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Stem Cells

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Andy Battaglia:
Even in donors for stem cell transplants, G-CSF is needed to mobilize sufficient stem cells to be used in the transplant, and this is from normal, non-thal donors. Sufficient quantities of stem cells for the transplant are not available without drug induced mobilization. In thals, it is even more difficult to collect sufficient stem cells to be used for gene therapy.

Taking blood from thal majors would not be done. In thal majors, the bone marrow is suppressed as much as possible to prevent the production of blood cells, as they are of negative value and expand the bone marrow, causing weak bones and much pain to the patients. Removing blood over a long period would have no meaning as transfusions would have to continue to keep the patient alive. Bleeding would be totally counter-productive in those who cannot make their own blood. This is why blood-letting which is commonly used to reduce iron load in those with hemochromatosis, is completely contraindicated in thalassemia.

Only with a drug induced mobilization are there sufficient quantities of stem cells collected to be useful. But even with this mobilization, a problem occurs with too many white blood cells being produced. This is another part of the problem that is being addressed, primarily through the use of hydroxyurea.

http://clinicaltrials.gov/ct2/show/NCT00336362  (From 2006).


--- Quote ---Before gene transfer methods can be attempted in individuals with beta thalassemia major, a safe method of obtaining blood stem cells needs to be developed. The purpose of this study is to investigate the safety and feasibility of collecting peripheral blood stem cells (PBSC) from individuals with beta thalassemia major. Research participants will be given G-CSF (filgrastim) for several days to increase the number of stem cells in the blood, a process called "mobilization." After mobilization, participants will undergo a procedure called apheresis to remove the white blood cells. Researchers in the laboratory will purify the stem cells from the mixture and test methods of putting a normal globin gene into the stem cells. Half of the participants will receive hydroxyurea (HU) prior to G-CSF mobilization. HU is used in splenectomized patients to attempt to reduce the risk of clotting during mobilization. In non-splenectomized patients, HU is given in an attempt to decrease the size of the spleen.
--- End quote ---

The results of this research. http://ash.confex.com/ash/2009/webprogram/Paper23321.html


--- Quote ---For gene therapy (GT) of thalassemia (TH), high numbers of genetically-modified hematopoietic stem cells (HSCs) are required to effectively compete for niche space in the hypercellular thalassemic bone marrow (bm). Mobilized peripheral blood is the preferable source of HSCs for thalassemia GT due to higher yields of CD34+cells compared to bm harvest. There is limited information on the mobilization efficacy of adult patients with major β-TH as well as on the safety of the procedure in a condition of splenomegaly and extramedullary hemopoiesis. Rare events of splenic rupture or thrombosis with G-CSF in normal donors raise safety concerns for its use in TH where chronic splenomegaly and hypercoagulability exist. Pretreatment of patients with hydroxyurea (HU) could reduce the risk of splenic rupture or thrombosis by decreasing the splenic hemopoiesis and thereby the spleen size in the non-splenectomized (non-SPL), and the circulating cells in the splenectomized (SPL) patients before G-CSF. In an on going mobilization study, we aim to assess the safety and efficacy of G-CSF mobilization with or without HU pretreatment in adult patients with β-TH major...
Overall, it seems that mobilization of SPL thalassemic patients is challenging.  Mobilization is not inherently inefficient in SPL patients but it results from mandatory G-CSF-dose modifications to avoid hyperleukocytosis. Patient-tailored schemes of G-CSF mobilization or alternative ways of mobilization (ie AMD 3100) will be required in order to obtain high numbers of HSCs from SPL patients. HU seems to play a safety role as pretreatment before mobilization, especially in the SPL patients, however the time to G-CSF initiation after HU cessation is critical for a sufficient CD34+cell yield.
--- End quote ---

As I said, this is anything but a simple process and many years of research has only now brought us to the point where there is sufficient stem cell mobilization to give stem cell therapy a chance to succeed.

ironjustice:
The thinning of the blood which happens
when one is bled may also be beneficial.
------
For blood stem cells, the force is strong
Blood flow, nitric oxide boost production of stem cells

By Tina Hesman
Saey Web edition : Wednesday, May 13th, 2009
Blood stem
cells grow with the flow, two new studies show.

The studies, led by independent groups at Children’s Hospital Boston,
report that an embryo’s heartbeat and blood circulation stimulate the
growth of blood stem cells.

The discovery could be a boon to researchers seeking to make blood
stem cells for people with blood cancers, immune system disorders and
other diseases that require bone marrow transplants. In children and
adults, blood stem cells reside in the bone marrow. Only about a third
of patients who require bone marrow transplants have matching donors.

“Basically we cannot offer optimal therapy to two-thirds of patients,”
says Leonard Zon, director of the Stem Cell Program at Children’s
Hospital Boston, and a coauthor of one of the new studies, which
appears online May 13 and in the May 15 Cell.

Scientists can make red and white blood cells easily in the
laboratory, but bone marrow patients need blood stem cells to
constantly replenish their blood supply. Producing these cells, also
called hematopoietic stem cells, is much more difficult, Zon says.

Now, his group suggests that a little force can boost blood stem cell
production in zebrafish embryos. Reporting online May 13 in Nature, a
group led by George Daley, director of the Pediatric Stem Cell
Transplantation Program at Children’s Hospital Boston, demonstrates
that blood flow also triggers hematopoietic stem cell production in
mouse embryos. Both groups found nitric oxide plays an important role.

Daley’s group directly tested the ability of blood flow to turn cells
into hematopoietic stem cells. The team placed mouse embryonic stem
cells in a centrifuge-like device that mimics sheer stress — the
frictional force blood creates when it flows over cells — in a mouse’s
aorta. In early embryos, blood stem cells first form on the floor of
the aorta. Later in development, they migrate to the bone marrow.

Embryonic stem cells exposed to the same magnitude of sheer stress as
found in the mouse aorta produced hematopoietic stem cells. Cells that
were exposed to a different magnitude of sheer stress, such as that in
the human aorta, did not.
A nitric oxide–blocking drug reduced the number of blood stem cells
induced by the sheer stress. Nitric oxide is a chemical produced
naturally in the body and is known to be important in regulating blood
vessel growth and elasticity.

When the researchers gave the nitric oxide–blocker to pregnant mice,
their embryos also had problems making blood stem cells.

Zon’s team used zebrafish embryos, which are transparent, to watch the
stem cells develop. He and his colleagues found that chemicals that
increase blood flow in the tails of zebrafish embryos also boost
activity of RUNX1, a master regulator of blood stem cells. Mutant
embryos that don’t have a heartbeat because of a defect in a heart
muscle protein don’t make hematopoietic stem cells in their tails.

When the researchers gave a nitric oxide compound to the mutant
embryos, however, the embryos produced more blood stem cells. The
nitric oxide–blocker also inhibited blood stem cell production, the
researchers found. Those findings suggest that blood flow may increase
nitric oxide levels, which then boost stem cell production, Zon says.

Intuitively, scientists might expect that mechanical forces play a
role in shaping development, but few biologists have studied this due
to experimental difficulties, says Ihor Lemischka, a stem cell
biologist at Mount Sinai School of Medicine in New York City.

“I think we’ll be seeing more of these types of studies,” Lemischka
says.

It’s still not clear how the cells sense sheer stress, and researchers
are trying to unravel the chain of events between mechanical force and
stem cell production in order to manipulate the process to make blood
stem cells for transplant.

Andy Battaglia:
Ironjustice,

Can I ask you to supply links to the original article when possible? I like to make sure that the original credits are seen.

Himanshu Kumar:
Dear  Andy,

I am writing this post on behalf of one of my friend whose daughter has recently been diagnosed with Multiple Sclerosis which is in the early stages. Incidentally, my friend's daughter too happens to be a Thal carrier. Are there any studies to prove that Multiple Sclerosis has some correlation with thalassemia major or minor?

Whatever little research we have done on Multiple Sclerosis so far suggests that the Multiple Sclerosis is irreversible and disease progression can be delayed and cannot be completely stopped.

Do you have any view on Multiple Sclerosis and its potential cure, medications etc. Can Stem Cell Transplant/Bone Marrow Transplant cure Multiple Sclerosis.

Regards,
Himanshu

Sharmin:
Dear Himanshu,

I am sorry to hear about the news your friend has recieved.  I do not know of any correlation between MS and thalassemia.

Novel treatments for MS, that are proving to be effective in the early stages have been recently published.  I will post what I have read soon.

Please convey my best wishes to your frined and your friend's daughter.

Sharmin

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