Study: Damaged liver cells undergo reprogramming to regenerate

Study: Damaged liver cells undergo reprogramming to regenerate
Sep 26, 2018 8
by Steph Adams | Science Writer

The Greek hero Prometheus was punished by being lashed to a rock and having his liver eaten each day by an eagle, a myth that hints at the extraordinary regenerative powers of the human liver. A new study offers insight into how RNA splicing generates alternate forms of the “Hippo signaling pathway” to promote liver regeneration.

Graphic by Jose Luis Vasquez, Beckman Institute

CHAMPAIGN, Ill. — In Greek mythology, Zeus punishes the trickster Prometheus by chaining him to a rock and sending an eagle to eat a portion of his liver every day, in perpetuity. It was the right organ to target – the liver has the ability to regenerate itself, though not overnight nor for eternity.

New research conducted by biochemists at the University of Illinois has determined how damaged liver cells repair and restore themselves through a signal to return to an early stage of postnatal organ development. The findings are reported in the journal Nature Structural & Molecular Biology.

“The liver is a resilient organ,” said U. of I. biochemistry professor Auinash Kalsotra, who led the new research. “It can restore up to 70 percent of lost mass and function after just a few weeks.

“We know that in a healthy adult liver, the cells are dormant and rarely undergo cell division,” he said. “However, if the liver is damaged, the liver cells re-enter the cell cycle to divide and produce more of themselves.”

The human liver can become chronically damaged by toxins such as alcohol and even certain medicines, but still continue to function and self-repair, Kalsotra said.

“This research looked at what is happening at the molecular level in a damaged liver that enables it to regenerate while still performing normal functions,” he said.

Using a mouse model of a liver severely damaged by toxins, the researchers compared injured adult liver cells with healthy cells present during a stage of development just after birth. They found that injured cells undergo a partial reprograming that returns them to a neonatal state of gene expression.

The team discovered that fragments of messenger RNA, the molecular blueprints for proteins, are rearranged and processed in regenerating liver cells in a manner reminiscent of the neonatal period of development. This phenomenon is regulated through alternative splicing, a process wherein exons (expressed regions of genes) are cut from introns (intervening regions) and stitched together in various combinations to direct the synthesis of many different proteins from a single gene. These proteins can have different cellular functions or properties.

“We found that the liver cells after birth use a specific RNA-binding protein called ESRP2 to generate the right assortment of alternatively spliced RNAs that can produce the protein products necessary for meeting the functional demands of the adult liver,” said graduate student Sushant Bangru, the lead author of the study. “When damaged, the liver cells lower the quantity of ESRP2 protein. This reactivates fetal RNA splicing in what is called the ‘Hippo signaling pathway,’ giving it instructions about how to restore and repopulate the liver with new and healthy cells.”

Kalsotra described the science in mythological terms: “When Zeus’ eagle comes in for its daily snack, damaging the liver, the alternatively spliced form of Hippos come into play – repairing Prometheus’s liver so the poor guy can go through this whole punishment again the next day.”

The National Institutes of Health, March of Dimes and American Heart Association supported this
research.

The paper “Alternative splicing rewires Hippo signaling pathway in hepatocytes to promote liver regeneration” is available online and from the U. of I. News Bureau.
DOI: 10.1038/s41594-018-0129-2

https://news.illinois.edu/view/6367/698670

Platelets promote the liver's regeneration process following surgery

Platelets promote the liver's regeneration process following surgery

(Vienna, 23 November 2015) A team of researchers at the MedUni Vienna has discovered that certain platelet-derived growth factors are of major significance for the liver's regeneration processes. It has been shown that platelets can encourage the regrowth of liver tissue in patients who have had parts of their liver removed surgically. This may also act as a starting point for the prediction of potential post-operative problems. The work has been published in the key journal on liver medicine, "Hepatology".

Platelets are a vital part of wound healing processes. They can specifically secrete key growth factors at the site of the injury and therefore start the damaged tissue's regeneration processes. In the latest study, which involved collaboration between the University Department of Surgery at the MedUni Vienna led by Patrick Starlinger and the Institute of Physiology led by Alice Assinger, scientists were able to demonstrate that the specific release of growth factors from the α granules was associated with post-operative liver regeneration.

The authors of this study demonstrated back in 2014 that serotonin stored in platelets can play a key role in post-operative liver regeneration. Serotonin is stored in the electron-dense granules (storage organelles) of platelets and is secreted after activation. As part of the platelet activation process, the contents of a second type of granule, known as the α granule, are also released. It has now been possible for the first time to prove a highly selective release of α granules in vivo and demonstrate the resulting pathophysiological consequences.

These granules contain both growth-promoting and growth-inhibiting factors. In vitro data from previous years have shown that platelets can be present not just, as was previously thought, in an activated or non-activated state, but instead that they are able, depending on the underlying stimulus, to release growth-promoting or growth-inhibiting factors on a highly specific basis. In the past, it was not known whether this mechanism also has a role to play in vivo and therefore has pathophysiological consequences.

The liver is the only organ that is able to regenerate itself, even after extensive damage or after parts of it have been surgically removed (resected). Up to 75 per cent of the liver tissue can be removed without the organ's metabolic functions being permanently impaired.

The liver's tremendous potential for regeneration and advancing developments in the field of liver surgery mean that even patients with impaired liver function are able to undergo intricate resections. However, impairment of liver function still occurs in a certain percentage of patients following surgery. This liver impairment can develop into life-threatening complications and is associated with a relatively high degree of mortality. The exact causes of liver failure are so far not fully understood.

Hepatic vein blood pressure could determine selective α granule release
The scientists have now also been able to show that there is a relationship between platelet-derived growth factors and hepatic vein blood pressure. Pre-existing liver disease, which causes changes to the blood pressure in the hepatic vein, is regarded as a risk factor for post-operative complications. "We were able to demonstrate that, in patients with high hepatic vein blood pressure, the release of growth-promoting substances is suppressed and increased levels of growth-inhibiting factors are released. These findings will help us to better understand the dangerous consequences of changes in hepatic vein blood pressure," explains Starlinger. The findings obtained from the study could make a major contribution towards the development of new treatment strategies aimed at ensuring improved liver regeneration following liver resection surgery and therefore also reducing the risk of liver failure that has to date been untreatable.

Service: Hepatology
The Profile of Platelet α-Granule Released Molecules Affects Postoperative Liver Regeneration. Starlinger P, Haegele S, Offensperger F, Oehlberger L, Pereyra D, Kral JB, Schrottmaier WC, Badrnya S, Reiberger T, Ferlitsch A, Stift J, Luf F, Brostjan C, Gruenberger T, Assinger A. 2015 Nov 3. doi: 10.1002/hep.28331http://www.ncbi.nlm.nih.gov/pubmed/26528955

Five research clusters at the MedUni Vienna
There are a total of five research clusters at the MedUni Vienna. The MedUni Vienna is increasingly focusing on fundamental and clinical research in these areas. The research clusters include medical imaging, cancer research / oncology, cardiovascular medicine, medical neurosciences and immunology. Surgical and hepatology research at the MedUni Vienna falls under the remit of the immunology cluster.

Source

New Liver Cell for Cellular Therapy to Aid in Liver Regeneration

 
Researchers Discover A New Liver Cell that Shows Promise for Cellular Therapy for Liver Regeneration

New research from the Icahn School of Medicine at Mount Sinai, published in the journal Cell Stem Cell today, suggests that it may one day become possible to regenerate a liver using cell therapy in patients with liver disease.

New York
  – June 6, 2013 /Press Release/ ––

Liver transplantation is the mainstay of treatment for patients with end-stage liver disease, the 12th leading cause of death in the United States, but new research from the Icahn School of Medicine at Mount Sinai, published in the journal Cell Stem Cell today, suggests that it may one day become possible to regenerate a liver using cell therapy in patients with liver disease. Investigators discovered that a human embryonic stem cell can be differentiated into a previously unknown liver progenitor cell, an early offspring of a stem cell, and produce mature and functional liver cells.

"The discovery of the novel progenitor represents a fundamental advance in this field and potentially to the liver regeneration field using cell therapy," said the study's senior author, Valerie Gouon-Evans, PharmD, PhD, Assistant Professor, in the Department of Developmental and Regenerative Biology, The Black Family Stem Cell Institute, at the Icahn School of Medicine at Mount Sinai. "Until now, liver transplantation has been the most successful treatment for people with liver failure, but we have a drastic shortage of organs. This discovery may help circumvent that problem."

In conjunction with the laboratory of Matthew J. Evans, PhD, from the Department of Microbiology at Icahn School of Medicine at Mount Sinai, investigators demonstrated the functionality of the liver cells generated from the progenitors, as the liver cells can be infected by the hepatitis C virus, a property restricted to liver cells exclusively.

A critical discovery in this research was finding that the novel progenitor has a receptor protein on its cell surface called KDR, or vascular endothelial growth factor receptor 2, which until now, was thought to be restricted to endothelial cells that form vessels, the progenitors for endothelial cells and the progenitors blood cells. The research team showed that activation of KDR on these novel liver progenitors differentiates them into mature liver cells. Additionally, work in a mouse model revealed similar cells, indicating that the progenitors are conserved from mouse to human, and therefore, they must be "important cells with promising potential for cell therapy in treating liver disease," explained Dr. Gouon-Evans.

Next, the research team will examine specifically whether these liver cells obtained from human embryonic stem cells in a dish help repair injured livers in preclinical animal models of liver disease.

Funding for this study was provided by The Black Family Stem Cell Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Robin Chemers Neustein Postdoctoral Fellowship, the American Cancer Society, and Pew Charitable Funds.

About The Black Family Stem Cell Institute
The Black Family Stem Cell Institute is Mount Sinai’s foundation for both basic and disease-oriented research on embryonic and adult stem cells. The therapeutic use of stem cells is a promising area of medicine for the decades ahead and researchers are examining why stem cells function in certain types of niches, microenvironments, and pockets of activity. Investigators are working to break the code in stem cell communication by determining how stem cells signal one another and other cells. The new knowledge that will result from this research holds the promise of diagnostic and therapeutic breakthroughs.

Studies show that it is possible to reprogram adult skin cells into cells that are very similar to embryonic stem cells. Once stem cells can be grown and differentiated in a controlled way to replace degenerated cells and repair tissues, medical science may then be able to diagnose and cure many intractable diseases at their earliest stages, such as type 1 diabetes, Parkinson’s disease, various cardiovascular diseases, liver disease, and cancer.

For more information, visit http://icahn.mssm.edu/research/institutes/black-family-stem-cell-institute/about-us

The Mount Sinai Medical Center

The Mount Sinai Medical Center encompasses both The Mount Sinai Hospital and Icahn School of Medicine at Mount Sinai. Established in 1968, the Icahn School of Medicine is one of the leading medical schools in the United States. The Medical School is noted for innovation in education, biomedical research, clinical care delivery, and local and global community service. It has more than 3,400 faculty in 32 departments and 14 research institutes, and ranks among the top 20 medical schools both in National Institutes of Health (NIH) funding and by U.S. News & World Report.

The Mount Sinai Hospital, founded in 1852, is a 1,171-bed tertiary- and quaternary-care teaching facility and one of the nation's oldest, largest and most-respected voluntary hospitals. In 2011, U.S. News & World Report ranked The Mount Sinai Hospital 16th on its elite Honor Roll of the nation's top hospitals based on reputation, safety, and other patient-care factors. Of the top 20 hospitals in the United States, Mount Sinai is one of 12 integrated academic medical centers whose medical school ranks among the top 20 in NIH funding and U.S. News & World Report and whose hospital is on the U.S. News & World Report Honor Roll. Nearly 60,000 people were treated at Mount Sinai as inpatients last year, and approximately 560,000 outpatient visits took place.

For more information http://www.mountsinai.org/
Find Mount Sinai on Facebook, Twitter and YouTube

Scientists have shed light on how the liver repairs itself

Boosting cell production could help treat liver disease

Source

Scientists have shed light on how the liver repairs itself with research that could help develop drugs to treat liver disease

Researchers at the Medical Research Council (MRC) Centre for Regenerative Medicine at the University of Edinburgh have discovered how to enhance the production of key cells needed to repair damaged liver tissue.

The study, published in the journal Nature Medicine, could help heal livers affected by diseases such as cirrhosis or chronic hepatitis.

Scientists were able to unpick the process of how different cells in the liver are formed.
When the liver is damaged it produces too many bile duct cells and not enough cells called hepatocytes, which the liver needs to repair damaged tissue.

They found they could increase the number of hepatocyte cells – which detoxify the liver – by encouraging these cells to be produced instead of bile duct cells.

Understanding how liver cells are formed could help to develop drugs to encourage the production of hepatocytes to repair liver tissue. This could eventually ease the pressure on waiting lists for liver transplants.
Professor Stuart Forbes, Associate Director at the MRC Centre for Regenerative Medicine at the University of Edinburgh, who is a consultant hepatologist and was the academic leader of the study, said: "Liver disease is on the increase in the UK and is one of the top five killers. Increasing numbers of patients are in need of liver transplants, but the supply of donated organs is not keeping pace with the demand. If we can find ways to encourage the liver to heal itself then we could ease the pressure on waiting lists for liver transplants."
Liver disease is the fifth biggest killer in the UK. There are almost 500 people waiting for a liver transplant, compared to just over 300 five years ago.

The production of hepatocyte cells was increased by altering the expression of certain genes in early stage liver cells.

Dr Luke Boulter, of the University of Edinburgh's MRC Centre for Regenerative Medicine and first author on the paper, said: "This research helps us know how to increase numbers of cells that are needed for healthy liver function and could pave the way for finding drugs that help liver repair. Understanding the process in which cells in the liver are formed is key in looking at ways to repair damaged liver tissue."

Dr Rob Buckle, Head of Regenerative Medicine at the MRC, said: "Liver transplants have saved countless lives over the years, but demand will inevitably outstrip supply and in the long term we need to look beyond replacing damaged tissues to exploiting the regenerative potential of the human body. The MRC continues to invest heavily across the breadth of approaches that might deliver the promise of regenerative medicine, and this study opens up the possibility of applying our increasing knowledge of stem cell biology to stimulate the body's own dormant repair processes as a basis for future therapy."

###

The study was carried out in collaboration with the University's MRC Centre for Inflammation Research, the Beatson Institute for Cancer Research in Glasgow and the K.U. Leuven in Belgium.

Contact: Catriona Kelly
Catriona.Kelly@ed.ac.uk
44-131-651-4401
University of Edinburgh

Regenerative Medicine: Growing more than 20 types of tissues

From Standford

Regenerating organs from scratch

By Bruce Goldman
Tony Atala, MD, was the guest speaker yesterday at Stanford's 5th annual Oscar Salvatierra, Jr., M.D. lecture in transplantation. Atala, a pediatric urologist and the director of the Wake Forest Institute for Regenerative Medicine in Winston-Salem, NC, is a highly regarded tissue-engineering pioneer. He and his colleagues are now growing more than 20 types of tissues, with some notable successes in delivering them to patients with failing or defective organs.

In general, the approach involves creating a scaffold that can be seeded either with the patient's cells, if those of the appropriate type can be harvested, or with stem cells.

The scaffold itself can be the collagenous extracellular matrix of a donor organ whose cells have been removed with detergents, or it can be a wholly artificial construct - Atala's team has been able to create off-the-shelf organ scaffolds using a desktop inkjet printer. The printer is modified to spray not ink but a cell-filled gel, layer by layer, according to a computer program. The output is an intricate three-dimensional structure. When fetal cardiomyocytes - the cells that compose heart muscle - were seeded onto a heart-specific scaffold generated this way, the resulting entity started beating within four hours, Atala told his attentive audience.

As for which kinds of starter-material cells to use, Atala spoke in some detail about a promising class of stem cells isolated from amniotic fluid and placenta. These cells seem somewhat more mature than either embryonic stem (ES) cells or induced pluripotent stem (iPS) cells. Yet they multiply robustly and have, so far, been shown capable of differentiating into bone, cartilage, liver, lung, kidney, blood, pancreatic beta cells, intestine and cardiac and endothelial tissues. On the other hand, they do not form teratomas or tumors, a major drawback of both ES and iPS cells. Cherry on the sundae: They appear to suppress immune rejection.
Sounds like progress to me.

I've said it before. One reason I love my job so much is that it's the opposite of writing obituaries.

Regenerative medicine workshops to debut at TERMIS North America Annual Conference

WINSTON-SALEM, N.C. – Tuesday, Nov. 16, 2010 –

Tying in with this year's conference theme, "Where Discovery Meets Innovation," two new pre-conference workshops will debut at this year's TERMIS-North America 2010 Conference and Expo (December 5-8, 2010) in Orlando, Fla.

The TERMIS (Tissue Engineering & Regenerative Medicine International Society) North America meeting is hosted by the Wake Forest Institute for Regenerative Medicine, and chaired by Anthony Atala, M.D., institute director. James Yoo, M.D., Ph.D., an associate director and chief scientific officer at the institute, is the meeting's scientific program chair.
The workshops, which are co-sponsored by Forecast Technology Group Inc., will offer attendees an opportunity to learn at a more in-depth level about the latest advancements in bone tissue regeneration and biomaterials for cell therapy.

Bone Tissue Engineering and Regeneration, will be held from 7 a.m. to 5 p.m. on Sunday, Dec. 5, and will focus on how to accelerate the translation from discovery science to clinical applications, highlight solutions that have been investigated to date, and discuss specific, practical clinician-based approaches versus opting for off-the-shelf products. The scientific organizing committee includes: Jeremy Mao, D.D.S., Ph.D., professor of dental medicine, Columbia University, Regis O'Keefe, M.D., Ph.D., professor of orthopaedics, University of Rochester, and Fei Wang, Ph.D., program director, Musculoskeletal Tissue Engineering and Regenerative Medicine Program, the National Institute of Arthritis and Musculoskeletal and Skin.

Hyaluronan Biomaterials for Cell Therapy, will also debut on Sunday, Dec. 5 from 1 p.m. to 5 p.m. Co-sponsored by Glycosan BioSystems, and organized by Glenn Prestwich, Ph.D., presidential professor of medicinal chemistry at the University of Utah, this educational program will focus on the chemistry and engineering of novel HA-derived biomaterials, by highlighting the design criteria for clinically useful HA biomaterials, as well as preclinical and clinical applications of HA-derived biomaterials.

A post-conference workshop, TERMIS-NA NIH Grant Writing, will close the annual conference on Wednesday, Dec. 8. The workshop, scheduled for noon to 6 p.m, is designed to help investigators write successful National Institutes of Health (NIH) grant applications through better understanding of the NIH grant processes, especially in light of the new application and review format. Each component of the new NIH application format will be discussed in detail and tips on how to interpret summary statement and prepare resubmission will be provided. Faculty members include experienced, funded investigators with first-hand NIH review experience. NIH program directors and review officers will be on hand to discuss NIH funding opportunities and review procedures. Students, postdoctoral fellows, clinical fellows, and faculty members are encouraged to attend to gain information and knowledge which will aid them to write competitive NIH grant applications.

The goal of these programs is to offer additional educational opportunities for conference and non-conference participants. More than 35 experts will share case studies and knowledge. Registration for all workshops is separate from the main conference. Due to limited seating, advanced registration is encouraged. For more information, visit www.termis.org/na2010.
###

Media Contacts: Karen Richardson, krchrdsn@wfubmc.edu, 336-716-4453.

About TERMIS-NA 2010
The TERMIS (Tissue Engineering & Regenerative Medicine International Society) North America's general conference will cover a wide range of topics within the fields of tissue engineering, biomaterials, stem cells and regenerative medicine. The meeting is designed to foster interactions among basic scientists engaged in discovery and development, translational researchers who bring scientific discoveries to the clinical forefront, clinicians, and those engaged with funding, regulatory and commercial endeavors. The goal of the event is to present and exchange new results and advances in tissue engineering and regenerative medicine. Register now for the conference by visiting the conference website at http://termis.org/na2010 or contact Anita Caufield, Executive Producer, Forecast Technology Group Inc., anita@conferencestrategists.com.

About the Wake Forest Institute for Regenerative Medicine
The Wake Forest Institute for Regenerative Medicine (http://www.wfirm.org/) is an established center dedicated to the discovery, development and clinical translation of regenerative medicine technologies by leading faculty. The institute has used biomaterials alone, cell therapies, and engineered tissues and organs for the treatment of patients with injury or disease. The Institute is based at Wake Forest University Baptist Medical Center (www.wfubmc.edu), an academic health system comprised of North Carolina Baptist Hospital, Wake Forest University Health Sciences, which operates the university's School of Medicine, and Wake Forest University Physicians. The system is consistently ranked as one of "America's Best Hospitals" by U.S. News & World Report.

About Forecast Technology Group Inc, http://www.conferencestrategists.com/
Forecast Technology Group Inc. is the executive producer of TERMIS-NA's annual conference and the creator/producer of Innovation Discovery Labs (IDL), a custom-developed educational program designed especially for professional societies and the industries they serve. Forecast provides conference management and educational development services for a variety of professional associations, universities, and businesses.

*Liver Growing Body Parts *Regenerative medicine

In case You Missed It

.

Advances in regenerative medicine

.

July 2010

Advances in regenerative medicine means it's possible for damaged body parts to be regrown from human cells, and 60 Minutes featured the growing area of study.
The Wake Forest Institute for Regenerative Medicine is working on this with all kinds of organs and parts of the body and hopes to fight the fact people are dying while on the transplant wait list.

Dr. Anthony Atala of the Wake Forest Institute told CBS the goal is to "provide replacement tissues and organs that can be used to help [such patients] survive."
Atala says some body parts are easier to recreate than others, such as the ear, though the hope is eventually all body parts can be regenerated.
So far, human bladders have already been replicated based on cells and replaced into the body. Each replication takes approximately 6 to 8 weeks.

.

Nov 2010

.

Liver Regeneration:Opening The Door To New Treatments for Regenerating Liver and Bone Marrow

.

Also See :Skin cells transformed into blood

.

AASLD:Human Cells Grow on Animal Liver Scaffolds

.

Regenerating body parts lost by soldiers who have been injured in war is the topic of our story from McGowan Institute for Regenerative Medicine at the University of Pittsburgh. “Powder Regenerates New Muscle” covers the encouraging results of an experimental procedure using a biologic compound made from harvested pig bladder. Watch to see how the experimental powder, when placed near a wound, actually signals the human body to begin generating new cells and has already been effective for regenerating the human esophagus, in addition to muscle regeneration.

..

Salk scientists discovered how stem cells respond to nutrient availability

,

New method to create bioartificial organs

.

Stem Cells/Presented at AASLD

,

Liver Regeneration:Opening The Door To New Treatments for Regenerating Liver and Bone Marrow

Specialized Blood Vessels Jumpstart and Sustain Liver Regeneration
Released: 11/11/2010 5:50 PM EST
Source: NewYork-Presbyterian Hospital/Weill Cornell Medical Center/Weill Cornell Medical College


Weill Cornell Medical College Studies Lay Groundwork for New Treatments for Regenerating Liver and Bone Marrow


Newswise — 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 blood-producing 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 http://www.med.cornell.edu/ .

http://www.newswise.com/articles/specialized-blood-vessels-jumpstart-and-sustain-liver-regeneration?ret=/articles/list&category=latest&page=4&search[status]=3&search[sort]=date+desc&search[has_multimedia]=

Two New Paths to the Dream: Regeneration

Two New Paths to the Dream: Regeneration

By NICHOLAS WADE

Published: August 5, 2010

,

Two research reports published Friday offer novel approaches to the age-old dream of regenerating the body from its own cells. Animals like newts and zebra fish can regenerate limbs, fins, even part of the heart. If only people could do the same, amputees might grow new limbs and stricken hearts be coaxed to repair themselves.
But humans have very little regenerative capacity, probably because of an evolutionary trade-off: suppressing cell growth reduced the risk of cancer, enabling humans to live longer. A person can renew his liver to some extent, and regrow a fingertip while very young, but not much more

.

In the first of the two new approaches, a research group at Stanford University led by Helen M. Blau, Jason H. Pomerantz and Kostandin V. Pajcini has taken a possible first step toward unlocking the human ability to regenerate. By inactivating two genes that work to suppress tumors, they got mouse muscle cells to revert to a younger state, start dividing and help repair tissue.
What is true of mice is often true of humans, and although scientists are a long way from being able to cause limbs to regenerate, the research is attracting attention. Jeremy Brockes, a leading expert on regeneration at University College London, said the report was “an excellent paper.” Though there is a lot still to learn about the process, “it is hard to imagine that it will not be informative for regenerative medicine in the future,” he said.
In recent years, most research in the field of regenerative medicine has focused on the hope that stem cells, immature cells that give rise to any specific type of cell needed in the body, can somehow be trained to behave as normal adult cells do. Nature’s method of regeneration is quite different in that it starts with the adult cells at the site of a wound and converts the cells to a stemlike state in which they can grow and divide.
The Stanford team has taken a step toward mimicking the natural process. “What I like is that it’s built on what’s happening in nature,” Dr. Blau said. “We mammals lost this regenerative capacity in order to have better tumor suppression, but if we reawaken it in a careful way we could make use of it in a clinical setting.”Dr. Pomerantz, a clinician, hopes the technique can be applied to people, though many more animal experiments need to be done first. “We have shown we can recapitulate in mammalian cells behavior of lower vertebrate cells that is required for regeneration,” he said. “We would propose using it in amputations of a limb or part of a limb or in cardiac muscle.” After a heart attack, the muscle cells do not regenerate, so any method of making them do so would be a possible treatment.
Interfering with tumor suppressor genes is a dangerous game, but Dr. Pomerantz said the genes could be inhibited for just a short period by applying the right dose of drug. When the drug has dissipated, the antitumor function of the gene would be restored.Finding the right combination of genes to suppress was a critical step in the new research. One of the two tumor suppressor genes is an ancient gene, known as Rb, which is naturally inactivated in newts and fish when they start regenerating tissue. Mammals possess both the Rb gene and a backup, called the Arf gene, which will close down a cancer-prone cell if Rb fails to do so.The Stanford team found that newts did not have the Arf backup gene, which mammals must have acquired after their lineage diverged from that of amphibians.
This suggests that the backup system “evolved at the expense of regeneration,” the Stanford researchers say in Friday’s issue of Cell Stem Cell.
The Stanford team shut off both Rb and Arf with a chemical called silencing-RNA and found the mouse muscle cells started dividing. When injected into a mouse’s leg, the cells fused into the existing muscle fibers, just as they are meant to.The Stanford researchers have learned how to block two genes thought to inhibit the natural regenerative capacity of cells, but it is somewhat surprising that the regenerative mechanism should still exist at all if mammals have been unable to use it for 200 million years. “One school of thought is that regeneration is a default mechanism and doesn’t require its own program,” Dr. Pomerantz said.
Dr. Brockes believes that this is true in part. Regeneration “depends on a largely conserved cellular machinery,” he said, meaning that it is present in all animals. The machinery comes into play in wound healing and tissue maintenance. But specific instances of regeneration, like regrowing a whole limb, are invoked by genes specific to various species. He has found a protein specific to salamanders that coordinates regrowth of a salamander limb.If the regeneration of a whole limb is a special ability that salamanders have evolved, then humans would not have any inherent ability to do the same. “I would beware of suggesting that this sort of manipulation is capable of unlocking ‘the newt within,’ ” Dr. Brockes said.A second, quite different approach to regenerating a tissue is reported in Friday’s issue of Cell by Deepak Srivastava and colleagues at the University of California, San Francisco. Working also in the mouse, they have developed a way of reprogramming the ordinary tissue cells of the heart into heart muscle cells, the type that is irretrievably lost in a heart attack.
The Japanese scientist Shinya Yamanaka showed three years ago that skin cells could be converted to embryonic stem cells simply by adding four proteins known to regulate genes. Inspired by Dr. Yamanaka’s method, Dr. Srivastava and his colleagues selected 14 such proteins and eventually found that with only three of them they could convert heart fibroblast cells into heart muscle cells.
To make clinical use of the discovery, Dr. Srivastava said he would need first to duplicate the process with human cells, and then develop three drugs that could substitute for the three proteins used in the conversion process. The drugs could be loaded into a stent, a small tube used in coronary bypass operations. With the stent inserted into a heart artery, the drugs would convert some of the heart’s tissue cells into heart muscle cells.Some researchers hope that with Dr. Yamanaka’s method of turning skin cells into embryonic stem cells, those stem cells can be converted into usable heart muscle cells. One problem with this approach is that any unconverted embryonic stem cells may form tumors. Dr. Srivastava’s method sidesteps this problem by avoiding the stem cell stage.