2012 Stem Cell News and Research

2013 Stem Cell News and Research

Archives
Archives- 2011
Stem Cell -  Recommended Sites 

Dec 2012
Tissue engineering: Growing new organs, and more
Frank panel on hidden dangers of stem cell treatments to patients at WSCS2012
Three-month-old Girl Receives Canada's First Liver Cell Transplant
Roche and the Innovative Medicines Initiative join forces to  promote use of Nobel Prize-winning stem cell
technology to enhance drug  development

Nov 2012
Study advances use of stem cells in personalized medicine

Our Stem Cell Future: What's Next? - Larry Goldstein UCSD 

Aug 2012

Study Uses Stem Cells to Boost Red Blood Cell Production

July 2012

Ruling frees FDA to crack down on stem cell clinics

Excerpt -  New Scientist

Peter Aldhous, San Francisco bureau chief

It's official: stem cells are drugs. At least, that's the opinion of the US district court in Washington DC, which has ruled that the
Food and Drug Administration (FDA) has the authority to regulate clinics  offering controversial stem cell therapies...
 
Treatments in which stem cells are harvested from bone marrow and injected straight back into the same patient are deemed part of  routine medical practice - not regulated by the US government. But if the cells are subjected to more than "minimal manipulation", the FDA maintains that the therapy becomes a "drug", which must be specifically approved for
use...
Full Article at New Scientist

Read more @ New Scientist , Scope, Nature and Knoepfler Lab Stem Cell
Blog.

Stem cell research aids understanding of of how cancer develops in the liver, pancreas and oesophagus

Stem Cell Lawsuit Against Korean Company

Read More On The Lawsuit At- Knoepfler Lab Stem Cell Blog, Health in the global village and Nature.

Stemming the commercial stem cell hype

Stem Cell Therapy Shown to be Effective in Treating Liver Cirrhosis

June 2012
Stem Cell Therapies Could Change Medicine-If They Get the Chance
Stem cell therapies have the potential to revolutionize the way we practice medicine. However, in the current climate several barriers and false assumptions stand in the way of achieving that goal.

Ten-year-old girl gets vein grown from her stem cells

Mature liver cells may be better than stem cells for liver cell transplantation therapy

May 2012
Canada OKs Osiris drug; first stem cell therapy
(Reuters) - Osiris Therapeutics Inc said on Thursday that Canadian health regulators have approved its treatment for acute
graft-versus host disease in children, making it the first stem cell drug to be approved for a systemic disease anywhere in the world.

April 2012
Bioengineered organs may hold the future for transplants

Teaching old cells new tricks
Much hyped by the media, stem cells have tremendous power to improve
human health. As part of the Cambridge Stem Cell Initiative, Dr Ludovic
Vallier’s research in the Anne McLaren Laboratory for Regenerative Medicine
shows how stem cells can further our understanding of disease and help deliver
much-needed new treatments.

How do you study a human disease that has no equivalent in animals and where the human
cells in question are so hard to grow outside the body they cannot be tested in the laboratory?
The  answer, until now, was with great difficulty. But by using a new stem cell
technique, that is set to change.

Dr. Ludovic Vallier, who holds an MRC Senior Fellowship in the Anne McLaren Laboratory for
Regenerative Medicine,  Department of Surgery at Cambridge in collaboration with Professor
David Lomas (Cambridge Institute for Medical Research and Department of Medicine), works on
a group of devastating genetic diseases affecting the liver.

“We target  metabolic diseases of the liver, diseases such as alpha 1 antitrypsin
deficiency. It’s one of the most common single genetic disorders and the protein
it affects – which is only produced by the liver – is really important because
it controls activity of elastase in the lung. Without this control, people
develop serious lung problems and the disease also affects the liver, so these
patients develop liver failure,” he explained.

The problem is that these diseases cannot be studied in vitro – in a dish – in the
laboratory, he said: “You can’t take cells from the liver of these very sick patients, and
 if you could they wouldn’t grow, which means you don’t have any way of screening drugs
that could help treat these diseases.”

Without effective drugs, the only current treatment is a liver transplant. “There is a huge shortage
of organs and  transplantation involves taking immunosuppressive drugs, which is heavy
treatment especially in already fragile patients,” Dr. Vallier said. “And the
disease is progressive so it’s very complicated to manage.” Understandably, Dr.
Vallier is excited that a new method of producing stem cells developed in Japan
has given him and other researchers a way of studying these diseases and
screening potential drugs to treat them.

“The new technology consists of taking cells from skin and reprogramming them so that they
become stem cells – cells that are capable of proliferating and differentiating into almost all
tissue types,” he said.

This reprogramming means a cell with a previously fixed identity can be taught a new
one – in this case taking skin cells and reprogramming them to become liver cells.
When the skin cells come from a patient with liver disease, these skin-turned-liver cells also have the
disease, making them ideal for studying the disease and screening potential drugs to
treat it.

According to Dr. Vallier: “Because we can generate liver cells
that mimic the disease of the original patient in vitro, that allows us to do
basic studies that were impossible by biopsy or primary culture and also to do
drug screening.” And because the skin cells can come from a whole range of
people, it gives researchers access to a broad diversity of patients as well as
overcoming some of the ethical concerns associated with embryonic stem
cells.

“That’s a very important step because it solves the problems associated with a limited
stock of stem cells,” he said, “and because it’s a simple method, it’s easily accessible to a
wide number of laboratories.”

Showing this can be done in a small number of liver patients in Cambridge is an important
proof of concept, and supports the possibility that a similar approach might be applicable to a
wide range of other serious diseases that still lack effective treatments, including
neurodegenerative diseases such as Parkinson’s and Alzheimer’s Disease as well
as heart diseases.

And Cambridge – which now has almost 30 groups doing
stem cell research and strong links between academic researchers and clinicians
– is perfectly positioned to make the most of this new technique.

“The Laboratory for Regenerative Medicine is starting to become an expert in this
disease modelling and we are all part of a larger consortium, the Cambridge Stem
Cell Initiative (SCI),” said Dr. Vallier. “Together, we are putting together
resources and scientific interest to really develop stem cells and their
clinical application. The SCI is a unique consortium because it brings together
a wealth of complementary expertise.”

While this first revolution involves in vitro disease modelling and drug screening,
Dr. Vallier hopes this work will ultimately lead to personalized cell-based therapies where liver
cells reprogrammed from a patient’s own skin cells could be used in place of a liver
transplant. “It will take time for us to assess this clinical use and show that
it is safe as well as effective,” he explained, “but if you ask me again in five
years I should be able to tell you whether we are going to do it.”

Provided by University of Cambridge
http://www.cam.ac.uk/research/features/teaching-old-cells-new-tricks/ 

Nitric oxide augments mesenchymal stem cell ability to repair liver  fibrosis
April 26
Liver  fibrosis is a major health problem worldwide and poses a serious obstacle for  cell based
therapies.  
Mesenchymal stem cells (MSCs) are multipotent and important  candidate cells 
forfuture clinical applications however success of MSC therapy  depends
upon their homing andsurvival in recipient organs............

Big IdeaTurning Lymph Nodes Into Liver-Growing Factories
If your liver fails, having 40 small but functional livers scattered around your body might be the next best
thing.

by Adam Piore
From the March 2012 issue; published online April 11, 2012
For people suffering from advanced liver disease, the prognosis is bleak. In many patients, such as those with cirrhosis, the liver becomes so clogged with scar tissue that healthy cells are choked off, preventing it from  fulfilling its role of filtering toxins. The only cure is a liver transplant. 

Yet with just 6,000 available organs for some 100,000 patients each year,  chances of winning the liver lottery are slim. And if you’re elderly or suffering from another disease, the chances 
are closer to zero......
Continue Reading At - Discover

China’s stem-cell rules go unheeded
Published in the journal Nature is a report on the unapproved stem-cell
treatments and clinics in China. The author David Cyranoski writes that the stem cell
trade in China is still quite prevalent despite stronger regulation by the
Chinese health ministry.

China’s stem-cell rules go unheeded
Health ministry’s attempt at regulation has had little effect.
 April 2012
David Cyranoski
 
Source Nature
Excerpt:  
Three months after the Chinese health ministry ramped
up its efforts to enforce a ban on the clinical use of unapproved stem-cell
treatments, a Nature investigation reveals that businesses around the
country are still charging patients thousands of dollars for these unproven
therapies.
The clinics operate openly, with websites promoting
the treatments for serious disorders such as Parkinson’s disease, diabetes and
autism, and attract thousands of medical tourists from overseas. They advertise
case studies of individual patients who they say have benefited from the
treatments, and some have clinics in major hospital complexes, giving them an
air of mainstream acceptance. Stem-cell experts contacted by Nature
insist that such therapies are not ready for the clinic and say that some
may even endanger patients’ health. But the Chinese government is struggling to
enforce its ban.
Continue reading at Nature

The Titanic & Dubious Adult Stem Cell Clinics
A final parallel between dubious adult stem cell therapies and the Titanic is that people can and in fact
have been killed in both cases. The risks are high for biologics treatments that are not fully vetted by the FDA
....Continue Reading

Improved stem cell line developed at CHOP
By Serena Gordon
THURSDAY, April 5 (HealthDay News) -- Developing stem cell lines that  don't  have cells that potentially grow into cancer has been one of the biggest challenges for stem cell therapies.
But researchers from the Children's Hospital of Philadelphia have generated a  new line of stem cells that may solve
that problem, at least for stem cells  destined for the digestive system or possibly the lungs.

"The most significant use short-term will be for disease modeling. We've had  to rely on mouse models, but we're different than
mice. A model with human cells  could be very powerful," said the study's senior author, Paul Gadue, an  assistant professor in the department of pathology and laboratory medicine at  the hospital's Center for Cellular and Molecular Therapeutics.
In the far future, he added, these stem cells could potentially be used as  therapies for diseases such as diabetes or liver disease.

For the current research, the scientists used embryonic stem cells and  induced pluripotent stem cells. Embryonic stem cells are derived from human  embryos, often unused embryos from fertility treatments that are donated for  research.
Induced pluripotent stem cells are genetically engineered from other  human cells, such as skin cells or blood cells. Both of these stem cell types  can give rise to cancer.

"One of the big issues that's critical when you think about potentially  transplanting embryonic stem cells or induced
pluripotent stem cells is that you  have to make sure there are no undifferentiated cells in that batch, because  undifferentiated cells can form  tumors called teratomas," said Gadue.

By stalling the development of these cells at what's called the endodermal  stage, the researchers found that the cells no longer created teratomas. The  endoderm is the innermost layer of cells found in an early embryo that  eventually develop into the lining of the digestive and respiratory tract.

These cells are then known as endodermal progenitor cells, and they have  nearly unlimited growth potential in the lab,
according to the authors.

But, delaying the cells at the endodermal stage does limit the type of cell  they can later become. Endodermal progenitor cells
can only become cells found  in the digestive tract, such as intestinal, liver or pancreatic cells, and  possibly lung cells, Gadue said.

It's as if the initial stem cells are college freshmen undecided about what  course of study they want to pursue. At this point, they can essentially choose  any career. For stem cells, that means some choose to become cancer.

However, Gadue and his colleagues found a way to guide the cells to the  school of study that might
be right for them, such as a school of engineering or  a school of art. And, for stem cells, that means the choice no longer includes  becoming a teratoma. But, that also means that the cells' pathways are more  limited, like an engineering
major who chooses a subspecialty of mechanical  engineering, but can no longer choose art.

Of course, while creating a stem cell line that doesn't produce teratomas is  important, it's also important that cells in that line
grow up (differentiate)  to become other cells. And Gadue's team was able to create pancreatic beta cells  that could produce some insulin. Beta cells are the cells that are damaged or  destroyed in people with diabetes.

The investigators found that in the lab, the newly created beta cells  produced insulin after being exposed to glucose (sugar), a function that is  absent or impaired in people with diabetes. However, the cells didn't achieve  full function, producing only about 20 percent of the expected insulin.

Juan Dominguez-Bendala, director of stem cell development for translation  research at the Diabetes Research Institute in Hollywood, Fla., said that the 20  percent function isn't much different than what's been seen in other studies,  and that
getting beta cells to mature fully in the lab is very difficult. He  added that beta cells will often complete maturation once they've been transplanted.

But overall, Dominguez-Bendala said, "this [research] presents two major  advantages over embryonic stem cells. First, by having this 'intermediate'  population, we are restricting the differentiation options of the stem cells.  For applications such as liver diseases or diabetes, these cells will readily  become [liver cells] or beta cells, without unwanted byproducts such as [nerve  or heart cells]." And second and more importantly, he said, they don't pose the  risk of forming tumors.

"If independently confirmed, this approach could certainly be of great  potential to design safer and more efficient differentiation protocols for the  treatment of diabetes and liver diseases, among other conditions,"  Dominguez-Bendala added.

Albert Hwa, scientific program manager of cure therapies at the Juvenile  Diabetes Research Foundation, called the new research "very interesting and  encouraging because they don't see teratomas." He also agreed that the  functionality of the
beta cell could be further optimized.

"This was a first try with this protocol. The function of these cells seems  very promising as well," said Hwa.

Hwa also said the findings need to be replicated, but that he could see such  stem cells being used for disease modeling.

However, Hwa added, a therapy for type 1 diabetes from this stem cell line is  less likely "until we can look at this process consistently in a large scale.  For the [U.S. Food and Drug Administration], you have to show data that you can  consistently produce the same product." Results of the study are published in the April 6 issue of the journal Cell/Stem Cell.

More  information
Learn more about stem cells from the U.S. National Institutes of Health.
Source

Feb 2012

UCLA Discovery that Migrating Cells "Turn Right' has Implications for Engineering Tissues, Organs 
Released: 2/15/2012 12:15 PM EST

Source: University of California, Los Angeles (UCLA), Health Sciences
Embargoed for Use Until 4 p.m. (EST), Feb. 17, 2012 Newswise —

What if we could engineer a liver or kidney from a patient's own stem cells?

How about helping regenerate tissue damaged by diseases such as osteoporosis and arthritis?

A new UCLA study bring scientists a little closer to these possibilities by providing a better understanding how tissue is formed and organized in the body. A UCLA research team discovered that migrating cells prefer to turn right when encountering changes in their environment.

The researchers were then able to translate what was happening in the cells to recreate this left–right asymmetry on a tissue level. Such asymmetry is important in creating differences between the right and left sides of structures like the brain and the hand. The research, a collaboration between the David Geffen School of Medicine at UCLA and the Center for Cell Control at UCLA's Henry Samueli School of Engineering and Applied Science, appears in the Feb. 17 issue of the journal Circulation Research.

"Our findings suggest a mechanism and design principle for the engineering of tissue," said senior author Dr. Linda L. Demer, a professor of medicine, physiology and bioengineering and executive vice chair of the department of medicine at the Geffen School of Medicine. "Tissue and organs are not simply collections of cells but require careful architecture and design to function normally.

Our findings help explain how cells can distinguish and develop highly specific left–right asymmetry, which is an important foundation in tissue and organ creation." Using microtechnology, the team engineered a culture surface in the lab with alternating strips of protein substrates that were cell-adhesive or cell-repellent, analogous to a floor with narrow horizontal stripes of alternating carpet and tile.

Cells may encounter such surface changes when they travel through the body. The researchers observed that as the migrating cells crossed the interface between "carpet" and "tile" sections, they exhibited a significant tendency to turn right by 20 degrees, and, like a marching band, lined up in long, parallel rows, producing diagonal stripes over the entire surface.

"We had been noticing how these vascular cells would spontaneously form structures in cultures and wanted to study the process," said first author Ting-Hsuan Chen, a graduate student researcher in the department of mechanical and aerospace engineering at UCLA Engineering. "We had no idea our substrates would trigger the left–right asymmetry that we observed in the cells. It was completely unexpected. "We found that cells demonstrated the ability to distinguish right from left and to self-organize in response to mechanical changes in the surfaces that they encounter.

This provides insight into how to communicate with cells in their language and how to begin to instruct them to produce tissue-like architecture." According to the researchers, the cells can sense the substrates beneath them, and this influences the direction of their migration and what shapes they form in the body.

Of most interest, the researchers said, was the fact that the cells responded to the horizontal stripes by reorganizing themselves into diagonal stripes.  The team hopes to harness this phenomenon to use substrate interfaces to communicate with cells and instruct them to produce desired tissue structures for replacement. By adjusting the substrates, the researchers say, they have the potential to guide what structures the cells and tissue form. The next stage of the research will be to control and guide cells to self-organize into two-dimensional and, eventually, three-dimensional patterns chosen by the researchers.

According to the research team, this is one of the first studies to demonstrate that encountering a change in substrate can trigger a cell's preference for turning left or right. It is also one of the first studies showing that cells can integrate left–right asymmetry into a patterned structure of parallel diagonal stripes resembling tissue architecture.

"Applications for this research may help in future engineering of organs from a patient's own stem cells," Demer said. "This would be especially important given the limited supply of donor organs for transplant and problems with immune rejection." The study was funded by the National Science Foundation and National Institutes of Health.

Additional authors included Jeffrey J. Hsu, Alan Garfinkel and Yin Tintut from the UCLA Department of Medicine; Yi Huang and Chih-Ming Ho from the UCLA Department of Mechanical and Aerospace Engineering; Xin Zhao, Chunyan Guo and Zongwei Li from the Institute of Robotics and Automatic Information System at China's Nankai University; and Margaret Wong from the UCLA Department of Bioengineering. For more news, visit the UCLA Newsroom and follow us on Twitter. Permalink to this article

Jan 2012

Stem cells may shed light on hepatitis, MIT researchers find
By Lori Valigra

Researchers at MIT and their colleagues said they have devised a way to produce liver-like cells from stem cells, a key step in studying why people respond differently to Hepatitis C.      
     
An infectious disease that can cause inflammation and organ failure, Hepatitis C has different effects on different people, but no one is sure why, the researchers said in a press release from MIT. Some people are very susceptible to the infection, while others are resistant.

The researchers said that by studying liver cells from different people in the lab, they may determine how genetic differences produce these varying responses. However, liver cells are hard to get and very difficult to grow in a lab dish because they tend to lose their normal structure and function when removed from the body.

The researchers, from MIT, Rockefeller University and the Medical College of Wisconsin, have come up with a way to produce liver-like cells from induced pluripotent stem cells (iPSCs), which are made from body tissues rather than embryos. Those liver-like cells can then be infected with Hepatitis C and help scientists study the varying responses to the infection.

The scientists claim this is the first time an infection has been made in cells derived from iPSCs. Their new technique is described in the Jan. 30 issue of the Proceedings of the National Academy of Sciences. The development, they said, may also eventually enable personalized medicine, in which doctors could test the effect of different drugs on tissues derived from the patient being treated and then customize therapy for that patient.

The new study is a collaboration between Sangeeta Bhatia, professor of health sciences and technology and electrical engineering and computer science at MIT; Charles Rice, professor of virology at Rockefeller; and Stephen Duncan, professor of human and molecular genetics at the Medical College of Wisconsin.

The iPSCs are derived from normal body cells, often skin cells. By turning on certain genes in those cells, the scientists can revert them to an immature state that is identical to embryonic stem cells, which can turn into any cell type. Once the cells become pluripotent, they can be directed to become liver-like cells by turning on genes that control liver development.

The researchers’ goal is to take cells from patients who have unusual reactions to hepatitis C infection, transform them into liver cells and study their genetics to see why people respond as they do. “Hepatitis C virus causes an unusually robust infection in some people, while others are very good at clearing it. It’s not yet known why those differences exist,” Bhatia said in a statement.

Stem Cell Therapy May Reverse Diabetes

Examining the dangers of stem cell tourism
The phenotypic fate and functional role for bone marrow-derived stem cells in liver fibrosis
Liver fibrosis is an outcome of chronic liver injury of any etiology. It is manifested by extensive deposition of extracellular matrix (ECM) proteins that produce a fibrous scar in the injured liver. Bone marrow (BM) cells may play an important role in pathogenesis and resolution of liver fibrosis. BM cells contribute to the inflammatory response by TGF-β1 secretion and activation of liver resident myofibroblasts. Moreover, BM itself can serve as a source of collagen expressing cells, e.g. BM-derived fibrocytes and mesenchymal progenitors, which in turn, have a potential to in situ differentiate into fibrogenic myofibroblasts and facilitate fibrosis. Finally, BM cells play an active part in resolution of liver fibrosis after cessation of fibrogenic stimuli. While natural killer (NK) cells are implicated in apoptosis of activated hepatic stellate cells/myofibroblasts, cells of myelo-monocitic lineage secrete matrix metalloproteinases to actively degrade the fibrous scar. The focus of this review is on the current understanding of the role of different subsets of BM cells in the onset, development and resolution of liver fibrosis...

New horizons for stem cell therapy in liver disease
Journal of Hepatology
Volume 56, Issue 2 , Pages 496-499, February 2012

Received 26 April 2011; received in revised form 20 June 2011; accepted 20 June 2011. published online 27 July 2011.

Summary 

There is an increasing range of potential applications of stem cells in liver diseases, with many clinical studies already undertaken. We identify four of the main areas which we propose stem cell therapy could be a realistic aim for in the future: (1) to improve regeneration and reduce scarring in liver cirrhosis by modulating the liver’s own regenerative processes, (2) to down-regulate immune mediated liver damage, (3) supplying hepatocyte-like cells (HLCs) derived from stem cells for use in extracorporeal bio-artificial liver machines, and (4) to use stem cell derived HLCs for cell transplantation to supplement or replace hepatocyte function.

Whilst there have been advances in our understanding of the role of stem cells in liver damage and repair as well as encouraging results using stem cells as cell therapy in pre-clinical animal models, the precise mode of action and optimal cell usage has not been completely defined. Moreover, clarity is required as to what effects are needed in different types and severity of liver disease (Fig. 1). Nonetheless, clinical trials of autologous cell therapy for liver disease have begun. Small scale cell therapy studies with autologous adult stem cells have demonstrated safety and suggested possible benefit [1]. This has driven the development of larger studies to more rigorously test these observations. It is clear that stem cells and their progeny have a variety of putative functional roles, requiring careful thought as to what biological action is intended after their infusion. For example, mesenchymal stem cells (MSCs) have immunomodulatory capacity and cells of the haematopoietic lineage may have anti-fibrotic and pro-regenerative effects, suggesting that the choice of therapeutic cell may need to be tailored to the type of liver disease targeted as the required therapeutic effect may be very different.

Requirements for different types of liver injury.
This figure illustrates the requirements that exist in differing types of liver injury.


Picture

Stem cells for the treatment of liver disease  The mismatch between the number of patients requiring transplantation for end stage liver disease and the number of available organs is set to grow, highlighting the need to develop new strategies to stimulate liver regeneration and reduce liver scarring. Recent work suggests that these two aims are inextricably linked, and that reducing hepatic fibrosis can result in activation of hepatic progenitor cells (HPCs) resulting in parenchymal regeneration [2].

Degradation of excess liver scar is thus a suitable target for cell therapy, and in this regard, Sakaida et al. have shown in a mouse model of liver fibrosis that autologous bone marrow cells (BMCs) injected via the tail vein can engraft the liver and are able to reduce liver scarring as well as stimulating this regenerative process [3]. In these studies, it was suggested that murine Liv8− non-haematopoietic cells were responsible for this effect [3], although the identity of these cells is not entirely clear. Furthermore, defining the exact nature of these cells in the human setting would be important to develop this approach as a human therapy. More compelling evidence for the action of human haematopoietic stem cells (HSCs) comes from their use in patients with liver cancer (mainly metastasis) and otherwise normal liver parenchyma [4]. Furst et al. included patients for whom [4] resection of the liver cancer was not possible at the outset as the residual liver volume would be insufficient for the patient to survive. Autologous bone marrow CD133+ cells were selectively infused into the non-occluded segments II and III portal branches 2–4h after portal vein branch embolisation (I, IV, V–VIII); to see if this would stimulate liver regeneration thus allowing earlier resection of the tumour. Liver volume increased much quicker in patients that received stem cells, such that cancer resection could be undertaken much sooner (27days±11 vs. 45days±21, p=0.6). It should be noted however that this was a small study and whilst there was a control arm it was not a randomised trial, and importantly none of the patients had intrinsic liver disease. Furthermore, as with many human studies, the mechanism of action was not explored.

Macrophages, cells of haematopoietic origin, are known to play a critical role in regulating liver fibrosis in murine models [5]. A single intraportal administration of macrophages has recently been shown to reduce fibrosis in a murine model of liver injury and increase regeneration [6]. Interestingly, the macrophages may have both direct and indirect effects upon the damaged liver as cell administration triggered the recruitment of endogenous inflammatory cells to hepatic scar areas and potentially amplified the donor cell effect [6]. This “cell amplification effect” does hold promise for clinical cell therapy where donor cell numbers may be limited. Epithelial progenitor cells have also been used successfully to reduce fibrosis in a rodent model of liver cirrhosis, however, it may be difficult clinically to isolate a source of endothelial progenitor cells for this purpose in humans [7].

There is some concern regarding the use of autologous unsorted BMCs as an injectable “therapy” for liver cirrhosis as the BMCs contain MSCs, cells that can differentiate into myofibroblasts, the scar forming cells of the liver [8] in certain settings. Of note, recent data showed that use of whole bone marrow as cell therapy in a rodent model of chronic liver injury leads to a worsening of liver fibrosis [6]. Uncontrolled clinical studies using infusions of unsorted autologous BM-derived mononuclear cells infusions for liver cirrhosis have been reported to show a reduction in Child’s Pugh score and liver scarring and increased hepatocyte proliferation [9]. This may reflect the absence of stromal cells in mononuclear cell preparations, but also highlights the possibility that there may be differences between human and murine responses to cell therapy. This will be challenging as use of novel cell populations or combinations in patients will generally be informed by rodent studies.

MSCs have been reported to contribute to the direct production of new hepatocytes as well as to stimulate proliferation of endogenous hepatocytes [10], [11], although this is not a universal finding [12]. Furthermore, the description of such “hepatocyte-like cells“ is often incomplete, and does not as yet represent their adoption of a majority of a hepatocyte’s complex phenotype by the MSC or their progeny [13]. To demonstrate that a MSC (or other stem cell) had differentiated into a hepatocyte would require the demonstration of hepatocytic functionality in vitro and in vivo for robust confirmation. It is therefore possible that much of the impact of injected MSCs in liver injury models may not relate to their adoption of a hepatocyte phenotype, but through other mechanisms. The immunomodulatory properties of MSCs have been demonstrated in a range of rodent models of non-hepatic [14] and hepatic [15] immune-mediated injury, as well as clinical studies in patients with GVHD who have hepatic damage where clinical benefit is reported [16]. Protocols for the isolation and characterisation of MSCs are evolving, and it is likely that there are different functional sub-sets which may mediate anti- and pro-inflammatory actions [17]. Despite this ambiguity regarding the function of MSCs in the literature there have been clinical studies reported suggesting that cell therapy with MSCs for liver cirrhosis can be beneficial but it is important to note that these studies are small and uncontrolled so whilst interesting should be interpreted with caution [18].

Of the clinical studies published, the overwhelming data suggests stem cell therapy is safe [1], although there are possible concerns regarding the route of delivery of cell therapy. Whilst no studies report superior outcomes when cells are directly injected into the liver (portal vein or hepatic artery), there have been complications such as hepatic artery dissection [19] and increased portal hypertensive bleeding [20] following this approach. Furthermore, the intravenous administration of autologous BM mononuclear cells resulted in hepatic homing of the injected cells suggesting this easier, safer route may be an adequate option for cell delivery [9], [21]. Assuming that delivery to the liver is important for stem cell infusions to exert their optimal effect, then developing a better understanding of the mechanisms regulating their hepatic ingress may allow for further improvements to treatment protocols.

Whilst patients with a wide range of disease severity have been included in clinical trials, the priority remains to irrefutably confirm the efficacy of cell/stem cell therapy. In this regard, choosing patients in which the benefit may be most reliably determined and of greatest value is important. Patients verging on the cusp of requiring a liver transplant (e.g. with MELD score approaching/just below 15) are good candidates as even a small percentage improvement in liver function may be sufficient to significantly delay or indeed remove altogether the need for liver transplant.

For patients with cirrhosis/advanced fibrosis, the data at present would support further studies with macrophages, HSCs and BM mononuclear cells, whereas the immunomodulatory/anti-inflammatory properties of MSCs require further confirmation in immune-mediated models of liver injury. Further data may allow for the tailoring of cell therapy towards specific types of liver injury (Fig. 2).

Fig. 2.  Tailoring cell therapy. This figure suggests possible tailored cell therapy options for the major types of liver disease.


Picture
Stem cells as a source of hepatocyte like cells  There have been many reports that various adult stem cells have the capacity to differentiate into hepatocyte like cells, although most of these studies incompletely characterise the stem cell derived hepatocytes “hepatocytic functions” or do not demonstrate in vivo functionality to the same extent as endogenous hepatocytes [13]. Whilst there are examples of “hepatocyte-like cells” produced from non-hepatic adult stem cells [22], it is our view, however, that this is unlikely to be a significant source of new hepatocytes that are of sufficient functionality to be clinically relevant. The liver’s own HPCs are a realistic potential source of hepatocytes, however thus far it has proven difficult to isolate and expand these cells from the human liver and then control their differentiation into hepatocytes of sufficient number and quality. Indeed, the liver’s own HPCs may be best targeted in situ via cell therapy, drugs or other such small molecule approaches.

Embryonic stem cells have the advantage of being able to proliferate in an unlimited fashion and produce large numbers of HLCs in both mouse and man settings [23]. In vitro, these cells have been shown to have reasonable functional capacity, although there is still caution about their use for transplantation due to their propensity to form both malignant and non-malignant tumours. Further work is required to reduce this risk, which may involve more definitive hepatocytic differentiation of HLCs, use of highly sorted populations to exclude contaminating cells and incorporation of clinically approved suicide genes (http://www.lentigen.com/products/lg690). In addition, there are ethical issues regarding the use of human embryonic stem cells, which will always have implications for their clinical use.

A recent development allows for the production of similar cells, induced pluripotent stem cells (iPSCs), by over-expressing transcription factors such as SOX2 and Oct4 in adult somatic cells. Keratinocytes isolated from skin biopsies have been used as a starting cell population to produce these iPSCs. This technology has great potential for disease modelling as the cells can be readily obtained from patients with metabolic diseases, and the derived cells are likely to exhibit metabolic defects, thus allowing the development of “liver disease in a dish” studies [24]. Hepatocytes derived from iPS cells have reasonable synthetic and metabolic capacity [25], and seem to be similar to cells derived from ES cells [26], [27]. However, the same concerns remain about their use in a transplant setting, as we cannot yet be certain that these cells would not undergo reversion to more primitive state with uncontrolled expansion within the recipient.

Conclusions  Cell therapy is an exciting but challenging frontier in Hepatology, offering the potential for a range of new therapeutic interventions. This reinforces the need to develop strategies to improve liver regeneration. In this regard, cells which modulate liver fibrosis, or which act directly on the liver’s own HPC population seem likely candidates as do small molecules and drugs. In addition, iPSCs are excellent candidates for the production of HLCs although there is caution about their in vivo use until long term data has shown that these cells can behave in an appropriate homoeostatic manner and not develop into tumours.

Conflict of interest  The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

Acknowledgments  S.J.F. is funded by the Sir Jules Thorn Trust, MRC and Scottish Enterprise. P.N.N. is funded by MRC, NIHR and BBSRC.

References 
  1. Houlihan DD, Newsome PN. Critical review of clinical trials of bone marrow stem cells in liver disease. Gastroenterology. 2008;135:438–450
  2. Kallis YN, Robson AJ, Fallowfield JA, Thomas HC, Alison MR, Wright NA, et al. Remodelling of extracellular matrix is a requirement for the hepatic progenitor cell response. Gut. 2011;60:525–533
  3. Sakaida I, Terai S, Yamamoto N, Aoyama K, Ishikawa T, Nishina H, et al. Transplantation of bone marrow cells reduces CCl4-induced liver fibrosis in mice. Hepatology. 2004;40:1304–1311
  4. Furst G, Schulte am Esch J, Poll LW, Hosch SB, Fritz LB, Klein M, et al. Portal vein embolization and autologous CD133+ bone marrow stem cells for liver regeneration: initial experience. Radiology. 2007;243:171–179
  5. Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M, Vuthoori S, et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest. 2005;115:56–65
  6. Thomas JA, Pope C, Wojtacha D, Robson AJ, Gordon-Walker TT, Hartland S, et al. Macrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration and function. Hepatology. 2011;53:2003–2015
  7. Nakamura T, Torimura T, Sakamoto M, Hashimoto O, Taniguchi E, Inoue K, et al. Significance and therapeutic potential of endothelial progenitor cell transplantation in a cirrhotic liver rat model. Gastroenterology. 2007;133:91–107
  8. Russo FP, Alison MR, Bigger BW, Amofah E, Florou A, Amin F, et al. The bone marrow functionally contributes to liver fibrosis. Gastroenterology. 2006;130:1807–1821
  9. Terai S, Ishikawa T, Omori K, Aoyama K, Marumoto Y, Urata Y, et al. Improved liver function in patients with liver cirrhosis after autologous bone marrow cell infusion therapy. Stem Cells. 2006;24:2292–2298
  10. Aurich H, Sgodda M, Kaltwasser P, Vetter M, Weise A, Liehr T, et al. Hepatocyte differentiation of mesenchymal stem cells from human adipose tissue in vitro promotes hepatic integration in vivo. Gut. 2009;58:570–581
  11. Kuo TK, Hung SP, Chuang CH, Chen CT, Shih YR, Fang SC, et al. Stem cell therapy for liver disease: parameters governing the success of using bone marrow mesenchymal stem cells. Gastroenterology. 2008;134:2111–2121
  12. Carvalho AB, Quintanilha LF, Dias JV, Paredes BD, Mannheimer EG, Carvalho FG, et al. Bone marrow multipotent mesenchymal stromal cells do not reduce fibrosis or improve function in a rat model of severe chronic liver injury. Stem Cells. 2008;26:1307–1314
  13. Sancho-Bru P, Najimi M, Caruso M, Pauwelyn K, Cantz T, Forbes S, et al. Stem and progenitor cells for liver repopulation: can we standardise the process from bench to bedside?. Gut. 2009;58:594–603
  14. Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell. 2008;2:141–150
  15. Wan CD, Cheng R, Wang HB, Liu T. Immunomodulatory effects of mesenchymal stem cells derived from adipose tissues in a rat orthotopic liver transplantation model. Hepatobiliary Pancreat Dis Int. 2008;7:29–33
  16. Kebriaei P, Isola L, Bahceci E, Holland K, Rowley S, McGuirk J, et al. Adult human mesenchymal stem cells added to corticosteroid therapy for the treatment of acute graft-versus-host disease. Biol Blood Marrow Transplant. 2009;15:804–811
  17. Waterman RS, Tomchuck SL, Henkle SL, Betancourt AM. A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an Immunosuppressive MSC2 phenotype. PLoS ONE. 2010;5:e10088
  18. Kharaziha P, Hellstrom PM, Noorinayer B, Farzaneh F, Aghajani K, Jafari F, et al. Improvement of liver function in liver cirrhosis patients after autologous mesenchymal stem cell injection: a phase I–II clinical trial. Eur J Gastroenterol Hepatol. 2009;21:1199–1205
  19. Couto BG, Goldenberg RC, da Fonseca LM, Thomas J, Gutfilen B, Resende CM, et al. Bone marrow mononuclear cell therapy for patients with cirrhosis: a Phase 1 study. Liver Int. 2011;31:391–400
  20. Salama H, Zekri AR, Bahnassy AA, Medhat E, Halim HA, Ahmed OS, et al. Autologous CD34+ and CD133+ stem cells transplantation in patients with end stage liver disease. World J Gastroenterol. 2010;16:5297–5305
  21. Lyra AC, Soares MB, da Silva LF, Braga EL, Oliveira SA, Fortes MF, et al. Infusion of autologous bone marrow mononuclear cells through hepatic artery results in a short-term improvement of liver function in patients with chronic liver disease: a pilot randomized controlled study. Eur J Gastroenterol Hepatol. 2010;22:33–42
  22. Newsome PN, Johannessen I, Boyle S, Dalakas E, McAulay KA, Samuel K, et al. Human cord blood-derived cells can differentiate into hepatocytes in the mouse liver with no evidence of cellular fusion. Gastroenterology. 2003;124:1891–1900
  23. Hay DC, Fletcher J, Payne C, Terrace JD, Gallagher RC, Snoeys J, et al. Highly efficient differentiation of hESCs to functional hepatic endoderm requires ActivinA and Wnt3a signaling. Proc Natl Acad Sci USA. 2008;105:12301–12306
  24. Rashid ST, Corbineau S, Hannan N, Marciniak SJ, Miranda E, Alexander G, et al. Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells. J Clin Invest. 2010;120:3127–3136
  25. Sullivan GJ, Hay DC, Park IH, Fletcher J, Hannoun Z, Payne CM, et al. Generation of functional human hepatic endoderm from human induced pluripotent stem cells. Hepatology. 2010;51:329–335
  26. Jozefczuk J, Prigione A, Chavez L, Adjaye J. Comparative analysis of human embryonic stem cell and induced pluripotent stem cell-derived hepatocyte-like cells reveals current drawbacks and possible strategies for improved differentiation. Stem Cells Dev. 2011;20:1259–1275
  27. Inamura M, Kawabata K, Takayama K, Tashiro K, Sakurai F, Katayama K, et al. Efficient generation of hepatoblasts from human ES cells and iPS cells by transient overexpression of homeobox gene HEX. Mol Ther. 2011;19:400–407
PII: S0168-8278(11)00565-4

doi:10.1016/j.jhep.2011.06.022

© 2011 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.