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Specialized Blood Vessels Jumpstart and Sustain Liver Regeneration
ScienceDaily (Nov. 14, 2010) — The liver's unique
ability among organs to regenerate itself has been
little understood. Now Weill Cornell Medical
College scientists have shed light on how the liver
restores itself by demonstrating that endothelial
cells -- the cells that form the lining of blood
vessels -- play a key role.
See Also:
Health & Medicine
 Stem Cells
 Liver Disease
 Immune System
 Leukemia
 Lymphoma
 Prostate Cancer
The results of their study are
published Nov. 10 in the online
edition of the journal Nature, with a
companion study in the Oct. 24 issue
of Nature Cell Biology describing how
endothelial cells are activated to
initiate organ regeneration.
It has long been known that
endothelial cells passively conduct
blood, passing oxygen, nutrients and
Reference
metabolic waste to and from tissues
 Healing
through capillary walls. However, in
 Embryonic stem cell
studies published in recent years, the
 Liver
Weill Cornell researchers have
 Lymphatic system
demonstrated that endothelial cells
actively influence the self-renewal of
certain stem cell populations and the
regeneration of tissue. Now, these
scientists have uncovered the endothelial cells' "instructive role"
in liver regeneration. Further, the researchers believe that in the
coming years it will be possible to facilitate healing damaged
livers by transplanting certain types of endothelial cells with
liver cells.
"We have found that specialized blood vessel cells in the liver -a specific type of sinusoidal endothelial cell -- initiate and
sustain liver regeneration by producing growth factors that we
have identified. This finding will open the door for designing
new therapies to treat damaged livers," says the study's senior
author, Dr. Shahin Rafii, who is the Arthur B. Belfer Professor in
Genetic Medicine and co-director of the Ansary Stem Cell
Institute at Weill Cornell Medical College and a Howard Hughes
Medical Institute investigator.
The liver performs many physiological functions, including
converting nutrients into essential blood components; storing
vitamins and minerals; producing bile for digesting fats;
regulating blood clotting; and metabolizing and detoxifying
substances that would otherwise be harmful. When the liver
malfunctions, the consequences can be grave. Liver failure,
Comp
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"Until our study, the molecular and cellular pathways that would
initiate and maintain liver regeneration were not known," says
Dr. Bi-Sen Ding, the study's first author and a senior
postdoctoral fellow in Dr. Rafii's lab. "Attempts to transplant
hepatocytes [liver cells] directly into the liver led to very limited
success. But now we have identified liver sinusoidal endothelial
cells (LSECs) -- that, when activated, are critical to liver
regeneration and may enable proper engraftment when
hepatocytes are implanted into the injured liver."
Dr. Rafii's team determined the mechanism by which LSECs
regulate liver regeneration by studying this process in
genetically engineered mice whose livers were 70 percent
removed. Through a series of experiments involving strategic
endothelial cell implantation, the team found that only those
LSECs whose genes were producing the angiocrine growth
factors Id1 or Wnt2 and "hepatocyte growth factor" (HGF)
would initiate and sustain liver regeneration. It is thought that
Wnt2 and HGF work together in initiating regeneration, and that
the LSECs and the liver cells must be next to each other for
successful regeneration were key findings.
"Therefore, to regenerate a long-lasting liver, we may need to
co-transplant hepatocytes with the properly activated
endothelium, which produces the right growth factors for the
hepatocytes to attach, grow and connect with other parts of the
liver. Co-transplantation of primed activated endothelium with
liver cells may be an important step to design future therapies
to regenerate the liver," says Dr. Ding.
Despite these new insights, Dr. Rafii points to an unsolved
enigma: How do endothelial cells sense the loss of liver tissue
and initiate the regeneration process? "Change of blood flow
might be one of the possibilities," suggests Dr. Sina Rabbany,
study co-senior author, who is an adjunct professor at Weill
Cornell and professor of bioengineering at Hofstra University.
"It is well known that endothelial cells can sense subtle
changes in the flow of blood because they are located at the
interface between the blood flow and vessel wall. The loss of a
liver lobe will inevitably alter the local blood flow patterns and
resulting shear stresses that are redirected into the remaining
lobes. This alteration in the biomechanical transduction process
is part of a complex system likely to 'activate' endothelial cells
to produce hepatocyte-active growth factors."
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Dr. David Lyden, a co-author on the paper and the Stavros
San Francisco Hospital — California Pacific
Niarchos Associate Professor in Pediatric Cardiology at Weill
Medical Center Providing Leading-edge Medicine
Cornell Medical College, says, "This is an important study. By
www.cpmc.org
targeting endothelial-specific genes such as Id1, as identified in
this research, I hope that it will facilitate the design of new
therapies to treat people with liver disease, whether due to
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infection, cancer, or acute or long-term damage."
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Earlier this year, Rafii's team developed a new technique and
described a novel mechanism for turning human embryonic and
pluripotent stem cells into plentiful, functional endothelial cells,
which are critical to the formation of blood vessels. The new
approach allows scientists to generate virtually unlimited
quantities of durable endothelial cells -- more than 40-fold the
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in this study and director and physician-in-chief of the Ronald
O. Perelman and Claudia Cohen Center for Reproductive
Medicine, as well as the director of the Tri-Institutional Stem
Cell Initiative Derivation Unit at Weill Cornell Medical College.
"One of the most remarkable findings of our studies is the
realization that endothelial cells within each organ are
functionally different, and once activated produce a unique set
of growth factors," states Dr. Rafii. "The challenge that lies
ahead is to discover the organ-specific growth factors produced
by the endothelial cells that initiate the regeneration of that
particular organ. Then, these factors could be exploited
therapeutically to induce selective regeneration of one organ
without affecting others."
Additional co-authors include Daniel J. Nolan, Jason M. Butler,
Daylon James, Alexander O. Babazadeh and Koji Shido, all of
the Ansary Stem Cell Institute in the Department of Genetic
Medicine, Weill Cornell Medical College, and the Howard
Hughes Medical Institute; Dr. Vivek Mittal, Department of
Surgery, Weill Cornell Medical College; and Dr. Thomas N.
Sato, Graduate School of Biological Sciences, Nara Institute of
Science and Technology, Nara, Japan.
How Vascular Endothelial Cells Renew Blood Stem Cells
and Control Stem Cells' Differentiation
Another study by the same group, published in the Oct. 24
issue of Nature Cell Biology, examines how a similar type of
sinusoidal endothelial cells that promote liver regeneration also
are activated to renew blood stem cells and control their
differentiation into various types of blood cells within the bone
marrow. The findings may be used to create mass quantities of
stem cells following trauma to the bone marrow's
microenvironment.
Following injury from therapeutic radiation or chemotherapy,
stem cells in the bone marrow are injured, hampering blood cell
production. Some patients experience severe and potentially
irreversible trauma to their ability to produce blood cells. Until
now it has been unclear how the body signals these stem cells
to regenerate and to differentiate into cells that form blood cells.
Dr. Rafii and his lab have shown that endothelial cells release
specific angiocrine growth factors into the environment of the
bone marrow, telling the body to produce more stem cells. The
researchers showed that the Akt-pathway is activated in the
endothelial cells, which turns on expression of a group of
growth factors that induces the bone marrow to produce more
stem cells. Following the activation of the Akt-pathway, the
MAP kinase pathway is activated, which stimulates the
production of angiocrine factors that control the differentiation
of the stem cells into various cells needed to make up blood.
Results from the study show a 10-fold increase of stem cell
production in mouse models that express higher levels of Akt
selectively in endothelial cells, when compared with control
mice. If proven applicable in humans, the findings may lead to a
new way of treating patients suffering from bone marrow
deficiencies.
Dr. Jason Butler, who along with Dr. Hideki Kobayashi is the
study's co-first author and senior postdoctoral fellows in Dr.
Rafii's lab.
"Using properly activated organ-specific endothelial cells to
propagate enough stem and progenitor cells, such as those of
bone marrow and liver, so they can be used clinically has broad
therapeutic implications not only for regenerative medicine, but
also for the study of genetic diseases," concludes Dr. Rafii.
Additional co-authors include Mariko Kobayashi, Bi-Sen Ding,
Bryant Bonner, Vi Chiu, Daniel Nolan, Koji Shido, all from Weill
Cornell; and Laura Benjamin and Rebekah O'Donnell, from the
Beth Israel Deaconess Medical Center, Harvard Medical
School, Boston, Mass.
The Nature and Nature Cell Biology studies were both
supported by grants from the Howard Hughes Medical Institute,
the Ansary Stem Cell Institute, the National Institutes of Health,
Qatar National Priorities Research Program, the Anbinder
Foundation, Newman's Own Foundation, the Empire State
Stem Cell Board, and the New York State Department of
Health.
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Story Source:
The above story is reprinted (with editorial adaptations by
ScienceDaily staff) from materials provided by NewYorkPresbyterian Hospital/Weill Cornell Medical College, via
Newswise.
Journal References:
1. Bi-Sen Ding, Daniel J. Nolan, Jason M. Butler, Daylon
James, Alexander O. Babazadeh, Zev Rosenwaks, Vivek
Mittal, Hideki Kobayashi, Koji Shido, David Lyden, Thomas
N. Sato, Sina Y. Rabbany, Shahin Rafii. Inductive
angiocrine signals from sinusoidal endothelium are
required for liver regeneration. Nature, 2010; DOI:
10.1038/nature09493
2. Hideki Kobayashi, Jason M. Butler, Rebekah O'Donnell,
Mariko Kobayashi, Bi-Sen Ding, Bryant Bonner, Vi K. Chiu,
Daniel J. Nolan, Koji Shido, Laura Benjamin, Shahin Rafii.
Angiocrine factors from Akt-activated endothelial cells
balance self-renewal and differentiation of
haematopoietic stem cells. Nature Cell Biology, 2010; 12
(11): 1046 DOI: 10.1038/ncb2108
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NewYork-Presbyterian Hospital/Weill Cornell
Medical College (2010, November 14).
Specialized blood vessels jumpstart and sustain
liver regeneration. ScienceDaily. Retrieved June
1, 2011, from http://www.sciencedaily.com
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