Stem Cells Preserve Vision in an AMD-Like Model

Stem cell transplantation is a promising potential treatment for retinal degenerative diseases. Because retinal degeneration often leads to blindness, stem cells might be one of the up-and-coming tools in the battle against blindness.

The laboratory of Shaomei Wang (Cedars-Sinai Medical Center, Los Angeles) have assessed the effectiveness of stem cell-based therapeutic strategies using the Royal College of Surgeons (RCS) rat model, which mimics the disease progression of age-related macular degeneration (AMD). In RCS mice, the retinal pigment epithelium or RPE degenerates and is disrupted, which leads to the death of photoreceptors (Mullen RJ and LaVail MM Inherited retinal dystrophy: primary defect in pigment epithelium determined with experimental rat chimeras. Science 1976;192:799-801). The work by Wang and his colleagues has shown that human cortical-derived neural progenitor cells (hNPCctx) could dramatically rescue vision in the RCS rat (see Wang S, and others, Investigative ophthalmology & visual science 2008;49:3201-3206; Gamm DM, and others, Wang S, Lu B, et al. PLoS One 2007;2:e338). Unfortunately, the fetal origin of these cells presents an obstacle, because such cells are not readily available and come from aborted fetuses.

To overcome such obstacles, Wang and his colleagues assessed the ability of a stable neural progenitor cell line (iNPCs) derived from induced pluripotent stem cells (iPSCs) to preserve vision after sub-retinal injection into RCS rats (Sareen D, and others, J Comp Neurol 2014;522:2707-2728). A report in the journal Stem Cells by Wang and others establishes that iNPC injection leads to the reversal of AMD-related symptoms, the preservation of visual function, and may represent a patient-specific therapeutic option (Tsai Y, and others, Stem Cells 2015;33:2537-2549).

Wang and his others showed that an iNSC-treated eye scored higher in all functional tests used (optokinetic response (OKR), electroretinography (ERG), and luminance threshold responses (LTR)), compared to an untreated eye, in RCS mice at 150 days post-transplant. This improvement nicely correlates with the improved protection of photoreceptors in iNPC-treated eyes, which presented with normal cone morphology and the reversal of disease-associated changes throughout the retina.


So how do iNPCs help preserve the photoreceptors and visual function? Wang and his team found that iNPCs survived up to 130 days in RCS retinas, which when normalized to lifespan, represents around 16 years in humans. Additionally, they discovered that iNPCs were able to migrate to an area between the retinal pigment epithelial and photoreceptor layers. This allows the injection of cells into non-affected neighboring regions of the retina, which will not to worsen any compromised retinal components. iNPCs did, however, continue to express NSC/NPC markers and did not mature neural/retinal markers, suggesting that grafted-iNPCs remained phenotypically uncommitted progenitor cells and did not differentiate towards a retinal phenotype.

Further investigations found that iNPC-treatment reduced levels of toxic undigested bits of the photoreceptor cell membranes. Accumulation of these photoreceptor outer segments (POS) cause the photoreceptors to die off. Typically, the RPE cells goggle up these toxic membrane bits, degrade them, and recycle their components for the photoreceptors. The fact that these POS bits were not accumulating in the retinas of RCS mice suggested to Wang and his colleagues that the grafted-iNPCs restored POS degradation in RCS rats. They subsequently found that iNPCs expressed phagocytosis-related genes and could gobble up and degrade POS in culture. They extended these findings in living creatures by identifying the different stages of POS digestion and even viewed engulfed membranous discs inside the cytoplasm of iNPCs.

Overall, iNPC injection appears to be a safe and effective long-term treatment for Acute Macular Degeneration in the RCS rat preclinical model, and holds great promise for the translation into a patient-specific treatment for the preservation of existing retinal structure and vision during the early stages of AMD in humans. Wang noted that iNPC treatment in this model occurred at later stages of degeneration, which represents a more clinical relevant stage. However, an unstudied possibility is restoring phagocytosis by iNPCs to treat loss of visual acuity early on in the course of the disease.

Dallas Stem Cell Researchers Use Amniotic Tissue To Successfully Treat Non-Healing Surgical Wound

The founders of the Riordan-McKenna Institute, Neil Riordan, PhD and orthopedic surgeon, Wade McKenna, DO, have announced that the use of sterile, dehydrated amniotic tissue AlphaPATCH™, which was developed by Amniotic Therapies in Dallas, Texas, resulted in complete healing of an otherwise non-healing surgical knee wound.

The case involved a 78-year-old male who had a non-healing surgical wound from a total right knee replacement that had been performed six weeks earlier. The patient had not responded after 6 weeks of conservative wound care and the wound showed no signs of healing.

Dr. McKenna irrigated the wound in the operating room and then placed two AlphaPATCH dry amniotic membranes (4 cm x 4 cm) over the wound before dressing it.

At the two-week follow-up visit, a central scab had formed over the wound. At four-weeks, the wound had completely scabbed over, and by eight-weeks, the scab had just fallen off and the wound was healing well, covered by a patch of immature skin about the size of a penny. At the ten-week follow-up visit, the wound was completely healed.

The case report, entitled “Case Report Of Non-Healing Surgical Wound Treated With Dehydrated Amniotic Membrane” is published in the July issue of the Journal of Translational Medicine. This milestone in Dr. Riordan and Dr. McKenna’s ongoing study of the use of amniotic tissue products and stem cells to stimulate or augment wound healing is the third peer-reviewed journal article on regenerative medicine published by the Riordan McKenna Institute.

Dehydrated amniotic membrane products like AlphaPATCH is thought by most people to contain live stem cells, which is not the case. However, dehydrated amniotic membrane does contain several growth factors that promote healing and stimulate the body’s own stem cells to behave more similar to stem cells in a younger person.

“It’s gratifying to have this new tool in my toolbox. I treated conservatively and was getting nowhere. Even in a patient with a significant smoking history and decreased blood flow to his legs, we were able to achieve this result. Chronic wounds can be very frustrating for both the patient and the caregiver,” remarked Troy Chandler, PA-C, who participated in the patient’s treatment.

Stem Cell Treatments Decrease the Effects of Aging

There is a new study in the journal Stem Cells Translational Medicine has shown that stem cell injections helped rats live almost a third longer than normal. In addition, the stem cell-treated animals remained both physically and mentally active longer throughout their life spans.

Aging is characterized by the loss of regenerative capacity of cells and tissues. This leads to the shrinkage of body mass and increased susceptibility to stress. “When new cells are not able to replace the ones that die, tissue integrity and functions decline. Therefore, it has been suggested that exhaustion of stem cells may be a major cause of aging in humans and that the proliferative potential of stem cells is related to life span,” said Yun-Bae Kim, D.V.M., Ph.D., at Chungbuk National University’s College of Veterinary Medicine in Seoul, South Korea. Dr. Kim as the principal investigator in this study, in collaboration with Jeong Chan Ra, D.V.M., Ph.D., at the Biostar Stem Cell Research Center in Seoul.

Kim and his colleagues hypothesized that replenishing stem cells might have an anti-aging effect. The rationale behind these experiments came from studies conducted on mice suffering from a very rare genetic disease called progeria that causes premature aging. Laboratory animals with progeria were had their lived extended after receiving stem cell treatments. Other studies have shown that the treatment of laboratory mice with Alzheimer’s disease with stem cells causes improved cognitive function.

The Kim and Ra research teams decided to test whether stem cell treatments might have the same benefits for healthy animals.

They divided 10-month-old male rats into two groups and intravenously transplanted each group with either human amniotic-membrane-derived mesenchymal stem cells (AMMSCs) or adipose-tissue-derived mesenchymal stem cells (ADMSCs). These transplantations were carried out once a month for the remainder of the animals’ lives. The animals were compared to a control group of 7-month-old rats that received no cells.

At the end of the 20-month study, only 30 percent of the control group survived, compared to 70 percent and 100 percent of the animals in the AMMSC and ADMSC groups, respectively. “Collectively, the mean life span of the rats (604.6 days) was extended to 746.0 days (23.4 percent increase) and 793.8 days (31.3 percent increase) by treatment with AMMSCs and ADMSCs, respectively. The animals also remained both cognitively and physically active longer than normal, too,” Dr. Kim said.

“We think these improvements in cognitive and motor functions might be due to the increased ACh (acetylcholine concentration, a major neurotransmitter or message sender) levels in the brain and muscles originating not only from the transplanted stem cells, but also from restored neurons,” Dr. Ra added. “These results could be a starting point for more studies on ways to achieve similar results in humans, extending their health and lifespans using their own stem cells, too.”

“As this line of research progresses, it will be interesting to learn more about the mechanisms behind these results and whether they will apply to other species,” said Anthony Atala, M.D., Editor-in-Chief of STEM CELLS Translational Medicine and Director of the Wake Forest Institute for Regenerative Medicine.

Cellular Dynamics Announces Launch of World’s Largest Public Stem Cell Bank With 300 Available iPSC Lines

The Madison, Wisconsin-based biotechnology company, Cellular Dynamics, has announced the launch , of the world’s largest public stem cell bank and the availability of the first 300 iPSC lines.

Cellular Dynamics International, Inc. (CDI), a FUJIFILM company, has announced the launch of the world’s largest publicly available stem cell bank, the California Institute for Regenerative Medicine (CIRM) hPSC Repository.  Additionally, CDI has also announced the availability of the first 300 induced pluripotent stem cell (iPSC) lines in September, 2015.  These high quality, disease-specific iPSC resources are now accessible to academic and industry researchers to model diseases, target discovery and drug discovery.

In 2013, CDI was awarded $16 million by the CIRM to create induced pluripotent stem cell (iPSC) lines for each of 3,000 healthy and diseased volunteer donors across 11 common diseases and disorders to be made available through the CIRM hPSC Repository.

In September, the CIRM hPSC Repository will make the first 300 iPSC lines available to researchers.  These lines include cells from healthy donors and donors suffering from non-alcoholic steatohepatitis (NASH), dilated cardiomyopathy, diseases of the eye and autism.  The number of available cell lines is expected to increase to 750 by February 2016.

iPSC lines can be created from any individual, and thus provide a powerful tool for understanding disease as well as studying genetic variation between individuals. Patient samples are collected primarily from standard doctor’s office blood draws.

The iPSC lines are accompanied by detailed demographic and clinical data and each line was derived from tissue samples collected from living donors.

iPSCs have the potential to be differentiated into any cell type in the human body, and CDI already routinely manufactures 12 iPSC-derived cell types, including high-quality heart, neural, liver and endothelial cells, in high quantity, and at very high levels of purity.  Through CDI’s MyCell® Product portfolio, researchers can order iPSC line(s) of interest and have them differentiated into the cell type of choice.

Researchers can obtain undifferentiated iPSC lines through the Coriell Institute for Medical Research.

What are researchers saying about this advance:

Kaz Hirao, CDI Chairman and CEO, said, “iPSCs are proving to be powerful tools for disease modeling, drug discovery and the development of cell therapies, capturing human disease and individual genetic variability in ways that are not possible with other cellular models. We’ve seen a dramatic increase in the availability of iPSC lines. We’re pleased to be the vendor of choice for creating high quality iPSC lines and enabling scientists from academia and industry to better understand and help develop treatments for major diseases. The lines available from the CIRM stem cell bank directly complement CDI’s ability to provide differentiated cells corresponding to each of these iPSC lines, which will allow researchers to model the diseases represented, better understand disease progression, perform more targeted drug discovery, and ultimately lead to better treatments.”

Jonathan Thomas, Ph.D., J.D., CIRM Chairman, said, “We believe the bank will be an extraordinarily important resource in helping advance the use of stem cell tools for the study of diseases and finding new ways to treat them. While many stem cell efforts in the past have provided badly needed new tools for studying rare genetic diseases, this bank represents common diseases that afflict many Californians. Stem cell technology offers a critical new approach toward developing new treatments and cures for those diseases as well.”

Michael Christman, Ph.D., president and CEO of Coriell said, “Coriell Institute is a leader in managing large and complex biospecimen collections and distributing samples and data worldwide to promote research. We are very pleased to be part of this CIRM initiative and advance stem cell research for several devastating yet common diseases.”

Velcro Used to Grow Living Heart Tissue

Now it turns out that Velcro is not just for shoes and watch bands. A Velcro-inspired technology that binds strips of cells together could potentially be used to make living bandages for the heart.

“Tissue-Velcro,” which is the name given to this technology by its developers, is made by growing heart cells on meshes that contain tiny holes and hooks. Once these meshes are placed in contact with each other, they snag on to each other, which allows the tissue to be built up layer by layer. Over time, the polymer used to make this mesh breaks down. After having been grown in this special mesh for just four days, single-cell layers of rat heart muscle began to contract on their own. A stack of these layers of heart muscle tissue were able to grow together to contract with the same rhythm.

This technology opens up the possibility of making patches of heart muscle to repair the damage caused by heart attacks, or to sculpt scar tissue over wounds in a more seamless way.

“Each case that a surgeon would be presented with is going to be unique,” says team member Miles Montgomery at the University of Toronto, Canada. “You could build it in situ, almost like designer tissue.” The team plans to seek regulatory approval for use in human patients soon.

“I think this technology is very cool,” says Jay Zhang of the University of Minnesota, Minneapolis, although he adds that clinical applications are some way off. “The real test is how it works in vivo, to repair hearts, to repair vessels, to repair valves.”

The technique could potentially be used to grow other types of complex tissues as well, such as skin or liver. “If you can prove that you can do this with notoriously difficult tissue to grow, such as cardiac tissue, then it’s paving the way,” says Montgomery.

Newly Discovered Liver Cells Regenerate Liver Without Forming Tumors

The means by which the liver repairs itself is still a matter of debate. Now a new study from the University of San Diego has discovered a population of liver cells that do a better job at regenerating liver tissue than ordinary liver cells, or hepatocytes. This study has identified a cell population called “hybrid hepatocytes” that are able to regenerate liver tissue without giving rise to cancer.

This latest study was led by Michael Karin, PhD, Distinguished Professor of Pharmacology and Pathology at University of San Diego. Karin and his colleagues published their study in the August 13th edition of the journal Cell, and their paper is the first to identify these so-called “hybrid hepatocytes.” Karin and his coworkers also showed that hybrid hepatocytes are able to regenerate liver tissue without giving rise to cancer. Although the majority of the work described in this study was done in mouse models, Karin and his group also found similar cells in human livers.

Of all major organs, the liver has the highest capacity to regenerate. This is the main reason some liver diseases, including cirrhosis and hepatitis, can often be cured by transplanting a piece of liver from a healthy donor. The liver’s regenerative properties were previously credited to a population of adult stem cells known as oval cells. However, recent studies concluded that oval cells do not give rise to hepatocytes, since oval cells tend to make bile duct cells. These discoveries prompted researchers to begin looking for other cell populations in the liver that serve as the primary source of new hepatocytes in liver regeneration.

To find this new cell population, Karin and others traced the cells responsible for replenishing hepatocytes following chronic liver injury after laboratory animals were fed the liver toxin carbon tetrachloride. The liver regeneration that was stimulated by carbon tetrachloride-induced liver damage was traced to a unique population of hepatocytes in one specific area of the liver, called the “portal triad.” The portal triad is a region of the liver named after its triangular shape and its three major components: the hepatic artery, the hepatic portal vein, and the hepatic ducts, or bile ducts. The portal triad is also known by its clinical term, portal hepatis, transverse fissure and portal fissure. The portal triad serves as a blood-vessel gateway or entrance of the liver’s hepatic lobule. These special liver cells that reside in the portal triad hepatocytes undergo extensive proliferation and replenish liver mass after chronic liver injuries. Since these cells are similar to normal hepatocytes, but express low levels of bile duct cell-specific genes, Karin and his team dubbed these cells “hybrid hepatocytes.”

Portal Triad

Many other research labs around the world are attempting to use induced pluripotent stem cells (iPSCs) to repopulate diseased livers and prevent liver failure. “Although hybrid hepatocytes are not stem cells, thus far they seem to be the most effective in rescuing a diseased liver from complete failure,” said Joan Font-Burgada, PhD, postdoctoral researcher in Karin’s lab and first author of the study.

While iPSCs hold a lot of promise for regenerative medicine, it might be theoretically difficult to ensure that they stop proliferating once their therapeutic job is done. As a result, iPSC-derived cells might pose a significant risk for tumor formation.  To test the safety of hybrid hepatocytes, Karin’s team examined three different mouse models of liver cancer. They found no signs of hybrid hepatocytes in any of the tumors, leading the researchers to conclude that these cells do not contribute to liver cancer caused by obesity-induced hepatitis or chemical carcinogens.

“Hybrid hepatocytes represent not only the most effective way to repair a diseased liver, but also the safest way to prevent fatal liver failure by cell transplantation,” Karin said.