Download STEM CELLS What are stem cells? What is the reason for the

STEM CELLS
What are stem cells? What is the reason for the current wide public
interest in stem cells?
Before I answer these questions, let's first review some basic principles of biology
and genetics so that our understanding of stem cells becomes more contextual.
[Readers familiar with school level biology may wish to skip this section.]
Introductory basics of biology and genetics
The human body is an organism that is made up of many organ systems working
together as one unit. Each organ system is made of individual organs. Take for
example the digestive system. This comprises the primary organs of mouth,
stomach, intestines and rectum, and the accessory organs of teeth, tongue, liver and
pancreas. Each organ, in turn, is composed of tissues designed for specific
functions like absorption and secretion. The tissues themselves are made up of cells
that are enjoined to perform special functions. The term germ cell is reserved for
sperm and egg cells and their precursors; other body cells are labeled as somatic
cells.
The cells in the human body have complex structures enclosed within membranes.
The internal components of a cell are called organelles. These are the nucleus,
which carries hereditary information or DNA and controls cellular growth and
reproduction, the cytoplasm, the fluid within the cell membrane outside of the
nucleus which holds the other cell organelles, namely, ribosomes that synthesize
protein, endoplasmic reticulum that transports material in the cell, Golgi apparatus
which feeds the exterior of the cell, mitochondrion that produces the energy to feed
the cell, lysosomes that destroy debris, and centrioles which allow the cell to divide.
The term eukaryotic cell is often used by biologists when referring to cells which
have nuclei. The nucleus contains structures called chromosomes, which are made
of DNA (deoxyribose nucleic acid). DNA is really an informational molecule
containing instructions that are passed from adult organisms to their offspring during
reproduction.
At the molecular level, DNA is made of a sequence of nucleotides of which there are
four- adenine (A), cytosine (C), guanine (G) and thymine (T). A nucleotide is
composed of a nitrogenous base, a five-carbon sugar (either ribose or 2deoxyribose), and one or more phosphate groups. Each chromosome consists of
two very long thin strands of DNA chains twisted into the shape of a double helix with
the two strands being held together by hydrogen bonding between base pairs. The
base pairs are adenine-thymine (AT) and guanine-cytosine (GC). Just like DNA,
ribonucleic acid (RNA) is vital for living beings. The large family of RNA that
mediates the transfer of genetic information from the cell nucleus to ribosomes in the
cytoplasm, where it serves as a template for protein synthesis is messenger-RNA
(mRNA). In most of its biological functions RNA is singly-stranded. However, RNA
can, by complementary base pairing, form intra-strand double helices, as in transferRNA, but the base pairs here are adenine-uracil and guanine-cytosine.
The chromosomes can be thought of as long strings of genes, which are really just a
series of the four nucleotides (A,C,T,G) that make up our cellular alphabet and
create the sequences, or instructions needed to form our bodies. DNA codes for
amino acids via these nucleotides. Amino acids play central roles both as building
blocks of proteins and as intermediates in metabolism. Humans can produce 10 of
the 20 amino acids that the body needs. The others must be supplied in the food.
The 10 essential amino acids that we can produce are alanine, asparagine, aspartic
acid, cysteine, glutamic acid, glutamine, glycine, proline, serine and tyrosine.
However, as there are just 4 nucleotides, a combination of three of these nucleotides
is used to code for different amino acids. Such combination of three nucleotides is
known as a codon. With three exceptions, each codon encodes for one of the
20 amino acids used in the synthesis of proteins. These codons make up the
genetic code. With such a combination there are 34 or 64 different possible codons
but again there are only 20 amino acids. As such one amino acid is now coded for by
more than one codon. This is known as degeneracy of the genetic code. The genetic
code can be expressed also as RNA codons. RNA codons occur in mRNA and are
the codons that are actually "read" during the synthesis of polypeptides (the process
called translation). But each mRNA molecule acquires its sequence of nucleotides
by transcription from the corresponding gene.
In eukaryotes, nuclear chromosomes are packaged by proteins into a condensed
structure called chromatin. This allows the very long DNA molecules to fit into the
cell nucleus. The primary protein components of chromatin are histones. The
complete set of chromosomes in the cells of an organism is its karyotype. The entire
DNA in the cell makes up the genome; genes make up only about 1% of the
genome. Both DNA methylation and histone modifications specifically modify the
way that genes are expressed. This has led to the theory that there is an epigenetic
code which serves to fine-tune the genetic code engraved in the DNA sequence.
Humans have in their body cells 46 chromosomes, made up of 23 pairs. The body
cells are said to be diploid. There are 44 chromosomes called autosomes that are
numbered from 1 to 22 according to size from the smallest to the largest as well as
the two sex chromosomes: X and Y. Women’s chromosomes are described as
46,XX; men’s as 46,XY. A mother passes 23 chromosomes (a haploid set) to her
child through her sex cell which is the egg and a father passes the other haploid set
through his sperm.
In order to grow and age as well as to ensure the genetic diversity and survival of our
progeny, our bodies must duplicate their cells. Cellular reproduction can occur in
two ways- mitosis and meiosis and both processes involve the replication and
division of chromosomes.
Mitosis is composed of several stages - prophase, metaphase, anaphase and
telophase - at the end of which one cell gives rise to two genetically identical
daughter cells. If the parent cell is haploid (23 chromosomes), then the daughter
cells will be haploid. If the parent cell is diploid (46 chromosomes), the daughter
cells will also be diploid. That is, the number of chromosomes does not get reduced
with cell division. This type of cell division allows multicellular organisms to grow and
repair damaged tissue.
In meiosis the parent diploid cell produces daughter cells that have one half the
number of chromosomes as the parent cell. Meiosis enables organisms to
reproduce sexually. Meiosis involves two divisions producing a total of four daughter
haploid sex cells or gametes. In the first meiotic division, the number of cells is
doubled but the number of chromosomes is not. This results in half as many
chromosomes per cell. The second meiotic division is like mitosis; the number of
chromosomes does not get reduced.
In human reproduction, the male and female gametes (sperm and egg, respectively)
which are haploid unite to form a diploid zygote. The zygote begins a journey down
the fallopian tube to the uterus where it must implant in the lining in order to obtain
the nourishment it needs to grow and survive. The zygote begins a two-week period
of rapid cell division and will eventually become an embryo.
The period of the zygote lasts for about 4 days. Around the fifth day, the mass of
cells becomes known as a blastocyst. It is preceded by the morula. The blastocyst
is a sphere of about 150 cells, with an outer layer (the trophoblast, which later
forms the placenta), a fluid-filled cavity (the blastocell), and a cluster of cells on the
interior (the inner cell mass or embryoblast) which subsequently forms the embryo.
The germinal period will last for 14 days, after which the embryonic period will begin.
The second period of development lasts from two weeks after conception through
the eighth week, during which time the organism is known as an embryo. At the ninth
week post-conception, the fetal period begins. From this point until birth, the
organism will be known as a fetus.
To make sure that genetic information is successfully passed from one generation to
the next in cellular reproduction, each chromosome has a special protective cap
called a telomere located at the end of its "arms". Telomeres are controlled by the
presence of the enzyme telomerase. A telomere is a repeating DNA sequence (e.g.
TTAGGG/AATCCC in humans) at the end of the body's chromosomes. The telomere
can reach a length of 15,000 base pairs. Telomeres function by preventing
chromosomes from losing base pair sequences at their ends. They also stop
chromosomes from fusing to each other. However, each time a cell divides, some of
the telomere is lost (usually 25-200 base pairs per division). Cells normally can
divide only about 50 to 70 times, with telomeres getting progressively shorter. When
the telomere becomes too short, the chromosome reaches a "critical length" and can
no longer replicate. The cells become senescent and eventually die by a process
called apoptosis. A cell can escape this fate by becoming a cancer cell. Although
telomerase activity is absent in most somatic cells, cancer cells acquire the ability to
activate the enzyme, ensuring their immortal growth characteristics and selective
advantage over normal somatic cells. Telomeres do not shorten with age in tissues
such as heart muscle in which cells do not continually divide.
Throughout one’s life, a constant battle is being waged between life-threatening
microbes and rogue (cancer) cells on the one hand and the immune system on the
other. The components of the immune system - monocytes, macrophages, dendritic
cells, polymorphonuclear leukocytes (also called granulocytes), lymphocytes (Band T-cells) and others like the antigen-presenting cells - work together as a wellorchestrated team. The macrophages, lymphocytes and others are particularly able
to recognize foreign products whose chemistry is only slightly different from their own
molecules and learn to tolerate every tissue, every cell and every protein in the body.
Self-recognition is not genetically determined but rather is learnt by the immune
system during the organism’s embryonic stage.
An antigen-presenting cell (APC) is a cell that displays foreign antigen complexed
with the major histocompatibility molecule (MHC) on its surface. T-cells may
recognize this complex using their T-cell receptor (TCR). T-cell receptors only
recognize and bind to their corresponding antigen on the APC if the antigen is bound
to an MHC molecule on the surface of the APC. There are two general classes of
MHC molecules. MHC I molecules display peptides from proteins synthesized within
the cell and are found on most cells. MHC II molecules, on the other hand, display
peptides from phagocytized protein and are found on macrophages, dendritic cells
(the key APCs) and B-cells. The MHC is the most gene-dense region of the
mammalian genome and plays an important role in the immune system,
autoimmunity, and reproductive success.
B-lymphocytes, the cells of the adaptive immune system, manufacture antibodies
and display them on the cell surface. If the antibody discovers a foreign antigen in
the bloodstream, it binds to it and delivers the antigen to a vesicle inside the cell.
Here the antigen is broken down into peptides. Each B-cell makes a different
receptor, so that the B-cells act as sentries, always on the lookout for microbes.
There are two classes of T-cells - Helper T-cells (Th, CD4+) (associated with MHC
class II) and Cytotoxic T-cells (Tc, CD8+) (associated with MHC class 1)
Th cells recognize peptides from proteins that have been taken up by macrophages
and other specialized antigen-capturing cells. Once activated, they divide rapidly and
secrete small proteins called cytokines that regulate or assist in the immune
response.
Tc cells react to samples of peptides originating within a cell itself, such as a
segment of a virus in an infected cell or mutant proteins in a cancer cell. Before a Tcell can attack, it must receive two signals. The first is the binding of the antigen
presented by MHC to the T-cell’s receptor. The second is typically the secretion and
binding of a protein, B7, which resides on the surface of the APC cell, with the T cell
surface protein CD28. If a T-cell is exposed to a self-antigen that is presented on a
non-stimulatory cell, it will get the receptor signal without the CD28 signal; the T-cell
is thereby inactivated or killed
Now that we have covered some basics and a bit beyond, let us address the
questions on stem cells.
Stem Cells
The stem cell is like all other cells without the DNA of its nucleus being turned on to
make it differentiate into specific cells. The classical definition of a stem cell requires
that it possess two properties {Ref: http://en.wikipedia.org/wiki/Stem_cell}:


Self-regeneration
(self-renewal):
the
ability
to
go
through
numerous cycles of cell division through mitosis while maintaining the
undifferentiated state.
Potency: the capacity to differentiate into specialized cell types. In the strictest
sense,
this
requires
stem
cells
to
be
either
totipotent or pluripotent. A totipotent stem cell (e.g. zygote) can develop into all
cell types including the embryonic membranes. A pluripotent stem cell can
develop into cells from all three germinal layers (e.g. cells from the inner cell
mass of the embryo). Other cells can be multipotent (e.g. hematopoietic cells)
oligopotent, bipotent or unipotent depending on their ability to develop into few,
two or one other cell type(s), respectively.
In mammals, there are two broad types of stem cells: embryonic stem cells, which
are isolated from the inner cell mass of blastocysts of four- or five-day-old human
embryo, and adult stem cells, which are found in various tissues such as the brain,
bone marrow, blood, blood vessels, skeletal muscles, skin, and the liver where they
remain in a non-dividing state unless activated by disease or injury. They are
thought to reside in a specific area of each tissue (called a "stem cell
niche").Unfortunately, once we are out of the womb, all of our embryonic stem cells
are gone. The origin of adult stem cells in some mature tissues is still uncertain.
Adult stem cells, similar to embryonic stem cells, have the ability to differentiate into
more than one cell type, but unlike embryonic stem cells they are often restricted to
certain lineages.
Stem cells can also be taken from umbilical cord blood just after birth and resemble
those in the bone marrow. Stem cells also can be fetal stem cells from the tissue of
an aborted fetus, located where the gonads would eventually exist. Bone marrow,
adipose tissue and blood are the usual sources of adult stem cells. Bone marrow
contains at least two kinds of stem cells – the hematopoietic stem cells that form
all types of blood cells in the body and the bone marrow stromal stem cells
(mesenchymal stem cells) that can generate bone, cartilage, fat, cells that support
the
formation
of
blood,
and
fibrous
connective
tissue
{Ref:
http://stemcells.nih.gov/info/basics/basics4.asp}.
Self-regeneration of stem cells is division with maintenance of the undifferentiated
state. During early development, the cell division is symmetrical, i.e. each cell divides
to give rise to daughter cells each with the same potential. Later in development, the
cell divides asymmetrically with one of the daughter cells produced being also a
stem cell and the other a more differentiated cell. Adult stem cells divide and create
fully differentiated daughter cells during tissue repair and during normal cell
turnover.
Symmetrical cell division (early in development):
→ stem cell + stem cell
(2-cell stage)
Asymmetrical cell division (late in development - 2 types):
stem cell (zygote)
stem cell (hematopoietic)
→
stem cell (hematopoietic) +
progenitor cell (lymphoid precursor)
progenitor cell (myeloid precursor) → differentiated cell (eosinophil) +
differentiated cell (erythrocyte)
The mechanisms of stem cell self-renewal are complex and have recently been
reviewed {Ref: S.He, D.Nakada and S J Morrison (2009), Annual Review of Cell &
Developmental Biology, 25: 377-406}. As summarised by these reviewers, “Selfrenewal programs involve networks that balance proto-oncogenes (promoting selfrenewal), gate-keeping tumour suppressors (limiting self-renewal), and care-taking
tumour suppressors (maintaining genomic integrity). These cell-intrinsic mechanisms
are regulated by cell-extrinsic signals from the niche, the microenvironment that
maintains stem cells and regulates their function in tissues.”
Embryonic stem (ES) cell lines are cultures of cells derived from the epiblast tissue
of the inner cell mass (ICM) of a blastocyst or earlier morula stage embryos (Fig.1)
or from cadaveric fetal tissue. Maintaining stem cells in an undifferentiated state
while in culture is important to ensure consistency and reproducibility among
experiments. Traditionally, mouse ES cells (mES) are grown on a layer of gelatin as
an extracellular matrix (for support) and require the presence of leukemia inhibitory
factor (LIF). Human ES cells (hES) are grown on a feeder layer of mouse
embryonic fibroblasts (MEFs) and require the presence of basic fibroblast growth
factor (bFGF or FGF-2). Without optimal culture conditions or genetic
manipulation, embryonic stem cells will rapidly differentiate. Research to establish
cell lines which can replicate indefinitely with retention of pluripotency currently uses
ES cells derived essentially from embryos and not from primordial germ cells of a
fetus. However, the establishment of stem cell banks still remains a challenge to the
scientific community.
Fig.1: Embryonic stem cell culture
[Source: http://www.stemcellresearchfoundation.org/WhatsNew/Pluripotent.htm]
ES cells being pluripotent give rise during development to all derivatives of the three
primary germ layers: ectoderm, endoderm and mesoderm. These three germ layers
are the embryonic source of all cells of the body. All tissues of the body develop from
these three primary germ cell layers. Transcription factors control the expression
of genes that maintain ES cell pluripotency or induce ES cell differentiation into
progenitors of all three germ layers during vertebrate embryogenesis. Transcription
factors are essentially protein molecules that bind to either enhancer or
promoter regions of DNA adjacent to the genes that they regulate. The transcription
factors Oct-4, Nanog, and Sox2 form the core regulatory network that ensures the
suppression of genes that lead to differentiation and the maintenance of
pluripotency. It is thought that they achieve this through alterations in chromatin
structure, such as histone modification and DNA methylation, to restrict or permit the
transcription of target genes.
In the undifferentiated state, the stem cells are said to be immature; when they
become differentiated into specialized cell types, they are said to be mature. A
human embryonic stem cell is also defined by the expression of several cell surface
proteins. The cell surface antigens most commonly used to identify hES cells are the
glycolipids stage specific embryonic antigen 3 and 4 and the keratan sulfate antigens
Tra-1-60 and Tra-1-81. {Ref: K. Nagano, Y. Yoshida and T. Isobe (2008).
Proteomics, 8: 4025–4035}
Embryonic stem cells (ESCs) are promising donor sources for cell transplantation
therapies. However, human ESCs are also associated with ethical issues regarding
the use of human embryos and rejection reactions after allogenic transplantation. In
most countries the debate still continues about the morality of research on human
embryos, including embryos arising from infertility treatments and embryos created
specifically for research purposes, and elective abortion. In the UK, the consensus,
enshrined in the Human Fertilisation and Embryology Act in 1990, is that the embryo
does have moral rights but not to the same extent as a living person. However, this
view point has been challenged by some religious groups, including the Catholic
Church. More recently, the UK law was changed to allow researchers to create
human embryos for use in research, so that embryonic stem cells could be
extracted, it being considered that embryos created for research cannot by law be
implanted in the womb, so never give rise to new individuals {Ref:
www.wellcome.ac.uk › ... › Stem cell basics}. In the US, federal funding ban for
embryonic stem cell research was lifted in 2009.
Scientists have long entertained the hope that the prevailing controversy on the use
of embryonic stem cells could be overcome by generating pluripotent stem cells
directly from a patient's somatic cells. This was the hypothesis that motivated
Professor Shinya Yamanaka of Japan’s Kyoto University, who shared the 2012
Nobel Prize in Medicine with Sir John B. Gurdon, to undertake his research that
gained him the critical breakthrough in 2006 when he noticed that somatic cell nuclei
acquired an embryonic stem-like status when fused with ESCs. He called such cells
induced pluripotent stem cells (iPS). He demonstrated induction of pluripotent
stem cells from mouse embryonic fibroblasts and adult mouse tail-tip fibroblasts by
the retrovirus-mediated transfection of four transcription factors, Oct3/4, Sox2, cMyc, and Klf4, under ES cell culture conditions. They started with 24 candidate
transcription factors, including Nanog, known to be important in the early embryo, but
found that just the four named genes finally sufficed to yield the iPS cells. The iPS
cells exhibited the morphology and growth properties of ES cells, were capable of
germline transmission and expressed ES cell marker genes {Ref: K.Takahashi and
S.Yamanaka (2006): Cell, 126(4):663-676}.
A scheme of the generation of induced pluripotent stem (IPS) cells.
[Ref: http://en.wikipedia.org/wiki/Induced_pluripotent_stem_cell]
(1) Isolate and culture donor cells. (2) Transfect stem cell-associated genes into the cells
by viral vectors. Red cells indicate the cells expressing the exogenous genes. (3) Harvest
and culture the cells according to ES cell culture, using mitotically inactivated feeder cells.
(4) A small subset of the transfected cells become iPS cells and generate ES-like colonies.
In the following year, Yamanaka and his team generated iPS cells from adult human
dermal fibroblasts (HDF) and other somatic cells by retroviral transduction of the
same four transcription factors with mouse iPS cells, namely Oct3/4, Sox2, Klf4, and
c-Myc, the first such group to do so. {Ref: S.Yamanaka et al (2007): Cell, 131 (5):
861–872}. They reported that the established human iPS cells were similar to hES
cells in many aspects, including morphology, proliferation, feeder dependence,
surface markers, gene expression, promoter activities, telomerase activities, in-vitro
differentiation, and teratoma formation. iPS cells, it is to be noted, are able to
multiply autonomously. This means they could conceivably multiply in a patient's
body and become tumors. According to Yamanaka, minimization of such risk
requires careful conduct of the process of reprogramming the somatic cells to the
primordial state; Yamanaka himself is presently engaged in improving his original
four gene recipe by using two more transcription factors.
iPSCs are an important advance in stem cell research, as they may allow
researchers to obtain pluripotent stem cells, which are important in research and
potentially have therapeutic uses, without the controversial use of embryos. Because
iPSCs are developed from a patient's own somatic cells, it was believed that
treatment of iPSCs would avoid any immunogenic responses; however, this may not
be true.
The transcription factor approach has still many key challenges that need to be
overcome {Ref: http://en.wikipedia.org/wiki/Induced_pluripotent_stem_cell}. These
include:
1. Low throughput: 01-.1%.
2. Genomic Insertion: genomic integration of the transcription factors raises the
risk of mutations being inserted into the target cell’s genome. A common
strategy for avoiding genomic insertion has been to use a different vector for
input. Use of alternate forms of vectors: adenovirus, plasmids, and naked
DNA and/or protein compounds are being explored but they come with the
tradeoff of lower throughput.
3. Tumors: as some of the reprogramming factors (the Myc family of genes, for
example) are proto-oncogenes, they pose a potential tumor risk.
4. Incomplete reprogramming: This is particularly challenging because the
genome-wide epigenetic code must be reformatted to that of the target cell
type in order to fully reprogram a cell. But upon examining why some of the
cells did not fully make it to being iPS but stalled on the way, several reasons
emerged but a common one was too much methylation at important ES cell
genes. The stalled cells, however, impressively responded when 5-aza-2'deoxycytidine (AZA), a DNA-methylation inhibitor was introduced over 48
hours
{Ref:
http://genetics.thetech.org/original_news/news89}.
The
experimental results suggested that even throughput could be significantly
improved if AZA is added at the beginning of the process before the cells
stall.
Biologists hope the technique will enable replacement tissues to be generated from a
patient’s own cells for use against a wide variety of degenerative diseases. Presently
the only established use of stem cell therapy is in bone marrow transplantation for
the treatment of leukemia. Some indicative future medical uses are depicted in the
chart below {Photo credit: Wikipedia}.
Research in most of the proposed areas is being conducted with much hope and
enthusiasm, with cancers, diabetes mellitus, Alzheimer’s disease and Parkinson’s
disease commanding a lion’s share of the efforts. The recent discovery of induced
pluripotent cells has certainly been a welcome short in the arm for researchers,
although a lot of work is still needed before they can be considered for use in the
clinic as the reprogramming process is not yet well understood. An additional avenue
of current research is – trans-differentiation- converting one type of specialised cell
directly into another. Undeniably though, the research into embryonic and adult stem
cell biology continues to enrich our knowledge about how cells communicate with
each other. Stem cell research would also allow scientists at some stage in the
future to test a number of potential medicines and drugs directly on a population of
cells rather than on animals and humans.
Cancer research basically targets our frequently failing immune system. One
approach taken by researchers is to inject into the patient whose immune system
has been compromised umbilical cord blood stem cells (matched to the patient). The
injected stem cells develop in the patient into cancer-fighting T- and B-lymphocytes.
In addition, stem cells help repair the damaged immune system of a patient treated
with chemotherapy and/or radiation. Stem cells could also be used in combination
with other new immune therapies in the battle against cancer.
Another novel approach is the use of hematopoietic stem cells (HSC) and induced
pluripotent cells (iPS) to engineer a cancer-fighting immune system. Thus putting Tcell receptor (TCR) genes into stem cells could generate a renewable source of
cancer-fighting lymphocytes. The studies in mice have already provided compelling
evidence that inserting TCR genes into stem cells has several advantages for the
progeny lymphocytes, allowing them to better fight cancer.
The studies on Alzheimer’s disease have been equally promising, with the most
compelling one being a recent report by Korean scientists who showed that adult
stem cells not only have a positive effect on those suffering from the disease,
but can also prevent the disease {Ref: www.news-medical.net/.../Adult-stem-cellscan-prevent-Alzheimers-d..}. The team infused clinically approved human adipose
stem cells intravenously in Alzheimer model mice over a 10-month period and noted
that the stem cells caused improvement in the treated mice in every relevant wayability to learn, ability to remember, and neuropathological signs. This study also
showed for the first time that stem cells could cross the blood brain barrier; the levels
of beta amyloid and APP-CT, known to cause brain cell destruction, leading to
dementia and Alzheimer's disease, were markedly reduced in the mice following
the treatment. Other researchers, however, challenge the suggestion that replacing
damaged brain cells is the key to curing the disease as such loss of cells occurs late
in the disease. In their view it is the loss of the connections between the cells and
memories associated with those connections that are significant.
Most researchers in the medical field are of the opinion that Parkinson's disease,
spinal cord injuries, and dozens of other conditions might benefit from stem-cell
research. In the case of Parkinson's disease, researchers plan to use stem cells to
grow dopamine-producing nerve cells in the laboratory and then apply cell
replacement therapy based on results of transplantation studies done in the 1980s,
where cells from the adrenal glands of four Parkinson’s patients were transplanted
into the patients’ brains with improvements in the patients’ condition {Ref:
www.eurostemcell.org › About stem cells › Stem cell factsheets}.
Cell transplantation is also at the heart of stem cell treatment for type 1 diabetes.
Type 1 diabetes is a disease where the body's immune system attacks and destroys
the cells in the pancreas that produce insulin. Leading the research in this field is the
Diabetes Research Institute (DRI) {Ref: www.diabetesresearch.org/stem-cell-anddiabetes}. Using human embryonic stem cells, researchers at DRI have successfully
induced the cells to differentiate into insulin-producing beta cells by using pancreatic
transcription factors, notably Pdx1, Neurogenin 3, Pax4, Isl-1 and Nkx6.1. The invitro production of the cells was conducted in a rich oxygen environment as
developing stem cells require a great deal of oxygen to grow. More recently, stem
cells were discovered in the pancreas which were isolated and coaxed to turn into
insulin-producing cells {Ref:
http://www. medicalnewstoday. com/articles/
252759.php}.
Induced pluripotent cells hold much promise for the generation of transplantable
tissue from an individual’s own cells, but as has been cautioned by their
discoverer, Shinya Yamanaka, the reprogramming technique by which iPS cells
are generated has much scope for improvement, especially with respect to
immune-tolerance. Indeed, in a recent experiment it was shown that mice
rejected transplants of stem cells even though they had been generated from
skin cells genetically identical to their own {Ref: Y.Xu et al (2011), Nature doi:
10,1038}. The reason for the rejection was traced to the proteins produced by
the reprogrammed iPS cells, especially Oct4 which is one of the transcription
factors used to turn skin cells into iPS cells. Humans and mice are naturally
programmed to reject cells that produce this transcription factor. Clearly it is
necessary to screen iPS cells for such factors that might cause rejection before
medical studies are even entertained. Until then pursuing treatments based on
human embryonic stem cells seems to be the safer approach as these have so
far proved to be the most reliable and versatile for regenerating new cells and
tissue.
v g kumar das (21 Dec 2012)
[email protected]