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Stem Cells Research

Research about aging and health related issues


Category: Adult Stem Cells

NEW YORK (March 4, 2010) — In a leap toward making stem cell therapy widely
available, researchers at the Ansary Stem Cell Institute at Weill Cornell
Medical College have discovered that endothelial cells, the most basic building
blocks of the vascular system, produce growth factors that can grow copious
amounts of adult stem cells and their progeny over the course of weeks. Until
now, adult stem cell cultures would die within four or five days despite best
efforts to grow them.

“This is groundbreaking research with potential application for regeneration of
organs and inhibition of cancer cell growth,” said Dr. Antonio M. Gotto Jr., the
Stephen and Suzanne Weiss Dean of Weill Cornell Medical College and Provost for
Medical Affairs of Cornell University. “We are indebted to Shahla and Hushang
Ansary for founding this Institute and to the Starr Foundation Tri-Institutional
Stem Cell Initiative for ongoing support.”

This new finding sets forth the innovative concept that blood vessels are not
just passive conduits for delivery of oxygen and nutrients, but are also
programmed to maintain and proliferate stem cells and their mature forms in
adult organs. Using a novel approach to harness the potential of endothelial
cells by “co-culturing” them with stem cells, the researchers discovered the
means to manufacture an unlimited supply of blood-related stem cells that may
eventually ensure that anyone who needs a bone marrow transplant can get one.

The vascular-cell model established in this study could also be used to grow
abundant functional stem cells from other organs such as the brain, heart, skin
and lungs. An article detailing these findings appears in the March 5 issue of
the journal Cell Stem Cell.

In adult organs, there are few naturally occurring stem cells, so using them for
organ regeneration is impractical. Until now, strategies to expand cultures of
adult stem cells, which invariably used animal-based growth factors, serum, and
genetically manipulated feeder cells, have only been marginally successful. This
study, which employs endothelial cells to propagate stem cells without added
growth factors and serum, will likely revolutionize the use of adult stem cells
for organ regeneration, as well as decipher the complex physiology of the adult
stem cells.

“This study will have a major impact on the treatment of any blood-related
disorder that requires a stem cell transplant,” says the study’s senior author,
Dr. Shahin Rafii, the Arthur B. Belfer Professor in Genetic Medicine,
co-director of the Ansary Stem Cell Institute and a Howard Hughes Medical
Institute Investigator, at Weill Cornell Medical College. Currently, stem cells
derived from bone marrow or umbilical cord blood are used to treat patients who
require bone marrow transplants. Most stem cell transplants are successful, but
because of the shortage of genetically matched bone marrow and umbilical cord
blood cells, many patients cannot benefit from the procedure.

“Over the last few decades, substantial funding has been spent to develop
platforms to expand adult stem cell cultures, but these efforts have never been
able to coax an authentic adult stem cell to self-renew beyond a few days,”
continues Dr. Rafii. “Most stem cells, even in the presence of multiple growth
factors, serum, and support from generic non-endothelial stromal cells, die
after a few days. Now, employing our endothelial stem cell co-cultures, we can
propagate bona fide adult stem cells in the absence of external factors and
serum beyond 21 days with an expansion index of more than 400-fold.”

If this vascular-based stem cell expansion strategy continues to be validated,
physicians could use any source of hematopoietic (blood-producing) stem cells,
propagate them exponentially, and bank the cells for transplantation into

In a true first, the study demonstrates how this novel vascular cell platform or
“vascular niche” can self-renew adult hematopoietic stem cells for weeks, both
in vitro and in vivo, by co-culturing them on a bed of endothelial cells. The
researchers chose endothelial cells because they are in close contact with blood
stem cells, and previous work from Dr. Rafii’s lab had demonstrated that
endothelial cells produce novel stem-cell-active growth factors. However,
maintenance of the endothelial cells is cumbersome and if they are not “fed”
specific substances, such as growth factors known as “angiogenic factors,” they
immediately die. To get around this problem, the researchers genetically
engineered the endothelial cells to stay in a long-term survival state by
inserting a recently discovered gene cloned from adenoviruses, which does not
promote oncogenic transformation of the human cells. This earlier discovery,
using a single gene to put endothelial cells into a long-lasting “suspended
animation” state without harming their ability to produce blood vessels, was
also discovered in Dr. Rafii’s lab and published in the journal Proceedings of
National Academy Sciences in 2008.

Endothelial Cells Could Generate Stem Cells and Their Differentiated Progeny
In this study, the researchers also discovered that endothelial cells not only
could expand stem cells, but also instruct stem cells to generate mature
differentiated progeny that could form immune cells, platelets, and red and
white blood cells, all of which constitute functioning blood.

“We are the first group to demonstrate that endothelial cells elaborate a
repertoire of stem-cell-active growth factors that not only stimulate stem cell
expansion but also orchestrate differentiation of these stem cells into their
mature progeny,” says Dr. Jason Butler, a senior investigator at Weill Cornell
Medical College and first author of the study. “For example, we have found that
expression of specific stem-cell-active factors, namely Notch-ligands, by the
endothelial cells lining the wall of working blood vessels promote proliferation
of the blood-forming stem cells. Inhibition of these specific factors on the
endothelial cells resulted in the failure of the regeneration of the
blood-forming stem cells. These findings suggest that endothelial cells
directly, through expression of stem-cell-active cytokines, promote stem cell

Further describing this innovative concept, in a high-impact article published
in the January 2010 issue of Nature Reviews Cancer, Drs. Rafii and Butler, and
Dr. Hideki Kobayashi, who is also a co-author of the current study, have
elaborated on specific endothelial cell-produced growth factors that promote the
growth of tumor cells besides stem cells.

Development of the vascular-cell technology that supports long-lasting growth of
stem cells will also allow scientists to generate abundant sources of functional
and malignant stem cells for genetic and basic studies. This study has also
resolved a long-standing controversy in which several groups had claimed that
bone-forming cells (osteoblasts) exclusively support the expansion of
blood-forming stem cells. “However, using a highly sophisticated molecular
imaging approach, we show that regenerating blood-forming stem cells in the bone
marrow are in intimate contact with the blood vessels, indicating that
endothelial cells are the predominant regulator of stem cell repopulation in the
adult bone marrow,” states Dr. Daniel Nolan, a senior scientist in Dr. Rafii’s
lab and a co-author of the new study.

One other important concern addressed in this study was whether forced expansion
of the stem cells over a long period of time would induce cancerous mutations in
the stem cells. However, the authors of this study show that, even after one
year, there was no indication of tumor formation, such as leukemias, when the
expanded stem cells were transplanted back into mice. This suggests that the
endothelial cells provide a milieu that proliferates stem cells without creating
cancer risk.

Dr. Rosenwaks says, “Generation of endothelial cells derived from diseased
embryonic stem cells that are being propagated in our Derivation Unit will open
up new avenues of research to molecularly eavesdrop on the communication between
vascular cells and stem cells. This innovative line of investigation to
determine how normal and abnormal human vascular cells induce the formation of
organs during development of embryos and how dysfunction of endothelial cells
results in developmental defects will lay the foundation for novel platforms
for therapeutic organ regeneration.”

Dr. Rafii sees even more opportunities. “Identification of as yet unrecognized
growth factors produced by human embryonic cell-derived endothelium and adult
endothelial cells that support stem cell expansion and differentiation will
establish a new arena in stem cell biology. We will be able to selectively
activate endothelial cells not only to induce organ regeneration, but also to
inhibit specifically the production of endothelial cell-derived factors in order
to block the growth of tumors. Our findings are the first steps toward such
goals and they highlight the potential of vascular cells for generating
sufficient stem cells for therapeutic organ regeneration, tumor targeting, and
gene therapy applications,” concludes Dr. Rafii.

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Before going further into the article, let me give you some information about stem cells. Stem cells are found in all multi-cellular organisms and are categorized as undifferentiated cells-meaning that they have the potential to develop into various specialized cells in the body during early development of an organism. Stem cells have the capacity to differentiate into specialized cells/organs such as kidney, liver, lungs, heart etc- and hence are of primary importance to human beings.

Stem cells have two special properties- firstly; they are unspecialized cells, having the ability to renew themselves through cell division and secondly, under certain experimental conditions they can be induced to become tissue or organ specific cells with specialized functions. Stem cells are basically of two types- embryonic stem cells or adult stem cells. The embryonic stem cells are derived from the early morula stage embryos or the inner cell mass of the blastocyst. On the other hand, the adult stem cells are undifferentiated stem cells that are found among differentiated tissues/organs and multiply be cell division to repair/renew the tissues in which they are

Adult Stem cells are found in various organs such as brain, bone marrow, peripheral blood, blood vessels, heart, gut, skin, teeth, skeletal muscle, liver etc. The research on adult stem cells has aggravated lots of excitement and debate amongst the scientists all over the world. Scientists have found out that lots of adult stem cells are present in structured tissues and organs- which is an indication of the fact that these cells can be used for transplants or can be induced to grow into specialized cells. However, one of the major drawbacks in using adult stem cells is that they are often restricted to certain types of lineages-meaning that the adult stem cell of a particular lineage will not be able to divide into different type of lineage!

In spite of the above drawback, the adult stem cells have been used for several years for successfully treating leukemia and related bone/blood cancers. The use of adult stem cells has not been considered controversial so far because unlike the embryonic stem cells (which are derived from the embryo), they are derived form the adult organs-and it does not require the destruction of the embryo.

The first successful example of using adult stem cells for transplant was carried by Paolo Macchiarini, at the Hospital Clinic of Barcelona, on a Columbian adult female whose trachea had been distorted due to tuberculosis. The entire procedure of carrying out the transplant occurred normally and the tissue exhibited no signs of rejection, even after months of transplant.

Adult stem cells are very valuable and a lot of research is still going on to find out the other applications or uses of these cells. Adult stem cells have numerous potential and if the information is decoded wisely, then soon we will have a world free of diseases!