March 5, 2010 by

Histostem Works With Korean Government Agency to Provide Cord Blood Storage for Multicultural Families

The US company Amstem through subsidiary signed a
partnership agreement with the Songpa-Gu Office of the Seoul Metropolitan
Government, to provide umbilical cord blood banking to multicultural families
for up to 15 years.  Cord blood is currently used for treatment of patients with
blood disorders such as leukemias as an alternative to bone marrow. 
Unfortunately many patients do not have suitable donors, this is especially true
in patients of various ethnicities.  The current program is designed to overcome
this problem.

The president of AmStem International, Inc., David Stark
 stated  "This provides AmStem and Histostem with another ‘badge of validity’
with government health agencies around the world. A diverse genetic catalogue of
autologous, HLA-typed stem cell resources such as cord blood is in extremely
high demand right now — not only by individual families, but by
government-sponsored scientists and other researchers worldwide. This is exactly
the kind of collaborative, networking opportunity that AmStem hopes to expand in
North America and Europe."

In recent years the use of cord blood for diseases not
associated with blood has been increasing.  For example, the Cord Blood Bank
Viacell has patents on the use of cord blood for treatment of Duchenne Muscular
Dystrophy (Kraus et al. US patent #7452529 – Treatment of muscular dystrophy
with cord blood cells).  The Cellmedicine.com group has collaborated with
the US company Medistem at publishing use of cord blood together with other
cells for treatment of a patient with Duchenne Muscular Dystrophy that resulted
in functional improvement (Ichim et al. Mesenchymal stem cells as anti-inflammatories:
implications for treatment of Duchenne muscular dystrophy. Cell Immunol.
2010;260(2):75-82).  The reason why cord blood appears to be useful in
treatment of a variety of conditions is believed to be due, at least in part, to
ability of the cells to produce numerous therapeutic factors that stimulate stem
cells already in the body to start multiplying.  Additionally, numerous studies
have shown that cord blood derived stem cells can produce cells ranging from
liver to brain to heart muscle.  A description of cord blood stem cells may be
seen on this video

http://www.youtube.com/watch?v=z6CP-OL1Kuc .

Dr. Hoon Han, AmStem’s Chairman, commented on the cord
blood bank, "With more than 1.1 million foreigners now living in Korea, the
number of multicultural marriages and families is on the rise. By providing
these families the opportunity to store the donated umbilical cord blood, we
give them access to autologous stem cells that may be used in the future
treatment of certain cancers, such as leukemia, as well as immune and genetic
disorders. In addition, by addressing the multicultural population in Korea,
this collaborative opportunity also increases the genetic diversity of the
available supply of umbilical cord blood derived stem cells — which may benefit
Korean and foreign patients alike."

Filed Under: Adult Stem Cells, Cord Blood Stem Cells, News, Stem Cell Research Tagged With: , , ,
March 5, 2010 by

Stem Cell Treatment for Heart Attacks: Timing is Everything

Skeletal myoblasts are a type of muscle-specific stem cell
that have been used previously in several clinical trials, particularly for
heart failure and post-heart attack patients.  Advantages of this type of stem
cell include the fact that they are from adult sources (no risk of cancer), they
are already committed to becoming muscle cells, and they can easily be grown in
the laboratory.  Disadvantages include the possibility of arrhythmias, as well
as lack of efficacy in several systems. Additionally, unlike mesenchymal stem
cells, which can be used as "universal donors" because of their
anti-inflammatory effects, skeletal myoblasts have to either be used from the
same patient (autologous), or co-administered with immune suppression to prevent
their rejection.

In a recent publication (O’Blenes et al. Engraftment is
optimal when myoblasts are transplanted early: the role of hepatocyte growth
factor. Ann Thorac Surg. 2010 Mar;89(3):829-35) Canadian researchers at
Dalhousie University sought to determine whether an optimum time exists for
myoblast administration after cardiac injury. 

Using rats, the scientists cut off circulation to the
coronary artery to mimic a heart attack by ligation using microsurgery. 
Myoblasts where implanted at the time of ligation or 5 weeks after the infarct. 
Much higher engraftment of the cells was observed in animals that received the
cells immediately after the infarct.  Additionally, the hearts that received
myoblasts earlier seemed to have less damage.  This prompted the scientists to
ask the question; "why would delayed administration result in less homing and
retention?"

Previously we at Cellmedicine discussed the biological
observation that after a heart attack the injured heart muscle generates
chemicals that attract the body’s own stem cells.  One of these chemicals is
VEGF, which was discussed in this video

http://www.youtube.com/watch?v=NqEggEYilh0. Another chemical made by injured
heart tissue is hepatocyte growth factor (HGF).  Both of these proteins are made
when cells "sense" reduced oxygen, as well as various alterations in their
environment.  In the current study it was found that levels of HGF are
substantially elevated after the infarct and subsequently diminish by the 5th
week.  The investigators found that HGF stimulated proliferation and activity of
the myoblasts, and therefore believed that the decline in HGF may be one of the
reasons for the decreased efficacy with time. 

This could be a possible explanation for their results,
however, numerous factors may also be important to consider.  For example, it is
known in various situations of injury that as scar tissue forms, components of
the scar tissue inhibit regeneration.  Stem cells such as bone marrow
mesenchymal cells contain matrix metalloproteases that actively can "dig
through" scar tissue and support regeneration.  Myoblasts do not express such
enzymes, and additionally do not have the same homing ability to injured tissue.

The study would have substantially made more of a strong
case for the importance of HGF in stem cell activity if they used blocking
antibodies or knock-out mice specific for this gene.  Such a study would have
conclusively demonstrated the importance of HGF in this situation by
demonstrating less stem cell homing in its absence. 

One interesting point that is made is the possibility of
administering HGF into the myocardium of patients so as to enhance stem cell
homing.  Indeed, some companies such as Bioheart are already using such an
approach, see link

http://www.bioheartinc.com/prod-myocellsdf1.html.

Filed Under: Adult Stem Cells, Heart Disease, News, Stem Cell Research Tagged With: , , , ,
March 3, 2010 by

Butyrate Greatly Enhances Derivation of Human Induced Pluripotent Stem Cells by Promoting Epigenetic Remodeling and the Expression of Pluripotency-Associated Genes

Generation of inducible pluripotent stem cells (iPS) offers
the possibility of creating patient-specific stem cells with embryonic stem cell
therapeutic potential from adult sources.  Recently the main hurdle of iPS cell
generation, the need for introduction of oncogenes in the adult cells, has been
removed by use of chemical modulators as well as alternative non-cancer causing
genes.  Another drawback of creating iPS cells is the need for mass screening of
many transfected target cells before identification and extraction of the
correct cell can be made.  In the current paper the histone deacetylase
inhibitor butyrate was used to enhance potency of iPS generation in vitro. 
Histone deacetylase inhibitors are a type of compounds that decrease the density
of DNA in chromosomes.  By performing this function the DNA because more
amenable to reprogramming, in the sense that the cells can be coaxed to
de-differentiate with less effort.  Another histone deacetylase inhibitor,
valproic acid, which is used clinically to treat convulsions, has been shown to
increase the ability of blood making stem cells to self-replicate with higher
efficiency, which is a characteristic of earlier de-differentiation.    

In a recent paper it was demonstrated that temporary
treatment with butyrate increases efficacy of iPS generation by 15-51 fold using
two techniques that are commonly used for generation of these cells.  It was
demonstrated that in the presence of butyrate stimulation a remarkable (>100-200
fold) increase on reprogramming in the absence of either KLF4 or MYC transgene.

This suggests that butyrate may be a useful agent to
incorporate in the iPS generation protocols that are currently under
development.  Furthermore, butyrate treatment did not negatively affect
properties of iPS cell lines established. The generated iPS cell lines,
including those derived from an adult patient with sickle cell disease by two
methods show normal karyotypes and pluripotency.

To mechanistically identify molecular pathways of butyrate
enhancement of iPS generation, the investigators performed conducted genome-wide
gene expression and promoter DNA methylation microarrays and other epigenetic
analyses on established iPS cells and cells from intermediate stages of the
reprogramming process.

 By day 6-12 after exposing cells to butyrate, enhanced
histone 3 acetylation, promoter DNA demethylation, and the expression of
endogenous pluripotency-associated genes including DPPA2, whose over-expression
partially substitutes for butyrate stimulation is known.

According to Dr. Mali " Thus, butyrate as a cell
permeable small molecule provides a simple tool to further investigate molecular
mechanisms of cellular reprogramming. Moreover, butyrate stimulation provides an
efficient method for reprogramming various human adult somatic cells, including
those from patients that are more refractory to reprogramming"

Methods of increasing efficacy of iPS generation have
included not only chemical manipulation but also starting from cell sources that
are generally considered more immature.  For example a previous study
demonstrated that mesenchymal stem cells create a much higher per-cell number of
iPS cells as compared to skin fibroblasts. 

One of the interesting points of this finding is that
butyrate may theoretically be useful at expanding potential of stem cells
already in an organism.  Since butyrate is used clinically for treatment of urea
cycle disorders and is non-toxic at pharmacological doses, it may be a good
candidate for expanding stem cells in vivo.  Manipulation of the stem cell
compartment by administration of therapeutic agents has already been performed
for mobilization, which has been published with the neutraceutical Stem-Kine

http://www.translational-medicine.com/content/pdf/1479-5876-7-106.pdf.

Filed Under: Adult Stem Cells, Embryonic Stem Cells, News, Stem Cell Research Tagged With: , , , , ,
March 3, 2010 by

The Senescence-Related Mitochondrial/Oxidative Stress Pathway is Repressed in Human Induced Pluripotent Stem Cells

Embryonic stem cells possess the ability to propagate in
tissue culture indefinitely.  This is different than differentiated cells, for
example, skin cells which can only multiple in tissue culture approximately 50
times before undergoing senescence.  The ability of embryonic stem cells to
escape senescence is related to expression of the protein telomerase.  Usually
when cells multiply the ends of the chromosomes, called telomeres, progressively
reduce in size.  When the telomeres become critically short, the gene p53 is
activated, which is involved in instructing the cells to stop multiplying and
exist in a semi-alive state called senescence.  Tumor cells and embryonic stem
cells escape senescence by expressing the enzyme telomerase.  This enzyme
essentially allows cells to repair their telomeres by progressively adding new
nucleic acids.  Although much is known about senescence or lack thereof in adult
cells and embryonic stem cells, little research has been performed in whether
inducible pluripotent stem cells (iPS) can also escape proliferative
senescence.  In a recent publication this question was examined.

In a similar manner to embryonic stem cells, iPS cells were
shown to express high levels of the enzyme telomerase, and propagation in tissue
culture was achieved up to 200 passages without senescence occurring. 
Furthermore the investigators studied the mitochondrial stress pathway.  It was
found that somatic mitochondria within human iPSCs revert to an immature
ESC-like state with respect to organelle morphology and distribution, expression
of nuclear factors involved in mitochondrial biogenesis, content of
mitochondrial DNA, intracellular ATP level, oxidative damage, and lactate
generation. When iPS cells were differentiated into adult cells, mitochondria
within iPSCs demonstrated maturation and anaerobic-to-aerobic metabolic
modifications. This same finding was observed in embryonic stem cells. 

These data suggest that iPS cells possess several important
properties similar to embryonic stem cells, which further supports the
possibility of interchangeably using ES and iPS cells for experimental purposes.
The next question is whether iPS cells may be generated in large quantities so
that their mitochondria may be transferred to aged cells. 

Another interesting finding in the current study is that
the metabolic pathway used by both iPS and embryonic stem cells is analogous to
that found in cancer cells.  Therefore it will be interesting to follow studies
using iPS as a model of cancer.

Filed Under: Embryonic Stem Cells, News, Stem Cell Research Tagged With: , , , , ,
March 1, 2010 by

Cord blood stem cells help meet minority marrow needs

Leukemias are cancers of the cells that give rise to white
blood cells.  For example in myeloid leukemias the cells that normally would
become the blood cells neutrophils or macrophages start to make copies of
themselves but refuse to mature.  What happens is that the body is flooding with
cells that on the one hand do not protect the patient from disease, and on the
other hand start to interfere with organ function.  In lymphocytic leukemias the
cells that give rise to lymphocytes such as T and B cells, stop maturing. 
Despite advances in our knowledge of the molecular basis for many leukemias, in
many situations the only definitive cure can be achieved through stem cell
transplantation. Traditionally this has been performed using bone marrow stem
cells from donors that are matched with recipients.  The process of
transplantation involves initial destruction of the recipient bone marrow and
leukemic cells by administration of high doses of radiation and chemotherapy. 
Subsequently donor bone marrow is given which contains high numbers of stem
cells.  These donor stem cells eventually take over the function of making blood
and the recipient is cured of leukemia but has someone else’s stem cells inside
of them.

One of the major barriers to complete success of bone
marrow transplantation is that donors must be matched very strictly.  If the
donor is not matched then the immune cells in the bone marrow start to attack
the recipient.  This is called graft versus host disease, and is one of the most
devastating side effects of bone marrow transplantation, which in some cases is
lethal.

The current story from CNN describes a personal experience
of a lady, Diana Tirpak, who could not find a bone marrow donor.  In general it
is rather difficult to find an unrelated matching donor.  In minorities the
process is even more difficult.  Tirpak, a retired school nurse in Hudson, Ohio
was so convinced that the search for a donor was futile that she helped her
husband buy a suit for her funeral.  "I was bound and determined he was going to
look fine at the funeral," she said. 

Fortunately advances in "alternative sources" of stem cells
have saved Tirpak’s life.  While it is known that stem cells reside in the bone
marrow, another source that is only in recent times being appreciated is cord
blood.  Originally cord blood transplantation was restricted to children since
the number of stem cells per cord is relatively small.  However new advances in
transplantation, as well as introduction of "two cord" approaches have opened up
this procedure for adults.

Dr. Mary Laughlin, founder and medical director of the
Cleveland Cord Blood Center stated "Cord blood is rich in stem cells and easier
to match than adult bone marrow because the immune cells are not developed.
Also, patients can get the treatment in about three weeks — as opposed to six
to eight for bone marrow from an adult donor.  That can be a critical time
interval for a patient who is in remission," she said, noting that doctors often
fear a patient’s relapse while awaiting the transplant.

To get a sense of how difficult it is to find bone marrow
donor matches, the National Bone Marrow Registry has more than 12 million donors
that meet the needs of only about 60 percent of Caucasians in the United
States.  In contrast, only 5 to 15 percent of minorities have available donors. 

Another example of the difficulties minorities face in
obtaining a suitable donor is the story of Nathan Mumford, who is
African-American and was diagnosed with leukemia shortly after finishing
college.  "We went through that process, and nobody had a match. Siblings are
the best matches. My brother or my sister wasn’t a match. My friends, aunts,
uncles, cousins, nobody was a match. So, couldn’t go that route," Mumford said. 
Luckily he too was eligible for a cord blood transplant.  "That was an
opportunity," said Mumford, who survived Hodgkin’s disease as a child. "That was
a chance for me to live. I’m not a quitter. I’ve never been a quitter, so I
wasn’t going to quit."

In November of 2004 he was treated by cord blood
transplantation.  Now his leukemia is cured and he claims he is in great shape. 
I just feel amazing," he said. "I have a lot of energy, and I’m just excited
about it."

The use of cord blood transplants among unrelated donors
have risen from 1 percent in 2001 to 24 percent last year, Dr. Laughlin says.

It should be noted that the use of cord blood for leukemias
is different than its use for other conditions that do not need destruction of
the recipient’s bone marrow.  For example in patients with heart failure there
is a need for stem cells that can either directly give rise to new heart cells,
or produce growth factors that activate stem cells in the heart.  The use of
cord blood derived stem cells for heart failure has yielded some positive
results in animal studies and in several individual case reports as seen in this
video

http://www.youtube.com/watch?v=PcFQeRNuPDo . 

Filed Under: Adult Stem Cells, Cord Blood Stem Cells, News, Stem Cell Research Tagged With: , , ,
February 28, 2010 by

Ahmedabad-based institutes get patent to use stem cells in kidney transplant

According to an article IndianExpress.com, an international
patent has been issued to the G R Doshi K M Mehta Institute of Kidney Diseases
and Research Centre (IKDRC) and Dr HL Trivedi Institute of Transplantation
Sciences (ITS) from Ahmedabad, Indian for utilization of stem cells in treatment
of patients having undergone kidney transplantation.  Given that we could not
find a patent number written in the article, as well as the fact that
"International Patents" do not exist, we presume the authors meant a provisional
patent having international priority under Paris Convention, or a Patent
Cooperation Treaty (PCT) application. 

The subject matter discussed is the use of stem cells to
circumvent the need for immune suppression during transplantation.  While immune
suppressants such as cyclosporine, rapamycin, and FK-506 have saved many lives
by making transplantation possible, they have numerous side effects associated
with their long-term use.  These include increased risk of cancer, higher number
of bacterial/viral infections, and possibility of kidney failure.  The work
discussed in the article uses the ability of stem cells to "immune modulate" and
therefore inhibit rejection.  A video describing stem cell mediated immune
modulation may be seen at this link

http://www.youtube.com/watch?v=ECi2uBSSQg8.  

Dr Aruna Vanikar, Head of Pathology, Lab Medicine,
Transfusion Services and Immuno hematology department, IKDRC-ITS, who according
to the article recently received the patent, stated, "We have been working on
the use of stem cells since 1998. The study involved several phases. When a
patient undergoes kidney transplant, he/she might face difficulties, including
complete rejection. To suppress that, several drugs are used…Sometimes, the body
also reacts to high dosage of drugs. With this patent, patients will not have
any such complications. The stem cells would comprise mesenchymal cells
generated from the donors’ fat, and haematopoetic stem cells taken from donors’
bone marrow and blood. These cells are infused in the recipients’ liver, as it
is considered the most tolerogenic organ of the body."

While the article did not provide technical details, we
found on

www.pubmed.com some of Dr. Vanikar’s work.  A recent publication: Effect of
co-transplantation of mesenchymal stem cells and hematopoietic stem cells as
compared to hematopoietic stem cell transplantation alone in renal
transplantation to achieve donor hypo-responsiveness. In the journal Jan 19th
edition of the International Urology and Nephrology Journal described the
reduction of immune suppressant dosage by administration of bone marrow and fat
derived stem cells.  Another paper from the same group described the reduction
of immune suppressant dose by a similar stem cell protocol, termed the
"Ahmedabad tolerance induction protocol".  It will be interesting to see if
these early clinical results can be translated into Phase III placebo controlled
trials.  Commenting on the "tolerance induction protocol" Dr Aruna Vanikar said:
"With modification in Ahmedabad tolerance induction protocols for
transplantation without conventional immunosuppression, the results are
rewarding. Secondly, the incidences of acute and chronic rejection and
recurrence of basic disease have decreased."

Filed Under: Kidney and Lung, News, Stem Cell Research Tagged With: , , , ,
February 26, 2010 by

Adult Stem Cells Healing Hearts

Adult stem cells are being more and more used in patients
to achieve effects.  In the treatment of patients with heart failure, Dr. David
Prentice, discussed two studies in which adult stem cells appear to have some
benefit. 

The first study was the result of a Brazil-Florida joint
effort in which it was discovered that adult stem cells injected directly into
the heart could relieve angina. These data are not all that surprising given
that the first use of stem cells for heart failure involved a similar injection
procedure in Japan more than a decade ago.   Stem cell administration for
cardiac conditions has been performed in numerous clinical trials, here is a
link to a video on a previously published Phase III study in patients who
previously had a heart attack

http://www.youtube.com/watch?v=flv0RmzPyLU

In the current study eight patients were received the stem
cell treatment and according to the principle investigator Dr. Nelson Americo
Hossne, Jr, all of the patients treated exhibited some degree of improvement. 
The study suggested that the patients improved through stimulation of production
of new blood vessels.  Furthermore, the authors believed that the cells and the
procedure used to administer them are safe and effective. 

Dr. Hossne stated "For our patients, angina symptom
relief began as early as three months post-procedure with continuing improvement
through the twelfth month and sustained improvement past 18 months. Symptom
relief improved in all patients, suggesting that the effect is sustained, not
transitory."

The second study that Dr. Prentice discussed is from a
Chinese group in which the protein apelin was demonstrated to have an effect on
the ability of cardiac regenerative mechanisms.  In the study, 20 heart failure
patients were treated with their own bone marrow, 20 received placebo, and 20
healthy patients were compared for control.  All twenty of the heart failure
patients treated with adult stem cells showed significant improvement in cardiac
function within 21 days of treatment, while the standard medication patients
showed no improvement. The patients who received stem cells demonstrated a
significant increase in levels of apelin, which correlated with the recovery of
cardiac function.

Dr. Amit Patel, a world-recognized stem cell pioneer,
professor at University of Utah School of Medicine and an Editor of the journal
in which the papers were published stated: "Both studies demonstrate a
possible mechanistic approach in a clinical trial. These important findings
further enhance the understanding of the use of bone marrow derived cell therapy
for the treatment of cardiovascular disease."

Filed Under: Adult Stem Cells, Heart Disease, News, Stem Cell Research Tagged With: , , , , ,
February 26, 2010 by

Fat May Serve a Purpose in Stem Cell Research

Scientist Dr. Joseph Wu at the Stanford University School
of Medicine has recently published a new and improved method to generate stem
cells "artificially".  For almost a decade there has been substantial
controversy regarding the use of embryonic stem cells, with the debate becoming
socially and politically focused as opposed to based on science: one camp
believing that embryonic stem cell research must be supported at all costs, the
other camp believing that adult stem cells can do anything that embryonic stem
cells can do, so there should be no research performed in this area.  This
debate became somewhat irrelevant when the Japanese group of Yamanaka discovered
a method of "dedifferentiating" adult cells into cells that appear at a
molecular and functional level similar to embryonic stem cells.  These
"artificial" stem cells, called inducible pluripotent stem cells (iPS) have
several unique properties:  They don’t need to be extracted from embryos; they
can be made from the same patient that they will be used on; and the methods of
manufacturing can be relatively standardized. 

To date these cells have been demonstrated to be capable of
generating not only every tissue in the body tested, but they also can improve
disease conditions in animal models ranging from heart attacks, to liver
failure, to bone marrow reconstitution.  Unfortunately the biggest problem with
iPS cells is that they are difficult to generate.  In order to understand this,
it is important to first mention how the cells are made.  Adult cells have the
same DNA blueprint as embryonic stem cells.  However in adult cells certain
portions of the DNA are not used to make proteins.  So in liver cells the DNA
that encodes for proteins found in the skin is "silenced" or "blocked" from
making proteins by various chemical modifications that occur as a cell is
maturing.  Embryonic stem cells are considered "blank slate" cells because the
DNA is capable of expressing every protein found in the body.  In order to make
an adult stem cell "younger" so as to resemble an embryonic stem cell, it is
necessary to somehow reprogram the DNA in order to allow it to express every
gene.  So how would one go about doing this? There is one biological condition
in which adult cells take the phenotype of younger cells.  This is in cancer. 
This is the reason why some types of cancer start expressing proteins that other
cells normally produce.  For example certain liver cancers can produce insulin,
even though liver cells do not produce insulin.  The concept that certain cancer
genes can evoke a "rejuvenation" of adult cells was used by Yamanaka as a
starting point.  His group found that if you insert the oncogene c-myc, together
with the stem cell genes Nanog, Oct-4, and SOX-2 skin cells will start to look
like embryonic stem cells.  If these cells are placed on top of feeder cells
then they can be expanded and used as a substitute for embryonic stem cells.

The current problem with wide-scale use of this approach is
that insertion of the various genes into the cells requires the use of viruses
that literally infect the cells with the foreign genes.  Not only can the
viruses cause cancer, but also the genes administered can cause cancer because
they are oncogenes.  The other hurdle is that generation of iPS cells is a very
inefficient process.  It takes approximately 2-3 months to generate stable
cells, and these cells are usually generated from approximately 1 out of
100-300,000 starting cells.  We previously discussed advances that allowed for
uses of non-hazardous means of inserting genes into cells to make iPS

https://www.celllmedicine.com/thomson-safer-ips.asp , in this current article
another approach was described to increase efficacy.

Scientists used as starting population not skin cells,
which are considered substantially differentiated, but instead used fat derived
stem cells.  This type of stem cell is very much a mesenchymal stem cell

http://www.youtube.com/watch?v=qJN2RyBj78I and possesses ability to
transform into different tissues already.  Thus by starting with a cell that is
already more "immature", scientists have been able to increase the rate of iPS
generation, as well as, alleviate the need for the oncogene c-myc.

Other approaches being investigated on increasing
generation of iPS cells include use of chemicals that affect the DNA structure
such as valproic acid.  This is interesting because simple administration of
valproic acid on bone marrow stem cells has been demonstrated to increase their
"stemness"

http://www.youtube.com/watch?v=3Hc4LCUOSiA .

Although we are still far from the day when
individual-specific stem cells will be available for widespread use, we are
getting closer to this dream at a very fast pace.

Filed Under: Adult Stem Cells, Embryonic Stem Cells, News, Stem Cell Research Tagged With: , , , , ,
February 24, 2010 by

Stem Cells for HIV?

HIV infection causes its devastating effects on patients by
destruction of the CD4 T helper cell and macrophage component of the immune
system.  Entry of the virus into these cells occurs via binding to the molecules
CD4 and CCR5.  Interestingly a group of patients who appear to be resistant to
HIV infection have a mutation in the CCR5 protein.  Studies conducted on these
patients have demonstrated that the mutation in CCR5 results in resistance to
infection, while other components of the immune system of these patients are
intact.  Thus one possible method of treating HIV would be if somehow one could
induce the CCR5 mutation that is protective from HIV into the immune cells of
patients.  It is very difficult to selectively mutate established immune cells,
however, one possibility would be if one could induce such a mutation in stem
cells, and then administer the stem cells to the patient so that they
"differentiate" into immune cells.

Scientists from the Department of Microbiology, Immunology
and Molecular Genetics, at the David Geffen School of Medicine, University of
California at Los Angeles have started figuring methods of doing this. 
Specifically, a new technology called "RNA Interference" was used to selectively
block expression of the CCR5 gene on stem cells.  RNA interference is a process
that is normally used by mammalian cells to protect themselves against viruses. 
Specifically, RNA is found only as a single strand in mammalian cells.  Double
stranded RNA is found only in viruses.  When a mammalian cell recognizes double
stranded RNA it believes that a viral infection is occurring and two processes
are triggered.  The first is gene-nonspecific.  Regardless of what is coded in
the double stranded RNA, the cell starts to produce the protein interferon,
which blocks other cells from being infected, as well, the cell alters various
metabolic activities and enters a quiescent state.  The second process is
gene-specific, in that the cell will destroy any other RNA that resembles what
is encoded in the double strand.  While the first effect is useful for
inhibition of viral infections, it is non-specific and causes general toxicity
when administered at high enough levels to people or animals in order to elicit
an effect.  Thus a Nobel Prize was awarded in 2006 to Fire and Mello when they
discovered that by administering pieces of double stranded RNA shorter than 21
nucleotides, the selective gene-silencing effect could be induced in absence of
the non-selective "interferon effect".

In their recent paper, Liang et al used RNA interference to
block expression of the CCR5 gene on stem cells that are capable of giving rise
to both CD4 T cells, as well as macrophages.  They demonstrated that
gene-blockade was passed on to the progeny of the stem cell, and that the newly
generated cells were resistant to HIV infection in vitro.

In contrast to using stem cells for hematopoietic
transplantation, in which depletion of the original recipient cells is required,
the use of genetically engineered stem cells for treatment of HIV would not
require such myeloablation since the HIV infection will naturally be killing the
non-manipulated cells.

Filed Under: HIV, News, Stem Cell Research Tagged With: , , , , ,
December 30, 2009 by

Stem Cells Might Reverse Heart Damage From Chemo

One of the great findings of regenerative medicine was that organs previously believed to be incapable of healing themselves actually contain stem cells that in response to injury cause some degree of healing. The problem being that these "endogenous healing mechanisms" are usually too small to mediate effects that are visible at the clinical level. For example, the brain was considered to have very limited ability to heal itself after damage. Recent studies that have allowed for observation of brain cells after experimental strokes have led to the discovery of brain stem cells in the dendate gyrus and subventricular zones of the brain, stem cells that start to multiple after a stroke. Interestingly, various hormones such as human chonrionic gonadotropin, are capable of stimulating brain stem cell multiplication. This is currently being used in clinical trials for stroke by the company Stem Cell Therapeutics.

In the area of heart failure, it was also believed that once cardiac tissue is damaged, the only repair process that the body performs is production of scar tissue, which is pathological to the patient. While this scar tissue is found in the majority of the injured area, molecular studies have revealed the existence of cardiac specific stem cells, which start to multiply after injury and serve to repair, albeit in small amounts, the infarct area.

One way to augment endogenous repair processes is to administer stem cells from the bone marrow, which are known to produce various growth factors that assist the tissue-specific stem cell in mediating its activity. Another way is to physically extract the tissue specific stem cells, expand them outside of the body and reimplant them into the damaged area.

In a recent publication in the journal Circulation, Piero Anversa, M.D., director, Center for Regenerative Medicine, Departments of Anesthesia and Medicine and Cardiovascular Division, Brigham and Women’s Hospital, Boston and Roberto Bolli, M.D., chief, cardiology, and director, Institute of Molecular Cardiology, University of Louisville, Kentucky, describe the use of cardiac specific stem cells in treatment of animals whose hearts of been damaged by the chemotherapeutic drug doxorubicin.
Doxorubicin is a chemotherapeutic drug that is mainly used in the treatment of breast, ovarian, lung, and thyroid cancers, as well as for neuroblastoma, lymphoma and leukemia. One of the main limiting factors to increasing the dose of doxorubicin to levels that can lead to tumor eradication is that it causes damage to the heart muscle, the myocardium.

In the published study, the investigators expanded the cardiac specific stem cells from rats, gave the rats high doses of doxorubicin and in some rats injected back cardiac specific stem cells, whereas other rats received control cells. The rats that received the cardiac specific stem cells had both preservation of cardiac function, and also regeneration of the damaged heart tissue. This is an important finding since the type of damage that doxorubicin does to the heart is different from other types of heart damage that have been studies, such as the damage that occurs after a heart attack. These data seem to suggest that stem cell therapy may be useful in a variety of injury situations.

"Theoretically, patients could be rescued using their own stem cells," said study author Dr. Piero Anversa, director of the Center for Regenerative Medicine at Brigham and Women’s Hospital in Boston. Dr. Aversa is one of the original discoverers of the cardiac specific stem cell when he published experiments in dogs demonstrating multiplication of cells in the myocardium that seem to have ability to generate new tissue after damage (Linke et al. Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function. Proc Natl Acad Sci U S A. 2005 Jun 21;102(25):8966-71).

"A Phase 1 clinical trial using a similar procedure in people is already under way", said Dr. Roberto Bolli, chief of cardiology and director of the Institute of Molecular Cardiology at the University of Louisville in Kentucky, who is heading the trial. The FDA has approved a Phase I clinical trial using cardiac specific stem cells in 30 patients who have congestive heart failure due to disseminated atherosclerosis. "In the trial, participants’ cardiac tissue will be harvested, the stem cells isolated and then expanded in vitro from about 500 cells to 1 million cells over several weeks", Bolli explained. "Several months after the patient has undergone bypass surgery, the stem cells will be re-injected." A similar clinical trial is being performed at Cedars Sinai in Los Angeles.

While the problems of tissue extraction (which is performed by an invasive procedure requiring biopsy of heart tissue) and cost of expansion are still formidable hurdles to widespread implementation, it is believed that the clinical evidence of a therapeutic response will open the door to other avenues of expanding tissue specific stem cells, such as administration of growth factors that can accomplish this without need for cell extraction outside of the body.

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