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April 2020

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How stem cells decide their identity — ScienceDaily

Several hundred different cell types of the adult human body are formed during embryonic development, starting from just a few identical stem cells. The differentiation potential of the cells is progressively restricted in the course of this process, causing changes in their morphology and functions. A research team headed by Prof. Dr. Sebastian Arnold and Jelena Tosic from the Faculty of Medicine at the University of Freiburg has now succeeded in deciphering basic molecular control mechanisms by which stem cells decide which embryonic cell types to turn into. This is achieved at least partially through selective usage of the genes for each different cell type, despite the presence of the identical genetic information in every cell in the body. The scientists have published their findings in the journal “Nature Cell Biology.”

The undifferentiated stem cells of the embryo develop either into cells of the nervous system, the so-called neuroectoderm, or into cells of the meso- and endoderm, from which, for example, many different cell types of the internal organs or the muscles develop. For over 25 years it has been known that this decision is regulated by embryonic signaling molecules, such as TGFβ and Wnt signals. So far, however, it has remained unclear exactly how these signals control this first decision of cell differentiation. The study, carried out in the context of Tosic’s doctoral thesis, shows that the embryonic TGFβ and Wnt signals are transmitted by gene-regulating transcription factors of the T-box factor family, namely Eomes and Brachyury. These factors are responsible for “turning on” the differentiation gene programs for all meso- and endoderm cells. At the same time, these T-box factors also act as gene repressors, preventing the formation of neural tissue by suppressing the corresponding gene programs. This involves changes in the structure but not the content of the genetic information in the cell nucleus.

“The results of the study represent a crucial step towards understanding the basic mechanisms of how cells develop their future identity during development,” says Arnold. They also allow further studies on how cell identity is permanently encoded in a cell.

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Materials provided by University of Freiburg. Note: Content may be edited for style and length.

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Clues for cancer immunotherapy — ScienceDaily

Research on immune cells “exhausted” by chronic viral infection provides clues on how to refine cancer immunotherapy. The results are scheduled for publication in Immunity.

Scientists at Emory Vaccine Center, led by Rafi Ahmed, PhD, have learned about exhausted CD8 T cells, based on studying mice with chronic viral infections. In the presence of persistent virus or cancer, CD8 T cells lose much of their ability to fight disease, and display inhibitory checkpoint proteins such as PD-1 on their surfaces. PD-1 is targeted by cancer immunotherapy drugs, such as pembrolizumab and nivolumab, which allow CD8 T cells to regain their ability to attack and kill infected cells and cancers.

Those drugs are now FDA-approved for several types of cancer, yet some types of tumors do not respond to them. Studying exhausted CD8 T cells can help us understand how to better draw the immune system into action against cancer or chronic infections.

In previous research, Ahmed’s lab found that exhausted cells are not all alike, and the diversity within the exhausted T cell pool could explain variability in responses to cancer immunotherapy drugs. Specifically, they observed that a population of “stem-like” cells proliferated in response to PD-1-blocking drugs, while a more differentiated population of exhausted cells stayed inactive. The stem-like cells are responsible for maintaining the exhausted T cell population, but cannot kill virus-infected or tumor cells on their own.

The current paper defines a transitional stage in between the stem-like and truly exhausted cells. The truly exhausted cells are marked by a molecule called CD101, and are unable to migrate to sites of infection and contain lower amounts of proteins needed to kill infected or tumor cells.

“The transitional cells are not completely exhausted,” says postdoctoral fellow Will Hudson, PhD, first author of the Immunity paper. “They are still capable of proliferating and performing their ‘killer cell’ functions. In our experiments, they contribute to viral control.”

The transitional cells, lacking CD101, could be a good marker for response to PD-1 blocking drugs, Hudson says. Enhancing the proliferation or survival of these cells, or preventing their transition to lasting exhaustion, may be a novel therapeutic strategy for cancer.

“It is extremely exciting to have contributed to this project and know that our findings have the potential to inform cancer immunotherapy,” says co-author Julia Gensheimer, an Emory graduate, now a MD/PhD student at UCLA.

The Immunity paper also includes systematic identification of other markers for CD8 T cells in various stages of exhaustion, which could be a guide to efforts to promote their activity.

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Materials provided by Emory Health Sciences. Original written by Quinn Eastman. Note: Content may be edited for style and length.

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Two materials used at once better fabricate trachea constructs — ScienceDaily

Wake Forest Institute for Regenerative Medicine (WFIRM) scientists are the first to report using bioprinting to print a tracheal tissue construct comprised of multiple different functional materials. They printed different designs of smooth muscle and cartilage regions in artificial tracheal substitutes showing similar mechanical properties to human tracheal tissue.

Previous attempts of tissue engineered tracheal constructs have presented many different limitations, mainly because they focused only on using regenerated cartilage tissue. The WFIRM tracheal constructs are novel in that they were bioprinted with separate cartilage and smooth muscle regions at the same time using a biodegradable polyester material and hydrogels containing human mesenchymal stem cells which can self renew and can become a variety of cell types. In this case, the stem cells differentiated into two different cell types — chondrocytes and smooth muscles cells — in different regions of the bioprinted tracheal constructs. The cartilage portion is stiff to provide mechanical support to avoid collapse while the smooth muscle is pliable and connects the ends of the cartilage rings, allowing sufficient flexibility for airway contraction.

“People have tried other materials, but the problem has been they were using just one material that is not strong enough to hold the airways open and does not provide the flexibility needed. Our bioprinting method provides a combination of flexibility and strength needed to mimic native tracheal tissue,” said Sean Murphy, PhD, lead author and assistant professor of regenerative medicine at WFIRM.

The trachea is a hollow tube that is made of cartilage and smooth muscle tissue designed to allow a flexible airway that resists collapse. Tracheal stenosis is the abnormal narrowing and stiffening of the trachea, which can be caused due to prolonged intubation, inflammation and trauma or it can be a congenital abnormality. The primary treatments for the condition, which is rare but life threatening, are surgical interventions that have challenges and limitations.

For this study, published online in the journal Biofabrication, the research approach combines three tailored technologies: patient specific medical imaging, hydrogels designed to drive differentiation of stem cells, and polymeric scaffolding mimicking specific biomechanical properties.

Murphy said the approach was to incorporate softer hydrogels containing stem cells into the pores of the bioprinted tracheal structures. “We already knew we could differentiate these cells in 2D into smooth muscle or cartilage, but the question of whether we could do that in bioprinted 3D constructs remained,” he said. “We added growth factors to help give them the extra push they needed.”

“This early proof-of-concept study shows that we can streamline bioprinting capabilities and could someday provide the opportunity for regenerative medicine treatments for the replacement of damaged or diseased tracheal regions,” said Anthony Atala, M.D., director of WFIRM and co-author of the paper. “Next steps in the research would be to evaluate long-term function to ensure appropriate tissue formation and strength retention.”

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Materials provided by Wake Forest Baptist Medical Center. Note: Content may be edited for style and length.

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New bone healing mechanism has potential therapeutic applications — ScienceDaily

Led by researchers at Baylor College of Medicine, a study published in the journal Cell Stem Cell reveals a new mechanism that contributes to adult bone maintenance and repair and opens the possibility of developing therapeutic strategies for improving bone healing.

“Adult bone repair relies on the activation of bone stem cells, which still remain poorly characterized,” said corresponding author Dr. Dongsu Park, assistant professor of molecular and human genetics and of pathology and immunology at Baylor. “Bone stem cells have been found both in the bone marrow inside the bone and also in the periosteum — the outer layer of tissue — that envelopes the bone. Previous studies have shown that these two populations of stem cells, although they share many characteristics, also have unique functions and specific regulatory mechanisms.”

Of the two, periosteal stem cells are the least understood. It is known that they comprise a heterogeneous population of cells that can contribute to bone thickness, shaping and fracture repair, but scientists had not been able to distinguish between different subtypes of bone stem cells to study how their different functions are regulated.

In the current study, Park and his colleagues developed a method to identify different subpopulations of periosteal stem cells, define their contribution to bone fracture repair in live mouse models and identify specific factors that regulate their migration and proliferation under physiological conditions.

Periosteal stem cells are major contributors to bone healing

The researchers discovered specific markers for periosteal stem cells in mouse models. The markers identified a distinct subset of stem cells that contributes to life-long adult bone regeneration.

“We also found that periosteal stem cells respond to mechanical injury by engaging in bone healing,” Park said. “They are important for healing bone fractures in the adult mice and, interestingly, their contribution to bone regeneration is higher than that of bone marrow stem cells.”

In addition, the researchers found that periosteal stem cells also respond to inflammatory molecules called chemokines, which are usually produced during bone injury. In particular, they responded to chemokine CCL5.

Periosteal stem cells have receptors — molecules on their cell surface — that bind to CCL5, which sends a signal to the cells to migrate toward the injured bone and repair it. Deleting the CCL5 gene in mouse models resulted in marked defects in bone repair or delayed healing. When the researchers supplied CCL5 to CCL5-deficient mice, bone healing was accelerated.

The findings suggested potential therapeutic applications. For instance, in individuals with diabetes or osteoporosis in which bone healing is slow and may lead to other complications resulting from limited mobility, accelerating bone healing may reduce hospital stay and improve prognosis.

“Our findings contribute to a better understanding of how adult bones heal. We think this is one of the first studies to show that bone stem cells are heterogeneous and that different subtypes have unique properties regulated by specific mechanisms,” Park said. “We have identified markers that enable us to tell bone stem cell subtypes apart and studied what each subtype contributes to bone health. Understanding how bone stem cell functions are regulated offers the possibility to develop novel therapeutic strategies to treat adult bone injuries.”

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Materials provided by Baylor College of Medicine. Note: Content may be edited for style and length.

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Immune outposts inside kidney tumors predict post-surgery outcomes — ScienceDaily

The immune system establishes “forward operating bases,” or lymph node-like structures, inside the tumors of some patients with kidney and other urologic cancers, researchers at Winship Cancer Institute of Emory University have discovered.

Patients with well-supported immune cells in their tumors are more likely to control their cancers’ growth for a longer time — findings that could guide treatment decisions after surgery for kidney cancer. In addition, ongoing work has found the observation is broadly applicable to many cancer types, and could help researchers expand the dramatic but sparse benefits of cancer immunotherapy to more people.

The results are scheduled for publication in Nature.

“We knew that if there are more T cells in a tumor, the patient is likely to respond better to cancer immunotherapy,” says lead author Haydn Kissick, PhD. “But we were looking at a more basic question: why do some tumors have lots of T cells in them, and others don’t?”

Kissick is assistant professor of urology and microbiology and immunology at Emory University School of Medicine, Emory Vaccine Center and Winship Cancer Institute. His lab collaborated with surgeons and oncologists at Winship to examine tumor samples removed from patients with kidney, prostate and bladder cancer.

CD8 T cells hunt down and eliminate intruders — in this case, cancer cells. In patients with high levels of CD8 T cells residing in their tumors, their immune systems appeared to be better trained to suppress cancer growth after surgery, when small numbers of cancer cells (micrometastases) may be lurking elsewhere in the body. The cancers of those who had lower levels of CD8 T cells tended to progress four times more quickly after surgery than those with higher levels.

The finding has important implications, says Viraj Master, MD, who performed many of the kidney cancer surgeries. In this situation, additional treatments are not performed unless or until kidney cancer reappears, says Master, who is professor of urology at Emory University School of Medicine and Winship’s Director of Integrative Oncology and Survivorship.

“Even after potentially curative surgery for aggressive kidney cancers, a significant fraction of patients will experience cancer recurrence,” he says. “But with this information, we could predict more confidently that some people won’t need anything else, thus avoiding overtreatment. However, on the basis of these findings, for others who are at higher risk of recurrence, we could potentially scan at more regular intervals, and ideally, design adjuvant therapy trials.”

The findings also provide insights for scientists interested in how the immune system successfully controls some cancers, but with others, the T cells become increasingly exhausted and ineffective.

“This study may lead to new insights into why immunotherapy can be so effective in some cancer types, but rarely works in others such as prostate cancer, and may highlight a path forward for developing more effective immunotherapy treatments,” says Howard Soule, PhD, executive vice president and chief science officer for the Prostate Cancer Foundation, which supported the Winship team’s work.

Kissick and his colleagues were surprised to find “stem-like” T cells, or precursors of exhausted cells, inside tumor samples. Stem-like T cells are the ones that proliferate in response to cancer immunotherapy drugs, which can revive the immune system’s ability to fight the cancer.

“Lymph nodes are like ‘home base’ for the stem-like T cells,” says Carey Jansen, an MD/PhD student who is the first author of the Nature paper. “We had expected that the stem-like cells would stay in lymphoid tissue and deploy other T cells to infiltrate and fight the cancer. But instead, the immune system seems to set up an outpost, or a forward base, inside the tumor itself.”

The researchers found that other immune cells called “antigen-presenting cells” or APCs, which are usually found within lymph nodes, can also be seen within tumors. APCs help the T cells figure out when and what to attack. Like high numbers of CD8 T cells, high numbers of APCs in tumors were also a predictor of longer progression-free survival in kidney cancer patients.

The APCs and the stem-like cells were usually together within the same “nests,” in a way that resemble how the two types of cells interact in lymph nodes. This relationship was apparent in kidney cancers and also in samples from prostate and bladder cancers.

“The question of how the stem-like cells get into a tumor was not answered, but we do think that the APCs support the stem-like cells and are necessary for their maintenance,” Kissick says. “Given that these are the cells responsive to cancer immunotherapy agents, focusing on the relationship between the APCs and the T cells within the tumors could be valuable.”

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New subtype of muscle stem cells that can be used in the development of gene therapies — ScienceDaily

Anyone who climbs the 285 steps to the viewing platform of Berlin’s Siegessäule, or Victory Column, will probably have quite a few sore muscles the next day. Out-of-the-ordinary activities such as climbing lots of steps or even normal exercise can put significant strain on muscles. Such activities cause tiny tears in the muscle fibers, which the body then repairs on its own.

Even when injuries occur, the muscles activate an endogenous regeneration program: A reserve supply of muscle stem cells, known as satellite cells, reside around the muscle fibers and are essential for the repair of damaged muscle cells. These satellite cells produce new muscle fibers in a process which results in muscle regeneration. People maintain this ability well into old age. Researchers are particularly interested in these cells since they could provide targets for new therapeutic approaches for people with muscle diseases.

An overrated protein

Researchers previously assumed that a certain protein — the transcription factor PAX7 — plays a key role in muscle regeneration. “Cells from which new muscles arise have enormous potential for developing gene therapies to treat muscle atrophy. And PAX7 is actually considered a characteristic property of muscle-building satellite cells,” says Prof. Simone Spuler.

The scientist and physician is a research group leader at the Experimental and Clinical Research Center (ECRC), a joint institution of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and Charité — Universitätsmedizin Berlin, and heads the Myology Group at the MDC. Her team has now reported in the journal Nature Communications that it’s possible for muscles to grow and regenerate without PAX7. The study characterized a previously unknown subtype of satellite cells that could play an important role in the future development of gene therapies from muscle stem cells.

“The findings will certainly surprise many researchers in the field,” says Dr. Andreas Marg, a senior scientist in Spuler’s lab and the lead author of the study. He himself was initially guided by the assumption that the transcription factor was crucial for muscle growth. “I previously focused my research on PAX7-positive cells. Our findings lead us down a new path.”

New muscles despite a mutation

The research team owes the discovery to a young girl: Lavin has suffered from a genetic form of muscular dystrophy since birth and is the protagonist in the study. Lavin has all the muscles of a healthy person, but each of her muscles is very small. The musculature along her spine is particularly affected by the disease. Lavin’s arms and legs are strong, but she suffers breathing problems and has difficulty bending forward and holding her head up.

Gene analysis shows that the gene for PAX7 is damaged in Lavin; her cells can’t produce this protein. The University Hospital Munich discovered this in 2017. Soon thereafter, Spuler and Marg learned of this extremely rare mutation — one that had not been described before. Lavin traveled with her parents to the Berlin-Buch campus, where the scientists took a sample of her muscle tissue. Marg used a new procedure to filter out Lavin’s satellite cells and then implanted them in mice. He observed that new muscle fibers grew in the mice from Lavin’s cells — despite the absence of PAX7.

Spuler presumes that PAX7 is not equally important for every cell. This would explain why Lavin can walk and climb relatively well, but has hardly any strength in her diaphragm, which causes the breathing problems. “We could perhaps develop a gene therapy for Lavin using the CRISPR-Cas9 gene-editing tool,” says Spuler. “However, to repair the defective gene, CRISPR-Cas9 would have to specifically target the cells of the axial musculature, and that is not yet possible.” But Spuler’s lab is working intensively to figure out how to repair defective genes in muscle cells. For Lavin and her family, this research offers a small glimmer of hope that a suitable therapy will be found.

A new subtype of muscle stem cells

Marg and Spuler collaborated on the study with many colleagues at the MDC and with scientists from institutions abroad. Prof. Nikolaus Rajewsky’s research group at the Berlin Institute for Medical Systems Biology (BIMSB) compared Lavin’s cells with those donated by healthy people. Single-cell analysis, which looks at the activity of each cell individually, revealed a previously unknown cell population. In around 20 percent of the donors, the majority of the activated satellite cells also don’t produce any PAX7, even though the genetic information is present in the cells. The team instead discovered something else in those cells in which the transcription factor was missing: CLEC14A, a protein that is found in many blood vessel cells. This very protein was highly expressed in Lavin’s muscle stem cells.

The new study describes a previously unknown subtype of satellite cells. First, the researchers identified these cells in the stem cell niche, which is where the satellite cells reside. Second, PAX7 is not present in these cells. Third, other characteristic proteins such as CLEC14A are present instead. And fourth, new muscle fibers can be derived from this cell population.

Up to now, only cells with PAX7 have been considered as targets for gene therapy research involving satellite cells. The new study shows that the subtype discovered should also play a role in therapeutic development.

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Mouse pups born from eggs derived from the granulosa cells that surround oocytes — ScienceDaily

By introducing a chemical cocktail to granulosa cells, researchers in China induced the cells to transform into functional oocytes in mice. Once fertilized, these oocytes were then successfully able to produce healthy offspring, showing no differences from naturally bred mice. The chemical reprogramming method appears December 24 in the journal Cell Reports.

Ovarian follicles are the basic functional unit of the ovary and consist of an oocyte, the immature egg, which is surrounded by granulosa cells. Besides being crucial to the development of follicles, studies have shown that granulosa cells possess plasticity that shows stem cell-like properties.

“The thing about in vitro fertilization is that they only use the oocyte for the procedure,” says senior author Lin Liu, of the College of Life Sciences at Nankai University. “After the egg retrieval, the granulosa cells in the follicle are discarded. It got us thinking, what if we can utilize these granulosa cells? Since every egg has thousands of granulosa cells surrounding it, if we can induce them into pluripotent cells and turn those cells into oocytes, aren’t we killing two birds with one stone?”

Granulosa cells tend to undergo cell death and differentiation once removed from the follicles. Liu and his team including PhD students Chenglei Tian and Haifeng Fu developed a chemical “cocktail” with Rock inhibitor and crotonic acid for creating chemically induced pluripotent stem cells (CiPSCs) from granulosa cells. The research team introduced Rock inhibitor to prevent cell death and promote proliferation. In combination with other important small chemicals, crotonic acid facilitates the induction of granulosa cells into germline-competent pluripotent stem cells that exhibit pluripotency similar to embryonic stem cells.

“It’s a surprising result,” says Liu. “The competency of induced pluripotent germline is usually lower than embryonic stem cells. Germline competency is crucial for germline cells to transfer genetic information to the next generation. With the co-formulation of Rock inhibitor and crotonic acid, it’s not only more efficient, but the quality also increased.”

Another cocktail of Rock inhibitor and vitamin C is introduced to the germline-competent pluripotent stem cells to improve the follicle development and induce meiosis. Meiosis is the process of a single cell becoming sex cells, the egg. Germ cells and oocytes rejuvenated from granulosa cells exhibit high genomic stability and successfully produce offspring that show normal fertility.

“We can consistently manipulate the concentration and treatment time of these small chemicals,” says Liu. Compared to traditional stem cell-inducing methods such as transfection, which reprograms cells by introducing transcription factors to somatic cells, chemical treatment provides higher controllability. “Transfection method may have a higher risk of genetic instability.”

“This is the first time we turned granulosa cells into oocytes, it is a crucial and interesting work in developmental and reproductive biology,” he says. “But implementing this research to humans from mice still has a long way to go. I think it has more prospect in preserving fertility and endocrine function, than in treating infertility.”

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Materials provided by Cell Press. Note: Content may be edited for style and length.

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Modeling the human eye in a dish — ScienceDaily

Despite its small size relative to the rest of the body, the eye is one of the most complex organs of the human body and has been difficult to study in a lab. Now, researchers from Osaka University have developed a novel method to model eye development and disease using human induced pluripotent stem cells (hiPSCs). In a new study published in Journal of Biological Chemistry, they showed how tracking the expression of PITX2, a key protein during eye development, in developing hiPSCs enables the isolation of a certain group of cells that play important roles in eye development, biology and disease.

Ever since their discovery over a decade ago, hiPSCs have continued to be used to replicate human biology and disease in a lab without the need for animals. Their streamlined use is accompanied by the possibility of easily genetically altering the cells to study the function of proteins. Although to date several cellular models of multiple organs have been developed using hiPSC, due to its complex and heterogeneous nature, the eye has been more difficult to recreate using these cells.

“Unlike other organs, the eye is more difficult to recreate in the lab due to the presence of heterogeneous cells in the eye,” says corresponding author of the study, Ryuhei Hayashi. “The goal of our study was to develop a novel human cellular eye model using hiPSCs that will help improve our understanding of how these different cell types develop to form the eye.”

To achieve their goal, the researchers established a reporter cell line by modifying hiPSCs using genome editing technology, such that the cells express the fluorescent protein eGFP whenever they express the protein PITX2. PITX2 is a transcriptional factor protein that plays a key role during embryonic development of several organs, including the eyes. In the eye, PITX2 is specifically expressed in what is called periocular mesenchyme (POM), a collection of cells that give rise to the cornea, as well as muscle cells and connective tissue within the eye. As a result, by using the genetically modified cells, the researchers were able to fluorescently label POM cells.

“We wanted to know whether our new cellular model was able to recreate elements of normal eye development and isolated POM cells for characterization,” says lead author of the study Toru Okubo.

The researchers first showed that the modified hiPSCs remained pluripotent after genome editing, so they still maintained the properties of pluripotent stem cells in the same way as unchanged hiPSCs. They then induced the development of POM cells from hiPSCs and showed that they formed so-called self-formed ectodermal autonomous multi-zones (SEAM), which are two-dimensional tissues consisting of different eye cells that form during normal eye development (first reported by Hayashi’s group in 2016). Previously, there were no methods to isolate POM cells, but this new generation of gene-edited iPSCs enables the team to isolate POM cells selectively from the SEAM. By isolating the fluorescent POM cells from other, non-fluorescent cells, the researchers were then able to show that POM cells maintained known molecular markers during further cell culture, validating the recreation of eye development using their hiPSC reporter cell line.

“These are striking results that show how human stem cells can be used to study development and disease processes,” says Hayashi. “Our model could offer a new opportunity to understand how different aspects of eye development happen.”

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Materials provided by Osaka University. Note: Content may be edited for style and length.

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For clogged and hardened hearts, a mussel is the solution — ScienceDaily

Early mortality of myocardial infarction (MI), one of fatal diseases, is about 30%. So, it is critical to have immediate and proactive treatment to prevent a heart attack. Contributing to developing an efficient treatment of this fatal disease, a research team from South Korea recently proposed an effective stem cell treatment system for myocardial infarction, using harmless protein from mussel and stem cells.

Prof. Hyung Joon Cha and Mr. Tae Yoon Park from Department of Chemical Engineering, POSTECH with Prof. Sung Bo Sim from Department of Thoracic and Cardiovascular Surgery, Yeouido St. Mary’s Hospital and Prof. Jongho Lee from Department of Thoracic and Cardiovascular Surgery, Daejeon St. Mary’s Hospital developed an ‘adhesive protein-based immiscible condensed liquid system’ (APICLS) that efficiently delivered the mesenchymal stem cells (MSCs) to the damaged cardiac muscular tissues and enabled the transplantation prolonged. By employing the phase separation phenomenon of mussel adhesive protein, they were able to easily encapsulate the MSCs in the liquid coacervate. Especially, based on the mass production of bioengineered mussel adhesive protein, their newly suggested platform can be expected to be an innovative therapeutic system for myocardial infarction.

Heart is a vital organ that circulates blood while repeating contraction and relaxation of muscles by electrical signals. When blood vessels are clogged, oxygens and nutrients cannot be supplied to the heart and it brings severe damages to a muscle of the heart, causing infarcted myocardium with disruption of blood networks. This causes a necrosis on wall of the myocardium, resulting in cardiac wall thinning and this phenomenon is known as myocardial infarction. Because the heart cannot regenerate itself when it is damaged, there is no method for innovatively regenerating damaged heart muscles. As current therapeutic strategies, patients are treated with either mechanical device or heart transplantation.

Recently, there have been numbers of research proposing on transplanting exogenous stem cells into the damaged myocardium to help heart regeneration as a future treatment technique. However, transplanted stem cells have very low survival rate due to harsh environment of the heart. Even when the transplantation is successful, most of the stems cells soon die.

For a successful stem cell therapy on MI, there are two conditions required to survive in harsh environment of the damaged heart. First, the stem cells must be efficiently transplanted and remained into the thinned cardiac muscles. Secondly, transplanted stem cells must integrate rapidly into resident surrounding tissues to improve their viability by forming blood vessels. However, the current therapeutic methods so far cannot deliver injected stem cells to infarcted cardiac muscular tissues successfully, making it very difficult to maintain the transplantation.

The joint research team injected the MSCs encapsulated in APICLS into the thinned and infarcted cardiac muscular wall efficiently. They demonstrated in vivo feasibility through rat MI model that transplanted MSCs survived in the infarcted cardiac muscular tissues for a long time due to the mussel adhesive proteins with its unique characteristics of adhesiveness and angiogenesis and the efficacy of MSCs. Furthermore, the damaged heart muscles formed new blood vessels, prevented further apoptosis of existing cardiomyocytes, and regenerated the damaged cardiac wall by reducing fibrosis.

It is anticipated that the new stem cell delivery system proposed in this research will play an essential role in the stem cell therapeutic market as it used biocompatible materials which are harmless to humans.

“By using mussel adhesive proteins, we demonstrated with the MI rat model and proved its therapeutic efficacy as an efficient stem cell injection strategy. We gives a hope that it can also be successfully applied to chronic diseases and ischemic diseases that have similar environment,” said Prof. Hyung Joon Cha who led the research.

In the meanwhile, this research was introduced as the most innovative technology found by POSTECH in the Most Innovative Universities 2019 by Reuters last year. It is also published on the website of Journal of Controlled Release, the world’s most renowned journal in the field of drug delivery. This study was supported by the Marine BioMaterials Research Center grant funded by the Ministry of Oceans and Fisheries, Korea.

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New in vivo priming strategy to train stem cells can enhance cardiac repair effectiveness — ScienceDaily

Human stem cells have been regarded as one of the promising cell sources for cardiac regeneration therapy. But their clinical use is hampered due to the poor performance after transplantation into failing hearts. Recently a stem cell biologist from City University of Hong Kong (CityU), together with his collaborators, has developed a novel strategy, called in vivo priming, to “train” the stem cells to stay strong after implantation to the damaged heart via the 3D-printed bandage-like patch. The positive results of the study show that an in vivo priming strategy can be an effective means to enhance cardiac repair.

Dr Ban Kiwon, Assistant Professor of CityU’s Department of Biomedical Sciences, collaborated with cardiologist and experts in 3D printing from South Korea in achieving this breakthrough. Their findings were published in the latest issue of the scientific journal Science Advances, titled “In vivo priming of human mesenchymal stem cells with hepatocyte growth factor-engineered mesenchymal stem cells promotes therapeutic potential for cardiac repair.”

Harsh environment in failing hearts hinders stem cell survival

One of the proposed approaches to treat myocardial infarction, commonly known as heart attack, with regeneration therapy is to inject the human stem cells directly into the failing hearts. In particular, human mesenchymal stem cells (hMSCs) have been considered as a competitive agent for clinical uses for their proven safety and significant paracrine effects supporting new blood vessel formation and inhibiting cell death. However, “the clinical trial results are disappointing as the micro-environment of a failing heart is very harsh for the injected hMSCs to stay alive,” said Dr Ban.

Therefore researchers have been exploring ways to increase the survival rate of hMSCs in failing hearts. “Priming, or called preconditioning, is a common strategy to empower the cells. The cells are educated through certain stimulations, and when they are relocated to tough environments, they are much stronger against bad condition and they will know how to react because of their previous experiences,” explained Dr Ban.

Conventionally, priming is performed in vitro (outside a living organism) before the cells are transplanted into the heart. “But the effects of priming done in this way usually last for two or three days only. To extend the duration of the priming effect, I have come up with an idea of ‘in vivo priming’, which means the hMSCs are primed directly on the failing hearts,” said Dr Ban.

Novel strategy: in vivo priming of hMSCs

To prove the concept, the research team loaded two types of MSCs into a tailor-made 3D-printed patch, namely the human bone marrow-derived MSCs, and the genetically engineered MSCs which have human hepatocyte growth factor protein. Hepatocyte growth factor (HGF) is involved in multiple biological activities, such as cell survival, blood vessel formation, anti-fibrotic activities, and important in adult organ regeneration and wound healing.

The patch, like a bandage, was then implanted on the top of the infarct area of the myocardial-infarction-induced heart of rats. “The genetically engineered MSCs can continuously secret human HGF protein to prime the hMSCs within the patch and make them ‘stronger’,” said Dr Ban.

Instead of directly injecting the genetically engineered cells into the heart, he added that encapsulating the cells in the patch for putting on the surface of the heart can help prevent mutation or other undesirable outcomes. And the patch is fabricated by 3D-printing of pig heart-derived extracellular matrix hydrogel, simulating the cardiac tissue-specific micro-environment.

It was found that the primed hMSCs had a higher survival rate compared with unprimed ones in the patches attached to the failing hearts. Those empowered hMSCs released greater amounts of paracrine factors beneficial for repairing damaged cardiac muscle tissues and regenerating vasculatures.

“We found that the primed cells can survive even after 8 weeks in the patch after implantation to the heart. Also, there is a significant improvement in cardiac function as well as vessel regeneration comparing to the unprimed cells,” said Dr Ban.

Great improvement of the priming effect

“Our team is the very first to achieve priming in hearts in vivo. But more importantly, by showing that in vivo priming of hMSCs can enhance the therapeutic potential for cardiac repair, we hope our study can bring significant implications for related stem cell therapy in future,” concluded Dr Ban. It took the team over two years to achieve these remarkable results. The team will explore the possibility of conducting the experiments on bigger animals and even clinical trials, as well as modifying the structure of the patch.

Dr Ban, Dr Jang Jinah from Pohang University of Science and Technology, as well as Professor Park Hun-Jun from The Catholic University of Korea are the leading authors of the paper. Mr Lee Sunghun, a PhD student from Department of Biomedical Sciences at CityU also participated in this research.

The study was supported by CityU, Hong Kong Research Grants Council, National Research Foundation of Korea, Ministry of Education as well as the Ministry of Science and ICT in South Korea.

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