Reconstructing healthy liver cells using a nanomaterial-based matrix

Reconstructing healthy liver cells using a nanomaterial-based matrix
National University of Singapore

NUS pharmaceutical scientists, together with clinicians from the National University Health System (NUHS), have developed a nanomaterial-based hydrogel that encourages amniotic epithelial cells (a type of stem cell) to grow into mature liver cells.

The liver performs many essential functions related to digestion, metabolism, immunity and storage of nutrients within the body. It is the body's "chemical factory", producing many important proteins and nutrients. It also breaks down toxic substances into harmless chemicals in the body. Not surprisingly, the majority of substances (including drugs) that enter the body are processed through the liver. This is why, a pathological condition in this organ is so deleterious and leaves very few therapeutic options. Liver diseases such as acute liver failure and liver cancer are increasingly prevalent health issues with no clear therapeutic solutions. Apart from a liver transplant, there are limited therapeutic options for the patient. However, there is a shortage of healthy livers from donors.

Prof HO Han Kiat and Prof Giorgia PASTORIN, both from the Department of Pharmacy, NUS, have collaborated with Prof DAN Yock Young from NUHS to develop a hydrogel that can mimic the stiffness level and nanoscale surface roughness found in healthy human livers. When amniotic epithelial cells (AECs, a type of stem cell derived from the amniotic fluid in pregnant women) are grown onto this artificial matrix, they are stimulated to develop into mature liver cells. These liver cells can potentially be used in cell therapy and tissue engineering to help patients with liver conditions.

These findings are built on an earlier discovery by Prof Ho and his collaborators. They had found that, when mesenchymal stem cells (another type of stem cell) are grown on a carbon nanotube-plated surface, they catalysed the transformation of stem cells into muscle cells even in the absence of additional growth factors (substances that stimulate growth in living cells). Using this strategy, the team adapted the original carbon nanotubes’ surface by incorporating them into a polyacrylamide gel. The idea is to recreate a softer matrix that better mimics that of a healthy liver to influence the transformation of the AECs into liver cells.

Prof Ho said, “This effort yielded very encouraging results. We found that the AECs acquired significant liver cell characteristics with the corresponding loss of stem cell markers. These cells demonstrated liver-specific functions in terms of expressing albumin and drug metabolising capabilities. The goal now is to expand the characterisation of the liver function of these cells and to scale up production so that this can potentially be a sustainable resource for clinical applications.”

Figure shows amniotic stem cells taking on significant liver cell characteristics after growing on carbon nanotube surface.

hAECs: Human amniotic epithelial cells.

HLCs: Hepatocyte-like cells (cells which are similar to those found in liver tissue).

References
Zhao CY; Lin JS; Choolani M; Dan YY; Pastorin G*; Ho HK*, "Enhanced hepatic differentiation of human amniotic epithelial cells on polyethylene glycol-linked multiwalled carbon nanotube-coated hydrogels" JOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE Volume: 12 Issue: 7 Pages: 1556-1566 DOI: 10.1002/term.2672 Published: 2018.

Zhao CY; Andersen H; Ozyilmaz B; Ramaprabhu S; Pastorin G*; Ho HK*, "Spontaneous and specific myogenic differentiation of human mesenchymal stem cells on polyethylene glycol-linked multi-walled carbon nanotube films for skeletal muscle engineering" NANOSCALE Volume: 7 Issue: 43 Pages: 18239-18249 DOI: 10.1039/c5nr04303d Published: 2015.

20 Sep 2018

http://www.science.nus.edu.sg/research-highlights/2446-reconstructing-healthy-liver-cells-using-a-nanomaterial-based-matrix

FDA seeks permanent injunctions against two stem cell clinics

Knoepfler lab stem cell blog: The Niche

In historic step, FDA & DOJ seek injunctions on 2 key unproven stem cell clinic firms

May 9, 2018 The DOJ and FDA are seeking permanent injunctions in federal court against two of the most widespread and influential of the for-profit, unproven stem cell clinic firms in the U.S. This story is breaking so I’ll have more later this week. 

In The Media

NY Times

F.D.A. Moves to Stop Rogue Clinics From Using Unapproved Stem Cell Therapies

The Food and Drug Administration said on Wednesday that it was seeking court orders to stop two clinics from using unapproved stem cell treatments that in some cases have seriously harmed patients.

FDA press release

FDA seeks permanent injunctions against two stem cell clinics
Actions part of a comprehensive approach to the oversight of regenerative medicine products

The U.S. Food and Drug Administration, in two complaints filed today in federal court, is seeking permanent injunctions to stop two stem cell clinics from marketing stem cell products without FDA approval and for significant deviations from current good manufacturing practice requirements.

“Cell-based regenerative medicine holds significant medical opportunity, but we’ve also seen some bad actors leverage the scientific promise of this field to peddle unapproved treatments that put patients’ health at risk. In some instances, patients have suffered serious and permanent harm after receiving these unapproved products. In the two cases filed today, the clinics and their leadership have continued to disregard the law and more importantly, patient safety. We cannot allow unproven products that exploit the hope of patients and their loved ones,” said FDA Commissioner Scott Gottlieb, M.D. “We support sound, scientific research and regulation of cell-based regenerative medicine, and the FDA has advanced a comprehensive policy framework to promote the approval of regenerative medicine products. But at the same time, the FDA will continue to take enforcement actions against clinics that abuse the trust of patients and endanger their health with inadequate manufacturing conditions or by purporting to have treatments that are being manufactured and used in ways that make them drugs under the existing law but have not been proven safe or effective for any use.”

A permanent injunction is being sought against US Stem Cell Clinic LLC of Sunrise, Florida, its Chief Scientific Officer Kristin Comella and its co-owner and managing officer Theodore Gradel for marketing to patients stem cell products without FDA approval and while violating current good manufacturing practice requirements, including some that could impact the sterility of their products, putting patients at risk. The FDA is taking this action because US Stem Cell Clinic did not address the violations outlined in a warning letter to the clinic and failed to come into compliance with the law. The FDA is seeking an order of permanent injunction requiring US Stem Cell and the individual defendants to cease marketing their stem cell products until, among other things, they obtain necessary FDA approvals and correct their violations of current good manufacturing practice requirements.

The FDA is also seeking a permanent injunction to stop California Stem Cell Treatment Center Inc., with locations in Rancho Mirage and Beverly Hills, California; Cell Surgical Network Corporation of Rancho Mirage, California; and Elliot B. Lander, M.D. and Mark Berman, M.D., from marketing to patients stem cell products without FDA approval. Berman and Lander control the operations of approximately 100 for-profit affiliate clinics, including the California Stem Cell Treatment Center. The FDA is seeking an order of permanent injunction requiring California Stem Cell Treatment Center Inc. and Cell Surgical Network Corporation and the individual defendants to cease marketing their stem cell products until, among other things, they obtain necessary FDA approvals and correct their violations of current good manufacturing practice requirements.

US Stem Cell Clinic 
The FDA issued a warning letter to US Stem Cell Clinic in August 2017 for marketing stem cell products without FDA approval and for significant deviations from current good manufacturing practice requirements, including some that could impact the sterility of their products. The warning letter also cited an FDA inspection of the clinic which found that it was processing adipose tissue (body fat) into stromal vascular fraction (a cellular product derived from body fat) and administering the product both intravenously or directly into the spinal cord of patients to treat a variety of serious diseases or conditions, including Parkinson’s disease, amyotrophic lateral sclerosis (ALS), chronic obstructive pulmonary disease (COPD), heart disease and pulmonary fibrosis. The FDA has not approved any biological products manufactured by US Stem Cell Clinic for any use.

During the inspection of US Stem Cell Clinic in April and May 2017, FDA investigators also documented evidence of significant deviations from current good manufacturing practices in the manufacture of at least 256 lots of stem cell products by the clinic. For example, the clinic was cited for its failure to establish and follow appropriate written procedures designed to prevent microbiological contamination of products purporting to be sterile, which puts patients at risk for infections.

The complaint for permanent injunction against US Stem Cell Clinic was filed by the U.S. Department of Justice on behalf of the FDA in the U.S. District Court for the Southern District of Florida.

California Stem Cell Treatment Center, Inc. and Cell Surgical Network Corporation 
In August 2017, the FDA took action to prevent the use of a potentially dangerous and unproven treatment belonging to StemImmune Inc. in San Diego, California and administered to patients at the California Stem Cell Treatment Centers in Rancho Mirage and Beverly Hills. On behalf of the FDA, the U.S. Marshals Service seized five vials of Vaccinia Virus Vaccine (Live) – a vaccine that is reserved only for people at high risk for smallpox, such as some members of the U.S. military. The seizure came after FDA inspections at StemImmune and the California Stem Cell Treatment Centers confirmed that the vaccine was used to create an unapproved stem cell product (a combination of excess amounts of vaccine and stromal vascular fraction – a cellular product derived from body fat). The product was then administered to cancer patients with potentially compromised immune systems and for whom the vaccine posed a potential for harm, including the possibility of inflammation and swelling of the heart and surrounding tissues. The unproven and potentially dangerous treatment was being injected intravenously and directly into patients’ tumors.

California Stem Cell Treatment Center products are also being used for the experimental treatment of patients who suffer from a variety of serious diseases or conditions, including cancer, arthritis, stroke, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), macular degeneration, Parkinson’s disease, chronic obstructive pulmonary disease (COPD) and diabetes. The FDA has not approved any biological products manufactured by California Stem Cell Treatment Center for any use.

During inspections of California Stem Cell Treatment Center’s Beverly Hills and Rancho Mirage facilities in July 2017, FDA investigators documented, among other violations, evidence of significant deviations from current good manufacturing practice requirements. For example, the clinics were cited for failing to establish and follow appropriate written procedures designed to prevent microbiological contamination of products purporting to be sterile, which puts patients at risk for infections.

The complaint for permanent injunction was filed by the U.S. Department of Justice on behalf of the FDA in the U.S. District Court for the Central District of California.

Regenerative medicine regulatory framework
These cases support the FDA’s comprehensive policy framework for the development and oversight of regenerative medicine products, including novel cellular therapies. The FDA issued four guidance documents in November 2017, two final and two draft, that build upon the FDA’s existing risk-based regulatory approach. Under this framework the FDA detailed its efficient, science-based process for helping to ensure the safety and effectiveness of these therapies, while supporting development in this area. One of the two draft guidance documents laid out a novel and efficient clinical development model by which promising cell-based products could pursue review and approval by the FDA. The suite of guidance documents also describes a risk-based framework for how the FDA intends to focus its enforcement actions against those products that raise reported safety concerns or potential significant safety concerns.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm607257.htm

Telomerase-expressing liver cells regenerate the organ

Telomerase-expressing liver cells regenerate the organ 

Stanford School of Medicine News

A subset of liver cells with high levels of telomerase renews the organ during normal cell turnover and after injury, according to Stanford researchers. The cells may also give rise to liver cancer.

April 05, 2018 

Liver stem cells that express high levels of telomerase, a protein often associated with resistance to aging, act in mice to regenerate the organ during normal cellular turnover or tissue damage, according to a study by researchers at the Stanford University School of Medicine.

The cells are distributed throughout the liver’s lobes, enabling it to quickly repair itself regardless of the location of the damage.

Understanding the liver’s remarkable capacity for repair and regeneration is a key step in understanding what happens when the organ ceases to function properly, such as in cases of cirrhosis or liver cancer.

“The liver is a very important source of human disease,” said professor of medicine Steven Artandi, MD, PhD. “It’s critical to understand the cellular mechanism by which the liver renews itself. We’ve found that these rare, proliferating cells are spread throughout the organ, and that they are necessary to enable the liver to replace damaged cells. We believe that it is also likely that these cells could give rise to liver cancers when their regulation goes awry.”

Artandi is the senior author of the study, which was published online April 4 in Nature. Postdoctoral scholar Shengda Lin, PhD, is the lead author of the article.

A unique organ 
The liver’s cells, called hepatocytes, work to filter and remove toxins from the blood. The liver is unique among organs in its ability to fully regenerate from as little as 25% of its original mass. Chronic alcoholism or hepatitis infection can cause cycles of damage and renewal that lead to irreversible scarring that impairs the organ’s function. But relatively little is known about how the organ regenerates, or which cells might be responsible for cancers.

“About 900,000 people die every year worldwide from cirrhosis,” Dr. Artandi said, “and liver cancer is the fifth-leading cause of cancer death in the United States. But our understanding of how the liver renews itself has languished in comparison to advances made in other organs.”

However, stem cells and some cancer cells make enough telomerase to keep their telomeres from shortening, effectively stopping the aging clock and allowing a seemingly unlimited number of cell divisions. Mutations that block telomerase activity cause cirrhosis in mice and humans. Conversely, mutations that kick telomerase into high gear are frequently found in liver cancers.

Telomerase is a protein complex that “tops off” the ends of chromosomes after DNA replication. Without its activity, protective chromosomal caps called telomeres would gradually shorten with each cell division. Most adult cells have little to no telomerase activity, and the progressive shortening of their telomeres serves as a kind of molecular clock that limits the cells’—and, some believe, an organism’s—life span.

Drs. Lin and Artandi wondered whether they could use telomerase expression as a marker to identify the subset of cells responsible for regenerating the liver during normal turnover. These cells, they believe, could also serve as the cell of origin for liver cancer.

Making new cells
Dr. Lin found that, in mice, about 3%-5% of all liver cells express unusually high levels of telomerase. The cells, which also expressed lower levels of genes involved in normal cellular metabolism, were evenly distributed throughout the liver’s lobules. During regular cell turnover or after the liver was damaged, these cells proliferate in place to make clumps of new liver cells.

“These rare cells can be activated to divide and form clones throughout the liver,” said Dr. Artandi, who holds the Jerome and Daisy Low Gilbert Professorship in Biochemistry. “As mature hepatocytes die off, these clones replace the liver mass. But they are working in place; they are not being recruited away to other places in the liver. This may explain how the liver can quickly repair damage regardless of where it occurs in the organ.”

The fact that these stem cells express fewer metabolic genes might be one way to protect the cells from the daily grind faced by their peers, and to limit the production of metabolic byproducts that can damage DNA.

“This may be one way to shelter these important cells and allow them to pass on a more pristine genome to their daughter cells,” Dr. Artandi said. “They are not doing all the ‘worker bee’ functions of normal hepatocytes.”

When Dr. Lin engineered the telomerase-expressing hepatocytes to die in response to a chemical signal and gave the mice with a liver-damaging chemical, he found that those animals in which the telomerase cells had been killed exhibited much more severe liver scarring than those in which the cells were functional.

“You could imagine developing drugs that protect these telomerase-expressing cells, or ways to use cell therapy approaches to renew livers,” said Dr. Artandi. “On the cancer side, I think that these cells are very strong candidates for cell of origin. We are finally beginning to understand how this organ works.”

Other Stanford authors are postdoctoral scholars Chandresh Gajera, PhD, Elisabete Nascimento, PhD, Lu Chen, PhD, and Patrick Neuhoefer, PhD; graduate student Alina Garbuzov; and assistant professor of ophthalmology Sui Wang, PhD.

The research was supported by the National Institutes of Health (grants CA197563 and AG056575), the Emerson Foundation and the California Tobacco-Related Disease Research Program.

Artandi is a member of Stanford Bio-X, the Stanford Cancer Institute and the Stanford Child Research Institute.

Stanford’s Department of Medicine also supported the work.

From infection-dodging stem cells, new tactics for research on viral disease

From infection-dodging stem cells, new tactics for research on viral disease
March 29, 2018
For a stem cell, the future is wide open. It can divide infinitely to create more stem cells, or it can grow up into other kinds of cells, taking its place in the heart, brain, or other organs. But the stem cell loses something during that maturation: its remarkable ability to fight off viruses.

It’s important that stem cells be protected from infection: some of them are starting material for babies, and others make up a crucial reservoir to build or rebuild body tissues as needed. An intruder that damaged or killed stem cells would be disastrous, but how they go about protecting themselves has been a decades-long mystery. In a recent study in Cell, Rockefeller scientists offer up an explanation: stem cells are on constant high alert, bristling with preemptive defenses—means of protection that other cells use only when a virus actually attacks.
“That just makes sense,” says senior author Charlie M. Rice, the Maurice R. And Corinne P. Greenberg Professor in Virology at The Rockefeller University. “Because stem cells are pretty important, the body would want to be especially protective of them.” While certain mature cell types might be considered almost dispensable—when destroyed, they can be made again with the body’s stem cells—the stem cells themselves are not.

Defenses ready
Most of the body’s cells have already settled on their identity, whether they’re a brain cell, a heart cell, or any other “differentiated” cell type. Stem cells are different; they haven’t taken on a final form. They can divide to make more stem cells, or differentiate as needed.

And for the past 40 years, scientists have been puzzled by another funny thing about stem cells: they’re unusually resistant to viral attack. Recent experiments by Rice’s group and others focused on plagues including dengue, HIV, and Zika: stem cells rebuff them all.

Xianfang Wu, a postdoctoral researcher in Rice’s lab, was working with stem cells to make liver cells and study hepatitis infections when he serendipitously found a clue: stem cells and liver cells use different viral defenses.

Most cells in the body stick to a relatively low-alert status until they detect a virus, at which point they pump out a molecule called interferon. Interferon prompts the cells making it, and those in the vicinity, to turn on hundreds of genes that fight the infection. For example, the genes can prompt a cell to call on immune cells for protection, or make it commit suicide.

But the stem cells, Wu observed, persistently turned on many of the antiviral genes that other cells activate in response to interferon, even if there was no interferon around. They were on high alert, all the time.

Wu then confirmed this finding in multiple stem cell types, including stem cells from embryos, stem cells artificially created by researchers, and stem cells that normally inhabit the pancreas, brain, or bone marrow. As these stem cells settled into final, differentiated cell types, they switched off the antiviral genes. Wu observed this phenomenon in human cells, but he also checked data from mouse and chimpanzee, where he saw the same patterns.

To confirm that these antiviral genes really were protecting the stem cells, Wu focused on one set of antiviral genes, called IFITM. They encode proteins that prevent viruses from entering a cell and are often turned on in the stem cells. When Wu deleted IFITM genes from stem cells, they became susceptible to dengue, flu, West Nile, and Zika viruses.

Ignoring interferon
This means that cells have two modes of defense, depending on whether they’re stem cells or not. Regular, differentiated cells wait for a virus to come, and interferon to signal, before they maximize their defenses. Stem cells ignore interferon and keep their antiviral systems on all the time.

The latter seems like a good strategy—so why don’t differentiated cells keep their defenses on constantly, too? Rice thinks it would be a bad idea for cells to display all their defenses at once. That would give viruses in the vicinity the opportunity to sample cellular defenses, possibly leading to the selection of a rare, genetically different virus that could overcome those defenses and cause disease. It’s better for regular, replaceable cells to respond only as needed, Rice suggests.

“By understanding more about this biology in stem cells, we may learn more about antiviral mechanisms in general,” says Rice.

Such knowledge, he adds, could someday lead to medical applications. For example, it might help researchers design better drugs to activate the antiviral response in people with infections. It might also inspire treatments to help the body’s immune system fight cancer, or to attack cancer stem cells with viral therapies.

https://www.rockefeller.edu/news/22268-infection-dodging-stem-cells-new-tactics-research-viral-disease/

From: The Stem Cellar

The Official Blog of CIRM, California's Stem Cell Agency

Secrets to the viral-fighting ability of stem cells uncovered

(Todd Dubnicoff)
I’ve been writing about stem cells for many years and thought I knew most of the basic info about these amazing cells. But up until this week, I had no idea that stem cells are known to fight off viral infections much better than other cells. It does makes sense though. Stem cells give rise to and help maintain all the organs and tissues of the body. So, it would be bad news if, let’s say, a muscle stem cell multiplied to repair damaged tissue while carrying a dangerous virus.

How exactly stem cells fend off attacking viruses is a question that has eluded researchers for decades. But this week, results published in Cell by Rockefeller University scientists may provide an answer.

The researchers found that liver cells and stem cells defend themselves against viruses differently. In the presence of a virus, liver cells and most other cells react by releasing large amounts of interferon, a protein that acts as a distress signal to other cells in the vicinity. That signal activates hundreds of genes responsible for attracting protective immune cells to the site of infection.

Stem cells, however, are always in this state of emergency. Even in the absence of interferon, the antiviral genes were activated in stem cells. And when the stem cells were genetically engineering to lack some of the antiviral genes, the cells no longer could stop viral infection.

Source: Stem Cell Roundup: Crafty Cancer, Fighting Viruses, and Brainstorm ALS Trial Expands to Canada
March 30, 2018 / Karen Ring

Cancer stem cells, allies of the tumor and enemies of the patient

Cancer stem cells, allies of the tumor and enemies of the patient
University of Extremadura

The scientists of the UEx Molecular Biology of Cancer Research Group have a very clear objective. They want to uncover the physiological mechanisms of the cancer stem cell, the arch-enemy of the patient because it is responsible for the progression of the tumour. With that in mind, they are working on identifying new cell proteins which control cellular differentiation. Cancer stem cells possess the capacity to adopt highly undifferentiated states, characteristic of pluripotent cells, which very possibly contribute to the progression and maintenance of the different cells that form the tumour, in the same way that a healthy stem cell can give rise to different cell phenotypes. "These cancer stem cells are more resistant to the attack of chemotherapeutic agents, they are capable of regenerating the tumour and helping the tumour cells to spread to other organs", explains Pedro Fernández Salguero, lead researcher on the project.

The deregulation of cellular differentiation plays a very important role from an oncological point of view because it fosters the development of more undifferentiated and aggressive tumours, whose prognosis is worse. "Therefore, we want to identify which proteins within the cells are involved in retaining the undifferentiated characteristics of the tumour, which would allow it to be attacked more successfully, or, on the contrary, those leading to differentiated characteristics which reduce tumour development", adds Fernández Salguero.

The dioxin receptor, implicated in hepatocellular carcinoma and melanoma

One specific protein might contribute to keeping the tumour in a more highly undifferentiated state that could affect its metastatic capacity and its response to therapy. In fact, this group of researchers has already observed how a certain cell protein, the dioxin receptor (Ahr), participates in this process of cellular differentiation. "We have studied lines of cancer stem cells derived from patients and analysed tumour markers of potential clinical interest in animal models. The results obtained from both models have been validated in biopsies from patients with hepatocellular carcinoma and melanoma at the Infanta Cristina Hospital, in Badajoz (Spain). In this validation, the investigators found different values for this protein within the tumour and in the non-cancerous tissue from the same patients, and in turn, that the protein changes its expression in advanced stages, compared with stages prior to the development of the tumour (hepatic cirrhosis or hepatitis, in the case of hepatocellular carcinoma).

Thus, the results point to a therapeutic value for this protein (Ahr) because controlling it might repress the pluripotency of the cancer stem cell and reduce the malignity of the tumour. Indeed, different naturally-occurring molecules have been identified that modulate the activity of this protein in specific ways. In addition, the dioxin receptor might also facilitate the development of tools for the prognosis and evolution of the types of cancer in the study, hepatocellular carcinoma and melanoma.

Liver cancer
Hepatocellular carcinoma is a primary liver cancer, which is distinct from hepatic metastases originated by other tumours, highly aggressive and generally with poor prognosis. Further, its incidence is rising because this tumour usually appears as a consequence of an alcoholic liver cirrhosis or an infection by hepatitis B or C. At the moment, those suffering from liver cancer have few therapeutic opportunities, one of the few alternatives being a liver transplant. Tools for molecular prognosis and therapeutic targets are very scarce and the current survival rate for patients with advanced hepatocellular carcinoma is below 10%. As a consequence, it is necessary to identify new molecules and therapeutic options which complement the use of surgical resection and the transplant.
https://www.eurekalert.org/pub_releases/2018-03/uoe-csc030518.php

Haemopoietic stem cell therapy in cirrhosis: the end of the story?

In Case You Missed It

Lancet Gastroenterology & Hepatology
Volume 3, No. 1, p3–5, January 2018
DOI: http://dx.doi.org/10.1016/S2468-1253(17)30359-X

Comment
Haemopoietic stem cell therapy in cirrhosis: the end of the story?
Nicolas Lanthier

Chronic liver diseases can lead to cirrhosis, characterised by fibrous septa dissecting the liver parenchyma, affecting both liver function (due to reduced functional mass) and normal intrahepatic venous pressure (due to increased stiffness). Some specific treatments for the underlying causes of the disease exist, such as antiviral treatment for hepatitis B or C virus infection, alcohol abstinence for alcohol-related liver disease, or weight loss strategies for metabolic non-alcoholic fatty liver disease, whereas other causes remain difficult to treat (like genetic disorders or autoimmune problems). Despite existing strategies, some patients still progress towards end-stage liver disease and its associated complications, including ascites, peritonitis, variceal bleeding, or hepatocellular carcinoma. No treatment is available to specifically target fibrosis and cirrhosis, and liver transplantation remains the only curative option. To avoid progression towards end-stage liver disease ultimately requiring a rescue transplantation—which is not devoid of disadvantages (donor organ shortage, challenging surgery, and lifelong immunosuppression)—many researchers are investigating strategies to restore liver functionality.

Cell therapy is an emerging approach being tested in this setting. Hepatocytes are the principal cells of the liver parenchyma and are responsible for maintaining liver function. They can originate from three sources.1 In a normal liver, hepatocytes themselves can proliferate to restore the functional liver mass, a mechanism that could be compromised in cirrhosis. Second, the liver contains liver progenitor cells that can also proliferate and differentiate into hepatocytes. However, in some circumstances, this differentiation does not occur.2 Finally, blood-derived stem cells can infiltrate the liver and become hepatocytes, although the participation of this process in liver regeneration is poorly understood.3

In a randomised controlled trial,4 Philip Newsome and colleagues investigated whether granulocyte colony-stimulating factor (G-CSF) with or without haemopoietic stem cell transplantation could improve liver function and reduce complications related to liver cirrhosis. Indeed, it has been proposed that bone-marrow-derived stem cells can engraft the diseased liver and differentiate toward hepatocytes, while G-CSF can stimulate bone marrow cell recruitment and liver progenitor cell proliferation.5, 6 This study is of interest because of its rigorous design and evaluation, and it adds to the evidence from numerous case reports and small studies that have suggested a beneficial effect from both strategies on liver function and patient survival. Unfortunately, in this trial, neither G-CSF alone nor combined with three autologous stem-cell infusions (harvested from the peripheral blood) into patients' peripheral veins improved liver function as assessed by MELD score, which was calculated by a routine blood test, after 3 months. Complications of cirrhosis were even more common in the combined therapy group. Finally, liver stiffness evaluation by transient elastography did not show any effect of the treatment.4

Notably, these results are in line with those from a previous randomised controlled trial7—the only trial on this subject to be regarded as a high-quality study8—which also found that G-CSF and bone-marrow-derived cells injected into the hepatic artery had no effect in the context of severe decompensated alcoholic cirrhosis. The new data provided by Newsome and colleagues' study show that even in liver disease with relatively low levels of inflammation, the treatment stimulus is not sufficient to promote liver regeneration and subsequent recovery of liver function.

These results highlight the importance of not drawing premature and possibly hazardous conclusions before solid preclinical evidence becomes available and subsequent well conducted clinical trials are done. Future research into potential treatments for cirrhosis should also include a refined assessment of treatment response. First, cell tracking experiments in human beings are needed to establish whether cells infused by the peripheral route or directly injected into the hepatic circulation in the context of portal hypertension really do engraft the liver or not. Studies of the biodistribution of labelled cells in humans could answer this question.9 Second, more specific biomarkers or at least more precise liver imaging to assess fibrosis are probably needed. Patient survival, MELD score, and liver elasticity changes do not seem to be sufficient to detect any therapeutic effect of cell transplantation, if there is one. However, concomitantly, or before such experiments are done, progress is needed in basic research to discover the determining factors explaining why some patients with cirrhosis will have decompensation despite adequate control of the causes of the disease. In this context, predictive baseline patient factors need to be identified, which could originate from several sources. These factors could be from the liver itself (eg, hypoxia, low-grade inflammation, and microscopic thrombotic events), and assessment of the liver tissue before and after treatment to characterise regenerative pathways or side-effects should provide important data.10 Indeed, it could simply be the case that if the diseased liver itself is not able to develop its own efficacious repopulation mechanisms, external strategies will also fail. Alternatively, factors originating from outside the liver, such as from the gut (eg, altered barrier function and microbiome dysregulation), the muscles (characterised by sarcopenia), or the inflamed adipose tissue in obesity, could also play an important part. Future trials to address these questions in an era of emerging liver disease epidemics will be of great interest. Ideally, future trials should target one cause of cirrhosis at a time, given that the mechanisms could be different depending on the cause of the liver disease. For example, chronic active hepatitis C, which characterised some patients in Newsome and colleagues' trial, might not remain a problem because of existing efficacious viral eradication approaches, making cirrhosis due to non-alcoholic fatty liver disease the primary cause of end-stage liver disease.

In conclusion, the robust data provided by Newsome and colleagues do not support G-CSF with or without haemopoietic stem-cell infusion having any effect on liver function in patients with cirrhosis. With liver regeneration and anti-fibrotic strategies remaining fascinating subjects of research, further efforts will be needed to shed light on the complexity and interconnectedness of regeneration and cirrhosis before novel effective clinical strategies can be developed to overcome the problem of a failing liver.

http://www.thelancet.com/action/showFullTextImages?pii=S2468-1253%2817%2930359-X

Voisin/Phanie/Science Photo Library

References

1. Lanthier, N, Rubbia-Brandt, L, and Spahr, L. Liver progenitor cells and therapeutic potential of stem cells in human chronic liver diseases. Acta Gastroenterol Belg. 2013; 76: 3–9
   • View in Article 
   • | PubMed
2. Dubuquoy, L, Louvet, A, Lassailly, G et al. Progenitor cell expansion and impaired hepatocyte regeneration in explanted livers from alcoholic hepatitis. Gut. 2015; 64: 1949–1960
   • View in Article 
   • | Crossref
   • | PubMed
   • | Scopus (40)
3. Alison, MR, Poulsom, R, Jeffery, R et al. Hepatocytes from non-hepatic adult stem cells. Nature. 2000; 406: 257
   • View in Article 
   • | Crossref
   • | PubMed
   • | Scopus (884)
4. Newsome, PN, Fox, R, King, AL et al. Granulocyte colony-stimulating factor and autologous CD133-positive stem-cell therapy in liver cirrhosis (REALISTIC): an open-label, randomised, controlled phase 2 trial. (published online Nov 7.)Lancet Gastroenterol Hepatol. 2017;
   http://dx.doi.org/10.1016/S2468-1253(17)30326-6
   • View in Article 
   • | Summary
   • | Full Text
   • | Full Text PDF
5. Forbes, SJ and Newsome, PN. New horizons for stem cell therapy in liver disease. J Hepatol. 2012; 56: 496–499
   • View in Article 
   • | Summary
   • | Full Text
   • | Full Text PDF
   • | PubMed
   • | Scopus (49)
6. Spahr, L, Lambert, JF, Rubbia-Brandt, L et al. Granulocyte-colony stimulating factor induces proliferation of hepatic progenitors in alcoholic steatohepatitis: a randomized trial. Hepatology. 2008; 48: 221–229
   • View in Article 
   • | Crossref
   • | PubMed
   • | Scopus (85)
7. Spahr, L, Chalandon, Y, Terraz, S et al. Autologous bone marrow mononuclear cell transplantation in patients with decompensated alcoholic liver disease: a randomized controlled trial. PLoS One. 2013; 8: e53719
   • View in Article 
   • | Crossref
   • | PubMed
   • | Scopus (43)
8. Moore, JK, Stutchfield, BM, and Forbes, SJ. Systematic review: the effects of autologous stem cell therapy for patients with liver disease. Aliment Pharmacol Ther. 2014; 39: 673–685
   • View in Article 
   • | Crossref
   • | PubMed
   • | Scopus (26)
9. Sokal, EM, Lombard, CA, Roelants, V et al. Biodistribution of liver-derived mesenchymal stem cells after peripheral injection in a hemophilia a patient. Transplantation. 2017; 101: 1845–1851
   • View in Article 
   • | Crossref
   • | PubMed
   • | Scopus (0)
10. Lanthier, N, Lin-Marq, N, Rubbia-Brandt, L, Clement, S, Goossens, N, and Spahr, L. Autologous bone marrow-derived cell transplantation in decompensated alcoholic liver disease: what is the impact on liver histology and gene expression patterns?. Stem Cell Res Ther. 2017; 8: 88
    • View in Article 
    • | Crossref
    • | PubMed
    • | Scopus (1)

Lancet Commission: Stem cells and regenerative medicine

Published: 04 October 2017 The Lancet 7 Oct 2017  Vol 390

Lancet Commission: Stem cells and regenerative medicine
Prof Giulio Cossu, MD Correspondence information about the author Prof Giulio Cossu Email the author Prof Giulio Cossu , Prof Martin Birchall, MD, Tracey Brown, BA, Prof Paolo De Coppi, MD, Emily Culme-Seymour, PhD, Sahra Gibbon, PhD, Julian Hitchcock, MBBS, Prof Chris Mason, PhD, Prof Jonathan Montgomery, LLM, Prof Steve Morris, PhD, Prof Francesco Muntoni, MD, Prof David Napier, PhD, Nazanin Owji, Msc, Aarathi Prasad, PhD, Jeff Round, PhD, Prince Saprai, PhD, Jack Stilgoe, PhD, Adrian Thrasher, PhD, James Wilson, PhD

In this Commission, we argue that a combination of poor quality science, unclear funding models, unrealistic hopes, and unscrupulous private clinics threatens regenerative medicine's social licence to operate. If regenerative medicine is to shift from mostly small-scale bespoke experimental interventions into routine clinical practice, substantial rethinking of the social contract that supports such research and clinical practice in the public arena will be required.

For decades, stem cell therapy was predominantly limited to bone marrow transplantation for haematological diseases and epidermis transplantation for large burns. Tissue engineering and gene therapy faced huge challenges on their way to clinical translation—a situation that began to change only at the end of the 1990s. The past 10 years have seen an exponential growth in experimental therapies, broadly defined as regenerative medicine, entering the clinical arena. Results vary from unequivocal clinical efficacy for previously incurable and devastating diseases to (more frequently) a modest or null effect. The reasons for these widely different outcomes are starting to emerge....

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Media Coverage Of This Article - BMJ Opinion
The false promise of regenerative medicine
Richard Lehman
 “In this commission, we argue that a combination of poor quality science, unclear funding models, unrealistic hopes, and unscrupulous private clinics threatens regenerative medicine’s social licence to operate.” To put it more bluntly, many people are beginning to think it is all rubbish, while others bankrupt themselves pursuing false hope. This article does not pull its punches: “… the number of poorly regulated clinics has grown...
Continue reading....

FDA acts to remove unproven, potentially harmful treatment used in ‘stem cell’ centers

FDA News Release

August 28, 2017

FDA acts to remove unproven, potentially harmful treatment used in ‘stem cell’ centers targeting vulnerable patients

Vaccinia Virus Vaccine (Live) seized after being used inappropriately in vulnerable cancer patients

The U.S. Food and Drug Administration took decisive action to prevent the use of a potentially dangerous and unproven treatment belonging to StemImmune Inc. in San Diego, California, and administered to patients at the California Stem Cell Treatment Centers in Rancho Mirage and Beverly Hills, California. On behalf of the FDA, on Friday, Aug. 25, 2017 the U.S. Marshals Service seized five vials of Vaccinia Virus Vaccine (Live) – a vaccine that is reserved only for people at high risk for smallpox, such as some members of the military. Each of the vials originally contained 100 doses of the vaccine, and although one vial was partially used, four of the vials were intact.

As the vaccine is not commercially available, the FDA has serious concerns about how StemImmune obtained the product for use as part of an unapproved and potentially dangerous treatment. The FDA is actively investigating the circumstances by which StemImmune came to possess the vaccine.

“Speaking as a cancer survivor, I know all too well the fear and anxiety the diagnosis of cancer can have on a patient and their loved ones and how tempting it can be to believe the audacious but ultimately hollow claims made by these kinds of unscrupulous clinics or others selling so-called cures,” said FDA Commissioner Scott Gottlieb, M.D. “The FDA will not allow deceitful actors to take advantage of vulnerable patients by purporting to have treatments or cures for serious diseases without any proof that they actually work. I especially won’t allow cases such as this one to go unchallenged, where we have good medical reasons to believe these purported treatments can actually harm patients and make their conditions worse.”

The seizure comes after recent FDA inspections at StemImmune Inc. and the California Stem Cell Treatment Centers confirmed that the vaccine was used to create an unapproved stem cell product (a combination of excess amounts of vaccine and stromal vascular fraction – stem cells derived from body fat), which was then administered to cancer patients with potentially compromised immune systems and for whom the vaccine posed a potential for harm, including myocarditis and pericarditis (inflammation and swelling of the heart and surrounding tissues). The unproven and potentially dangerous treatment was being injected intravenously and directly into patients’ tumors.

Serious health problems, including those that are life-threatening, can also occur in unvaccinated people who are accidentally infected with the vaccinia virus by being in close contact with someone who has recently received the vaccine. In particular, unvaccinated people who are pregnant, or have problems with their heart or immune system, or have skin problems like eczema, dermatitis, psoriasis and have close contact with a vaccine recipient are at an increased risk for inflammation and swelling of the heart and surrounding tissues if they become infected with the vaccine virus, either by being vaccinated or by being in close contact with a person who was vaccinated.

“I’ve directed the agency to vigorously investigate these kinds of unscrupulous clinics using the full range of our tools, be it regulatory enforcement or criminal investigations. Our actions today should also be a warning to others who may be doing similar harm, we will take action to ensure Americans are not put at unnecessary risk,” Gottlieb added. “I also urge health care providers, patients and consumers to report these kinds of activities or any adverse events associated with these unproven treatments to the agency through MedWatch.”

Health care professionals and consumers should report any adverse events related to treatments received at California Stem Cell Treatment Center to the FDA’s MedWatch Adverse Event Reporting program. To file a report, use the MedWatch Online Voluntary Reporting Form. The completed form can be submitted online or via fax to 1-800-FDA-0178.

The U.S. Department of Justice filed the seizure complaint, on behalf of the FDA, in the U.S. District Court for the Central District of California.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm573427.htm

Unproven stem cell 'therapy' blinds three patients at Florida clinic

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Unproven stem cell 'therapy' blinds three patients at Florida clinic
After three patients were blinded following a treatment marketed as a stem cell clinical trial, Stanford ophthalmologist Jeffrey Goldberg calls for increased patient education and regulation.

Three people with macular degeneration were blinded after undergoing an unproven stem cell treatment that was touted as a clinical trial in 2015 at a clinic in Florida. Within a week following the treatment, the patients experienced a variety of complications, including vision loss, detached retinas and hemorrhage. They are now blind.

A paper documenting the cases was published March 16 in The New England Journal of Medicine.

The article is a “call to awareness for patients, physicians and regulatory agencies of the risks of this kind of minimally regulated, patient-funded research,” said Jeffrey Goldberg, MD, PhD, professor and chair of ophthalmology at the Stanford University School of Medicine and co-author of the paper.

The three patients — all women, ranging in age from 72 to 88 — suffered from macular degeneration, a common, progressive disease of the retina that leads to loss of vision. Before the surgery, the vision in their eyes ranged from 20/30 to 20/200. Now, the patients are likely to remain blind, said co-author Thomas Albini, MD, an associate professor of clinical ophthalmology at the University of Miami, where two of the patients were subsequently treated for complications from the stem cell treatments. “Although I can’t say it’s impossible, it’s extremely unlikely they would regain vision.”
Appealing to patients ‘desperate for care’

Two of the patients learned of the so-called clinical trial on ClinicalTrials.gov, a registry and results database run by the U.S. National Library of Medicine, where it was called “Study to assess the safety and effects of cells injected intravitreal in dry macular degeneration.” Some of the patients believed they were participating in a trial, although the consent form and other written materials given to the patients did not mention a trial, Albini said.

“There’s a lot of hope for stem cells, and these types of clinics appeal to patients desperate for care who hope that stem cells are going to be the answer, but in this case these women participated in a clinical enterprise that was off-the-charts dangerous,” Albini said.

Each patient paid $5,000 for the procedure. Any clinical trial that has a fee should raise a red flag, the authors said.

“I’m not aware of any legitimate research, at least in ophthalmology, that is patient-funded,” Albini said.

At the clinic, which is not named in the paper, the patients had fat cells removed from their abdomens and a standard blood draw. The fat tissue was processed with enzymes, with the goal of obtaining stem cells. Platelet-dense plasma was isolated from the blood. The cells were then mixed with the platelet-dense plasma and injected into their eyes. Patients reported that the entire process took less than an hour, Albini said. The patients had both eyes treated at once — another red flag, Albini and Goldberg said, because most doctors would opt for a conservative approach to observe how one eye responds to an experimental treatment before attempting the other eye.

Shoddy stem cell preparation may have led to some of the patients’ complications, which could have been caused by injection of a contaminant or the cell wash solution into the eye, Albini said. When injected into the eye, the stem cells also could have changed into myofibroblasts, a type of cell associated with scarring.
No evidence of vision restoration

But even if executed correctly, there is no evidence suggesting that the procedure could help restore vision, Goldberg and Albini said. In fact, there is sparse evidence that adipose-derived stem cells, the type of cells that the clinic claimed to use, are capable of differentiating, or maturing, into retinal pigment epithelium or photoreceptor cells, which play a critical role in macular degeneration and are the cells some researchers are targeting to develop therapies.

“There is a lot of very well-founded evidence for the positive potential of stem therapy for many human diseases, but there’s no excuse for not designing a trial properly and basing it on preclinical research,” Goldberg said.

The “trial” lacked nearly all of the components of a properly designed clinical trial, including a hypothesis based on laboratory experiments, assignment of a control group and treatment group, collection of data, masking of clinical and patient groups, and plans for follow-up, Goldberg and Albini said. “There was a whole list of egregious things,” Albini said.

Listings on ClinicalTrials.gov are not fully scrutinized for scientific soundness, Goldberg said. Although still visible on the website, the listing now states: “This study has been withdrawn prior to enrollment.” The clinic is also no longer performing these eye injections, although it is still seeing patients, Albini said.

The procedures were arguably not subject to Food and Drug Administration approval because the cells were not transferred between patients and were considered “minimally processed,” according to Title 21, Part 1271.10, of the Code of Federal Regulations. The FDA released more specific guidelines in October 2015, after these procedures were performed, establishing the requirement for FDA oversight and approval for these types of procedures.
‘It’s alarming’

“We expect health care providers to take every precaution to ensure patient safety, but this definitely shows that the lack of oversight can lead to bad players and bad outcomes. It’s alarming,” Albini said.

The authors acknowledged that it is difficult for patients to know whether a clinical trial, or a stem cell therapy, is legitimate. Goldberg recommended that patients considering a stem cell treatment consult a website, A Closer Look at Stem Cells, maintained by the International Society for Stem Cell Research. It is also advisable to check if a trial is affiliated with an academic medical center, Goldberg said.

The lead author is Ajay Kuriyan, MD, assistant professor of ophthalmology at the University of Rochester Medical Center. Researchers from the University of Miami, University of Rochester, University of Oklahoma and the Center for Sight also co-authored the study.

The report was funded by the National Institutes of Health (grant P30EY014801), Research to Prevent Blindness, the Department of Defense and the Klorfine Foundation.

Stanford’s Department of Ophthalmology also supported the work.

http://med.stanford.edu/news/all-news/2017/03/unproven-stem-cell-therapy-blinds-three-patients-at-florida.html