Public release date: 11-Nov-2010
[ Print | E-mail |
Share ] [ Close Window ]
Contact: Andrew Klein
ank2017@med.cornell.edu
212-821-0560
New York- Presbyterian Hospital/Weill Cornell Medical Center/Weill Cornell Medical College
Specialized blood vessels jumpstart and sustain liver
regeneration
Weill Cornell Medical College studies lay groundwork for new treatments for regenerating liver
and bone marrow
NEW YORK (Nov. 11, 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.
The results of their study are published today 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
metabolic waste to and from tissues through capillary walls. However, in studies published in recent years,
the Weill Cornell researchers have 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, due to cirrhosis, various forms of hepatitis, and other diseases, kills
some 60,000 Americans per year. But the liver's capacity for regeneration is amazing.
"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."
Dr. David Lyden, a co-author on the paper and the Stavros Niarchos Associate Professor in Pediatric
Cardiology at Weill Cornell Medical College, says, "This is an important study. By 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 infection, cancer, or acute or long-term damage."
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 quantity possible with previous approaches. "These
embryonic-derived endothelial cells may provide a useful platform to expand liver and blood stem cells for
therapeutic transplantation," states Dr. Zev Rosenwaks, who is a co-author 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.
"You are essentially creating a cell culture bioreactor capable of producing large numbers of stem cells as well
as mature blood cells, which can restore bone marrow following trauma," says 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.
The Ansary Stem Cell Institute
The Ansary Stem Cell Institute brings together a premier team of scientists to focus on stem cells, which are
immature, unspecialized cells with the capacity to form all types of cells, tissues and organs in the body. The
Ansary Institute takes a collaborative approach to stem cell research by bringing together scientists from
varied areas of biomedical research. The Institute was established in 2004 with a generous gift from Mr.
Hushang Ansary. Since then, the Institute garnered approximately $26 million in external funding, including
support from the Starr Foundation Tri-Institutional Stem Cell Initiative and the Empire State Stem Cell Board
(NYSTEM). Ansary Institute researchers have made groundbreaking discoveries that show significant promise
for the future of regenerative medicine (marshalling the body's own resources to restore itself), the treatment
of cardiovascular disease, and more. Recent notable Ansary Institute discoveries include clear steps toward
the eventual clinical applicability of stem cells: identifying in adult mouse testes cells that can be converted to
stem cells that in turn generate cardiac, vascular and neuronal cell types; the unlimited expansion of bloodproducing stem cell cultures, whereas previous best efforts would result in a colony of stem cells dying after a
few days; and the unlimited generation of endothelial cells (the basic building blocks of the circulatory
system) from human embryonic stem cells. The Ansary Institute intends to lead the way in stem cell science
to relieve human suffering.
Weill Cornell Medical College
Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to
excellence in research, teaching, patient care and the advancement of the art and science of medicine,
locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in
cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and
sickness and toward developing new treatments and prevention strategies. In its commitment to global
health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil,
Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first
in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances -including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful
embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease,
and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious
brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its
faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.
The Medical College is also affiliated with the Methodist Hospital in Houston, making Weill Cornell one of only
two medical colleges in the country affiliated with two U.S.News & World Report Honor Roll hospitals. For
more information, visit www.med.cornell.edu.
[ Print | E-mail |
Share ] [ Close Window ]
AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for
the use of any information through the EurekAlert! system.