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April 2020

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A ‘cardiac patch with bioink’ developed to repair heart — ScienceDaily

The heart is the driving force of circulating blood in the body and pumps blood to the entire body by repeating contraction and relaxation of the heart muscles continuously. Human stem cells are used in the clinical therapies of a dead heart, which happens when a blood vessel is clogged or whole or a part of heart muscles is damaged. The clinical use of human bone marrow-derived mesenchymal stem cells (BM-MSCs) have been expanded but failure of the transplanted stem cells in the heart still remains a problem. Recently, an international joint research team of POSTECH, Seoul St. Mary’s Hospital, and City University of Hong Kong developed a ‘cardiac patch with bioink’ that enhanced the functionality of stem cells to regenerate blood vessels, which in turn improved the myocardial infarction affected area.

The joint research team consisted of Prof. Jinah Jang and Dr. Sanskrita Das of POSTECH Creative IT Engineering, Mr. Seungman Jung of POSTECH School of Interdisciplinary Bioscience and Bioengineering, Prof. Hun-Jun Park, Mr. Bong-Woo Park, and Ms. Soo-Hyun Jung of The Catholic University, and Prof. Kiwon Ban and his fellows from City University of Hong Kong. The team mixed genetically engineered stem cells (genetically engineered hepatocyte growth factor-expressing MSCs, HGF-eMSCs) developed by SL Bigen. Co., Ltd to make bioink in the form of a patch and introduced a new therapy by transplanting it to a damaged heart. They called this new strategy as ‘in vivo priming’. The name came from the principle that maximized function of mesenchymal stem cells are maintained in vivo as well as through its exposure to the growth factor secreted by the genetically engineered stem cells.

The joint research team first genetically engineered the existing BM-MSCs to produce hepatocyte growth factor consistently to improve the therapeutic potential of stem cells. The engineered stem cells (HGF-eMSCs) were then mixed with BM-MSCs to make the bioink. They transplanted the cardiac patch with this bioink to the heart muscles affected by myocardial infarction. Considering the limited amount of cells that could be transferred, they used heart-derived extracellular matrix bioink to make a cardiac patch.

Implanted cells in a patch survived longer in vivo and had more myocardiocytes survived than the only BM-MSCs transplanted experimental group. This was because the secretion of cytokine, which helps formation of blood vessels and cell growth was maximized and delivered nutrients fluently that promoted vascular regeneration and enhanced survival of the myocardiocytes.

The research team anticipated that this new method could be a breakthrough treatment of myocardial infarction as the implanted stem cells through HGF-eMSCs ultimately enhanced vascular regeneration and improved the myocardial infarction affected area.

“We can augment the function of adult stem cells approved by Ministry of Food and Drug Safety and FDA using this newly developed and promising 3D bioprinting technology with the engineered stem cells. It is our goal to develop a new concept of medicine for myocardial infarction in the near future,” said Prof. Jinah Jang who led the research.

POSTECH began to develop medicine for cardiovascular diseases based on this newly developed bioprinting method with the research team from The Catholic University in 2017. Now, it is being tested in animals for efficacy evaluation with Chonnam National University. Also, the technology is already transferred to T&R Biofab, which is a company developing 3D printers, software, and bioinks to print cells.

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Materials provided by Pohang University of Science & Technology (POSTECH). Note: Content may be edited for style and length.

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Advances in production of retinal cells for treating blindness — ScienceDaily

Researchers at Karolinska Institutet and St Erik Eye Hospital in Sweden have discovered a way to refine the production of retinal cells from embryonic stem cells for treating blindness in the elderly. Using the CRISPR/Cas9 gene editing, they have also managed to modify the cells so that they can hide from the immune system to prevent rejection. The studies are published in the scientific journals Nature Communications and Stem Cell Reports.

Age-related macular degeneration of the eye is the most common cause of blindness in the elderly. This loss of vision is caused by the death of the photoreceptors (the rods and cones) resulting from the degeneration and death of the underlying retinal pigment epithelial (RPE cells), which provide the rods and cones vital nourishment. A possible future treatment could be to transplant fresh RPE cells formed from embryonic stem cells.

Working with colleagues at St Erik Eye Hospital, researchers at Karolinska Institutet have now found specific markers on the surface of the RPE cells that can be used to isolate and purify these retinal cells. The results are published in Nature Communications.

“The finding has enabled us to develop a robust protocol that ensures that the differentiation of embryonic stem cells into RPE cells is effective and that there is no contamination of other cell types,” says principal investigator Fredrik Lanner, researcher at the Department of Clinical Science, Intervention and Technology and the Ming Wai Lau Center for Reparative Medicine at Karolinska Institutet. “We’ve now begun the production of RPE cells in accordance with our new protocol for the first clinical study, which is planned for the coming years.”

One obstacle when transplanting tissue generated from stem cells is the risk of rejection, which occurs if transplantation antigens of the donor and patient tissue differ. Research groups around the world are therefore working on creating what are known as universal cells, which ideally will not trigger an immune response.

In a study published in Stem Cell Reports the same group at Karolinska Institutet created embryonic stem cells able to hide from the immune system. Using CRISPR/Cas9 gene editing, they removed certain molecules, HLA class I and class II, which sit on the surface of the stem cells as a means by which the immune system can identify them as endogenous or not. The stem cells lacking these molecules were then differentiated into RPE cells.

The researchers have been able to show that the modified RPE cells retain their character, that no harmful mutations appear in the process and that the cells can avoid the immune system’s T cells without activating other immune cells. The rejection response was also significantly less and more delayed than after the transplantation of regular RPE cells, the surfaces of which still possess HLA molecules.

“The research is still in an early stage, but this can be an important initial step towards creating universal RPE cells for the future treatment of age-related macular degeneration,” says joint last author Anders Kvanta, adjunct professor at the Department of Clinical Neuroscience and consultant at St Erik Eye Hospital.

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Materials provided by Karolinska Institutet. Note: Content may be edited for style and length.

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Scientists explore newborn, regenerated neurons — ScienceDaily

The zebrafish is a master of regeneration: If brain cells are lost due to injury or disease, it can simply reproduce them — contrary to humans where this only happens in the fetal stage. However, the zebrafish is evolutionarily related to humans and, thus, possesses the same brain cell types as humans. Can a hidden regeneration potential also be activated in humans? Are therapies for stroke, craniocerebral trauma and presently incurable diseases such as Alzheimer’s and Parkinson’s possible?

Dresden scientists have succeeded in determining the number and type of newly formed neurons in zebrafish; practically conducting a “census” in their brains. Following an injury, zebrafish form new neurons in high numbers and integrate them into the nervous system, which is the reason for their amazing brain regeneration ability. The study was conducted as a collaboration project “made in Dresden”: Scientists from the Center for Regenerative Therapies TU Dresden (CRTD) combined their expertise in stem cell biology with the latest methods from the DRESDEN-concept Genome Center and complex bio-informatic analyses from the Max Planck Institute for the Physics of Complex Systems and the Center for Systems Biology Dresden. They have now published their results in the scientific journal DEVELOPMENT, which reports on topics of developmental, stem cell and regenerative biology.

For their study, the team led by Dr. Christian Lange and Prof. Dr. Michael Brand from the CRTD used adult transgenic zebrafish in whose forebrain they were able to identify the newborn neurons. The forebrain of the zebrafish is the equivalent to the human cerebral cortex, the largest and functionally most important part of the brain. The Dresden research team investigated the newborn and mature neurons as well as brain stem cells using single cell sequencing. Thus, they discovered specific markers for newborn neurons and were able to comprehensively analyse which types of neurons are newly formed in the adult brain of the zebrafish.

The scientists discovered two types of neurons that can be newly formed: Projection neurons, which create connections between brain areas, and internal neurons, which serve to fine-tune the activity of the projection neurons. The researchers also investigated the data obtained from brain cell sequencing of mice and found that zebrafish and mice have the same cell types. This also makes these results highly relevant for humans.

“On the basis of this study, we will further investigate the regeneration processes that take place in zebrafish. In particular, we will study the formation of new neurons after traumatic brain damage and their integration,” explains Prof. Dr. Michael Brand, CRTD Director and senior author of the study. “We hope to gain insights that are relevant for possible therapies helping people after injuries and strokes or suffering from neurodegenerative diseases. We already know that a certain regenerative ability is also present in humans and we are working on awakening this potential. The results of our study are also important for understanding the conditions under which transplanted neurons can network with the existing ones and thus could let humans re-gain their former mental performance.”

The CRTD at TU Dresden is the academic home for scientists from more than 30 nations. Their mission is to discover the principles of cell and tissue regeneration and leveraging this for recognition, treatment and reversal of diseases. The CRTD links the bench to the clinic, scientists to clinicians to pool expertise in stem cells, developmental biology, gene-editing and regeneration towards innovative therapies for neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, haematological diseases such as leukaemia, metabolic diseases such as diabetes, retina and bone diseases. The group of Prof. Dr. Michael Brand investigates the patterning and regeneration of the vertebrate brain and eye.

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Materials provided by Technische Universität Dresden. Note: Content may be edited for style and length.

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