connection between normal development
of blood cells and leukemia.
7
According to him, normal hematopoietic development requires the
interaction of
stem cell factor with
its receptor, c-kit. A hierarchy of stem and progenitor cells
differentiates and produces different sublineages of cells resulting
from response to varied growth factors. Malignancies of the hematopoietic
system originate from two sources: those with an increased growth
in an early stem cell produce acute leukemia, while those that
arise from a decreased response to death or differentiation in
a stem cell produce chronic leukemia.
The present-day challenge is to decode the common molecular mechanism
and genes involved in self-renewal for cancer cells and stem cells.
8
II. Stem cells used in research and clinical
applications
Rao and colleagues postulate that all stem cells, regardless
of their origin, share common properties.
9
These researchers have reviewed the literature for candidate "stemness"
genes. They conclude that there are a set of candidate genes that
are present in all stem cells and can serve as universal markers
for stem cells. These code for proteins are involved in self-renewal
and differentiation. In addition they predict some differences
in gene expression between different populations of stem cells.
A. Types and characteristics of stem cells for culture:
Embryonic stem (ES) cells are obtained from the inner cell mass and cultured as illustrated:
ES cells from mouse embryos have been cultured since the 1980s by
various groups of researchers working independently.
10
These pioneers established murine embryonic stem cells lines that
could differentiate into several different cell types.
11
ES cell lines have been established from other mammals (hamsters,
rats, pigs, and cows). Thompson and colleagues at the University
of Wisconsin reported isolation of primate ES cells in 1995 and
human ES cells in 1998.
12
ES cells are the best characterized of all the cultured stem
cells. Properties of ES cells:
13(i)
ES cells are pleuripotent, i.e. they have the ability to differentiate
into cells derived from all three germ layers, but not the embryonic
membranes.
(ii) ES cells are immortal i.e. cells proliferate in
culture and have been maintained in culture for several hundred
doublings. The advantage of maintaining stem cells in culture
is that they are a source of a large number of cells in the undifferentiated
state. So far other adult stem cells have not been maintained
indefinitely.
(iii) ES cells maintain a normal
karyotype (there are no
major structural changes in the chromosomes)
(iv) ES cells display
Oct-4 protein and other unique markers on the cell surface.
Generally, ES cells are maintained in culture on
feeder cells (mouse fibroblast cells) There have been recent reports of ES cultured on feeder cell-free medium.
14
ES cells can be induced to differentiate in vitro by culturing in suspension to form three-dimensional cell aggregates called
embryoid bodies (EBs).
15
The cells spontaneously differentiate into various cell types, e.g.
neurons, cardiomyocytes, and pancreatic beta cells. The addition of
growth factors to the culture directs differentiation to specific cell
types. However, it is still challenging to isolate pure differentiated
cell types.
Following injection of ES cells into immunodeficient mice, teratomas
develop with derivatives of all three germ layers. This is a major
disadvantage of using ES cells for cell therapy since any contaminating
undifferentiated cells could give rise to cancer.
Embryonic germ cells
Gearhart and colleagues originally derived stem cells from primordial germ cells.
16
Cells cultured from the genital ridge of the human embryo have been
isolated and cultured. These cells have a lesser capacity of
proliferation than ES cells but have an advantage in that they are not
tumorigenic, unlike ES cells.
17
Embryonal carcinoma cells
Embryonal carcinoma cell lines were first developed in 1967 by Ephrussi
and colleagues from mouse teratomas, followed in 1975 by Fogh and Tempe
from a human testicular teratocarcinoma. These cells are malignant
relatives of ES and EG cells, which were used in many of the techniques
to cultivate them. EC cells can differentiate under the right conditions
and have a potential to be used for research and perhaps clinical
applications.
18
Once they differentiate they would not be expected to cause cancer,
but these cells have not been studied as well as ES cells and are of
limited use at present.
Adult or somatic stem cells The existence of hematopoietic
stem cells was discovered in the 1960s, followed by the discovery
of
stromal cells (also called
mesenchymal cells). Only in the 1990s did scientists confirm the
reports of neural stem cells in mammalian brains. Since then stem
cells have been found in the epidermis, liver and several other
tissues.
19
 |
Figure 4: Hematopoietic and Stromal stem cell differentiation
Source: http://stemcells.nih.gov/info/scireport/chapter5.asp
|
Adult stem cells offer hope for cell therapy to treat diseases in
the future because ethical issues do not impede their use. In addition,
if the patient's own cells are used, immunological compatibility is not
an issue. However, ES cells have been found to be superior for both
differentiation potential and ability to divide in culture.
Two concepts are useful to describe characteristics of adult stem cells:
Plasticity is
a newly recognized ability of stem cells to expand their potential
beyond the tissue from which they are derived. For example, Dental pulp
stem cells develop into tissue of the teeth but can also develop into
neural tissue.
20
Transdifferentiation is the direct conversion of one cell type to another,
21
e.g. transdifferentiation of pancreatic cells into hepatic cells and
vice versa has been reported in both animals and humans as has the
transdifferentiation of blood cells into brain cells and vice versa.
22
Cell fusion: ES cells can fuse in vitro with neuronal cells and with hematopoietic stem cells.
17
This has started a new debate in adult stem cell plasticity, namely
that some cells may have fused and the nucleus was reprogrammed instead
of transdifferentiating.
Cord blood stem cells
Cord blood, from the umbilical cord, was believed to be an alternate
source of hematopoietic stem cells; however, it is impossible to obtain
sufficient numbers of stem cells from most cord blood collections to
engraft an adult of average weight. Development continues on techniques
to increase the number of these cells ex vivo. Cord blood contains both
hematopoietic and non-hematopoietic stem cells.
23
B. Research and Clinical Applications of Cultured Stem Cells
What are the uses of Cultured Stem cells? The most prominent is cell
therapy for treating conditions such as spinal cord injuries and for
curing disease. Stem cells are used to investigate questions to further
basic and clinical research. Here are the major applications to date:
- Functional Genomic studies
In 1986, Gossler et al. reported using mouse ES cells to produce transgenic animals.24
Soon after, two landmark papers in the field of mouse genetics
demonstrated the ability to manipulate a specific gene of ES cells.25
Combining these techniques, a specific gene can be introduced into ES
cells to produce transgenic mice. This gene can be transmitted to their
offspring through the germline. Today these techniques enable the study
of the function of mammalian genes and proteins in the mouse (through
introducing human histocompatibility genes into mice).26
- Study of biological processes
Studies of biological processes, namely development of the organism and
progress of cancer, are facilitated by the ability to trace stem cell
fate. The spleen colony assay developed by Till and McCulloch is an
example study of the development of blood cells. In this method single
cells were injected into heavily irradiated mice so that all the
hematopoietic cells in these mice originated from the original colony.
Studies of this nature helped decipher the clonal origin of cancer,
- Drug discovery and development
The combination of isolation and purification of mouse ES cells and
genetic engineering techniques has led to the use of murine ES cells in
drug discovery. With the sequencing of the human genome many potential
targets of new drugs have been identified. Studies using human ES may
follow those of murine ES cells.27 Interest in using stem cells as models for toxicology has also grown recently.28
- Cell-based therapy
Cultured ES cells spontaneously form embryoid bodies containing
different cell types from all three germ layers. The desired cells are
isolated and cultured and the differentiated cells are then used for
therapy. ES cells have been induced to differentiate into neurons,
cardiomyocytes and endoderm cells.
The identification of hematopoietic stem cells in mice by Till and McCulloch in 1961 heralded the use of stem cell therapy.
29 By 1999, 50 diseases had been treated by bone marrow and stem cell therapy with varying degrees of success,
30
among them leukemia, breast cancer, inflammatory bowel disease and
osteogenesis imperfecta (a bone disease) in humans. ES and adult stem
cells now offer hope for reversing the symptoms of many diseases and
conditions including cancer, neurodegenerative diseases, spinal cord
injuries, and heart disease.
The following stem cell characteristics make them good candidates for cell-based therapies:
31
i. Potential to be harvested from patients
ii. High capacity of cell proliferation in culture to obtain large number of cells from a limited source
iii. Ease of manipulation to replace existing non
functional genes via gene transfer methods
iv. Ability to migrate to host's target tissues, e.g.
the brain
v. Ability to integrate into host tissue and interact with surrounding tissue
Following is a summary of three diseases in which stem cell-based therapy has been used.
a) Heart disease
Cardiovascular disease is a leading cause of death worldwide killing 17 million people each year,32
especially due to heart attack and stroke. In the United States, heart
disease is the number one cause of death. The high rate of mortality
associated with heart diseases is the inability to repair damaged tissue33
due to the full differentiation of heart tissue. Interruption of blood
supply to the tissue causes infarction of the myocardium and death of
myocardiocytes.
A recent report used a swine model of atrioventricular block and
transplanted human ES cell-derived cardiomyocytes into the pig's heart
to work as a pacemaker.34
The ES cells survived, functioned and integrated well with the host
cells. The researchers used embryoid bodies to select spontaneously
beating areas of culture (cultured myocytes will actually beat in
synchrony just like a heartbeat). This study bodes well for future
myocardial regeneration using human ES cells.
Adult stem cells have also been used in cell therapy for the heart.35
Skeletal muscle myoblast transfers showed contraction but did not
differentiate into cardiomyocytes and did not integrate with the host
myocardium. Ideally, both contraction and integration with host
myocardium should have occurred in order for the therapy to be
effective. Endothelial progenitor cells transplants halted the
degenerative process but did not initiate regeneration. Early clinical
studies may soon follow.
Another approach is cardiac tissue engineering.36
Cohen and Leor grew embryonal heart cells in vitro with an alginate
scaffold (alginate is an algal polysaccharide) to provide 3D-support and
organization for the cells. They transplanted the cells with the
scaffold into the scar tissue of the rats with myocardial infarction and
observed extensively. The vascularization shows that there was
acceptance of the engineered tissue. This unique method of treating
heart disease is promising and may be explored in other animal models in
the future.
b) Diabetes
Elevated glucose levels in the blood are responsible for diabetes.
Diabetes affects 16 million Americans (5.9 percent of the population)
and is the seventh leading cause of death.37
Worldwide it afflicts 120 million people and the World Health
Organization estimates that the number will reach 300 million by 2025.38
Type I diabetes, or juvenile onset diabetes, is an autoimmune disease
that causes destruction of the insulin-producing beta cells in the
pancreas. Insulin injections are given to diabetics but they cause
surges in blood glucose levels followed by a drop in the glucose levels
and lack fine tuning. Pancreas transplantation has been performed in
diabetics as more recently has pancreatic islet cell transplantation.
The latter has the advantages that it does not require whole organ
transplantation. However, the need for immunosuppression to prevent rejection of allogeneic islet transplants and a serious shortage of organ donors are lingering problems.25
The Edmonton protocol, developed by Shapiro and colleagues, is
promising. This procedure transplants a large amount of islet cells and
uses a glucocorticoid-free type of immunosuppression regimen. In early
clinical testing it reversed diabetes in all of the patients tested.
c) Stem cell therapy for diabetes
Cells need to be able to
self-regenerate and differentiate. Also it has been observed that the
presence of all the islet cell types is preferable to only beta cells
since the former are better able to respond to changing levels of
glucose in the blood. Growth must be balanced with ability to produce
insulin. The insulin producing cells tend not to divide and those which
divide actively do not produce insulin.
Adult stem cells from the pancreas have been elusive
so far. However, a recent report of a clone from mouse pancreas that can
generate both pancreatic and neural cell lines is exciting, as is a
second report that adult small hepatocytes (liver cells) can be induced
to produce insulin.39 Both reports offer hope for using adult stem cells as a treatment and cure for diabetes.
d) Parkinson's Disease
Parkinson's disease is the second
most common neurodegenerative disease following Alzheimer's.
Approximately 1.5 million people in the United States suffer
from Parkinson's disease,40
which is caused when 80% or more of dopamine producing-neurons
in the substantia nigra of the brain die. Normally, dopamine
is secreted from the substantia nigra and transmitted to another
part of the midbrain. This allows body movements to be smooth
and coordinated.
Patients with Parkinson's disease are treated
with the drug levodopa (or L-dopa), which is converted to dopamine in
the body. Initially effective, the treatment's success is reduced over
time and side effects increase, leaving the patient helpless.41
It has been recognized that dopamine-producing cells are required to
reverse Parkinson's disease. Since the 1970s, many types of
dopamine-producing cells have been used for transplantation. These
include adrenal glands from the patient, human fetal tissue and fetal
tissue from pigs.42
Limited success has been achieved with these cells. Rat and monkey
models of Parkinson's were used to test fetal mesencephalic cells.41 Success with animal models led to clinical trials.
Fetal tissue transplantation has been performed in 350
patients, including trials using pig fetal tissue. So far, the success
of reversing Parkinson's disease using fetal tissue has been limited at
best. However, in the most successful cases, patients have been able to
lead an independent life without L-dopa treatment.43
The limitations include (i) lack of sufficient tissue for the number of
patients in need, (ii) variation in results between patients ranging
from no benefit to reversal of symptoms, and
(iii) Occurrence of uncontrolled flailing movements (called
dyskinesias).
The many criteria for the cells used in therapy include the ability to
produce dopamine, to divide and survive in the brain and to integrate
into the host brain. For these reasons, differentiated embryonic stem
cells offer more promise. Mouse ES cells have been used in rat models of
Parkinson's disease and recently human ES cells have been reported to
differentiate into dopamine-producing neurons in culture.44
Another consideration is the immune problem. It was
believed that the brain is an immunologically privileged site tolerating
transplanted cells from a different individual (meaning that the immune
system will not attack tissue transplanted into this location).
However, a recent report challenges this view.45 For this reason autologous cells may offer a safer alternative. Neural stem cells and hematopoietic stem cells are both likely candidates.31
Also, dental pulp cells in both rats and humans produce neurotrophic
factors and are a candidate for autologous transplantation in
Parkinson's.20
5)
Therapeutic cloning
Somatic cell nuclear transfer
was used to clone Dolly, the sheep.
42
Since then, seven animal species have been cloned using this technique.
44
A modified version for use in humans is as follows: The patient's
DNA is injected into an enucleated unfertilized egg and used to
generate ES cells which are then cultured and allowed to differentiate,
followed by transplantation into the patient. 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 5: Stem Cell Transplant Using a Patient's Own Cells
http://gslc.genetics.utah.edu/units/stemcells/scfuture/
|
Conclusion
This review has summarized the role of stem cells in basic biological
processes in vivo, namely in development, tissue repair and cancer in
Part I. Part II focused on cultured stem cells and their uses,
describing the different sources of stem cells, their properties and
their research uses and clinical applications.
Remarkable progress has been achieved in studying stem cells. The most
exciting use of cultured stem cells is the promise for curing many
devastating diseases like Parkinson's and diabetes. However, more basic
research remains before stem-cell based therapy is widely used.
Of the stem cells discussed, ES cells have the most capacity to
differentiate into a variety of cells and their proliferation capacity
is also unsurpassed by any other cell type. There are three major
problems with ES cells; ethical issues, immunological rejection problems
and the potential of developing teratomas.
In the future, ideally, somatic stem cells from the patient will be
extracted and manipulated and then reintroduced into the same patient to
cure debilitating diseases. This would preclude the use of embryonic
stem cells for cell therapy, eliminate the ethical objections against
stem cell research, and also resolve immunological rejection problems.
However, at present the cell proliferation and differentiation potential
of embryonic stem cells remains far more likely to produce a cure than
do the somatic cells.
2:34 AM
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