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November 2020

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Cutting edge technology to bioprint mini-kidneys — ScienceDaily

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Researchers have used cutting edge technology to bioprint miniature human kidneys in the lab, paving the way for new treatments for kidney failure and possibly lab-grown transplants.

The study, led by the Murdoch Children’s Research Institute (MCRI) and biotech company Organovo and published in Nature Materials, saw the research team also validate the use of 3D bioprinted human mini kidneys for screening of drug toxicity from a class of drugs known to cause kidney damage in people.

The research showed how 3D bioprinting of stem cells can produce large enough sheets of kidney tissue needed for transplants.

Like squeezing toothpaste out of a tube, extrusion-based 3D bioprinting uses a ‘bioink’ made from a stem cell paste, squeezed out through a computer-guided pipette to create artificial living tissue in a dish.

MCRI researchers teamed up with San Diego based Organovo Inc to create the mini organs.

MCRI Professor Melissa Little, a world leader in modelling the human kidney, first began growing kidney organoids in 2015. But this new bio-printing method is faster, more reliable and allows the whole process to be scaled up. 3D bioprinting could now create about 200 mini kidneys in 10 minutes without compromising quality, the study found.

From larger than a grain of rice to the size of a fingernail, bioprinted mini-kidneys fully resemble a regular-sized kidney, including the tiny tubes and blood vessels that form the organ’s filtering structures called nephrons.

Professor Little said by using mini-organs her team hope to screen drugs to find new treatments for kidney disease or to test if a new drug was likely to injure the kidney.

“Drug-induced injury to the kidney is a major side effect and difficult to predict using animal studies. Bioprinting human kidneys are a practical approach to testing for toxicity before use,” she said.

In this study, the toxicity of aminoglycosides, a class of antibiotics that commonly damage the kidney, were tested.

“We found increased death of particular types of cells in the kidneys treated with aminoglycosides,” Professor Little said.

“By generating stem cells from a patient with a genetic kidney disease, and then growing mini kidneys from them, also paves the way for tailoring treatment plans specific to each patient, which could be extended to a range of kidney diseases.”

Professor Little said the study showed growing human tissue from stem cells also brought the promise of bioengineered kidney tissue.

“3D bioprinting can generate larger amounts of kidney tissue but with precise manipulation of biophysical properties, including cell number and conformation, improving the outcome,” she said.

Currently, 1.5 million Australians are unaware they are living with early signs of kidney disease such as decreased urine output, fluid retention and shortness of breath.

Professor Little said prior to this study the possibility of using mini kidneys to generate transplantable tissue was too far away to contemplate.

“The pathway to renal replacement therapy using stem cell-derived kidney tissue will need a massive increase in the number of nephron structures present in the tissue to be transplanted,” she said.

“By using extrusion bioprinting, we improved the final nephron count, which will ultimately determine whether we can transplant these tissues into people.”

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Researchers uncover the unique way stem cells protect their chromosome ends — ScienceDaily

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Telomeres are specialised structures at the end of chromosomes which protect our DNA and ensure healthy division of cells. According to a new study from researchers at the Francis Crick Institute published in Nature, the mechanisms of telomere protection are surprisingly unique in stem cells.

For the last 20 years, researchers have been working to understand how telomeres protect chromosome ends from being incorrectly repaired and joined together because this has important implications for our understanding of cancer and aging.

In healthy cells, this protection is very efficient, but as we age our telomeres get progressively shorter, eventually becoming so short that they lose some of these protective functions. In healthy cells, this contributes to the progressive decline in our health and fitness as we age. Conversely, telomere shortening poses a protective barrier to tumour development, which cancer cells must solve in order to divide indefinitely.

In somatic cells, which are all the cells in the adult body except stem cells and gametes, we know that a protein called TRF2 helps to protect the telomere. It does this by binding to and stabilising a loop structure, called a t-loop, which masks the end of the chromosome. When the TRF2 protein is removed, these loops do not form and the chromosome ends fuse together, leading to “spaghetti chromosomes” and killing the cell.

However, in this latest study, Crick researchers have found that when the TRF2 protein is removed from mouse embryonic stem cells, t-loops continue to form, chromosome ends remain protected and the cells are largely unaffected.

As embryonic stem cells differentiate into somatic cells, this unique mechanism of end protection is lost and both t-loops and chromosome end protection become reliant on TRF2. This suggests that somatic and stem cells protect their chromosome ends in fundamentally different ways.

“Now we know that TRF2 isn’t needed for t-loop formation in stem cells, we infer there must be some other factor that does the same job or a different mechanism to stabilise t-loops in these cells, and we want to know what it is,” says Philip Ruis, first author of the paper and PhD student in the DNA Double Strand Breaks Repair Metabolism Laboratory at the Crick.

“For some reason, stem cells have evolved this distinct mechanism of protecting their chromosomes ends, that differs from somatic cells. Why they have, we have no idea, but it’s intriguing. It opens up many questions that will keep us busy for many years to come.”

The team have also helped to clarify years of uncertainty about whether the t-loops themselves play a part in protecting the chromosome ends. They found that telomeres in stem cells with t-loops but without TRF2 are still protected, suggesting the t-loop structure itself has a protective role.

“Rather than totally contradicting years of telomere research, our study refines it in a very unique way. Basically, we’ve shown that stem cells protect their chromosome ends differently to what we previously thought, but this still requires a t-loop,” says Simon Boulton, paper author and group leader in the DNA Double Strand Breaks Repair Metabolism Laboratory at the Crick.

“A better understanding of how telomeres work, and how they protect the ends of chromosomes could offer crucial insights into the underlying processes that lead to premature aging and cancer.”

The team worked in collaboration with Tony Cesare in Sydney and other researchers across the Crick, including Kathy Niakan, of the Human Embryo and Stem Cell Laboratory, and James Briscoe, of the Developmental Dynamics Laboratory at the Crick. “This is a prime example of what the Crick was set up to promote. We’ve been able to really benefit from our collaborator’s expertise and the access that was made possible by the Crick’s unique facilities,” says Simon.

The researchers will continue this work, aiming to understand in detail the mechanisms of telomere protection in somatic and embryonic cells.

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Drug guides stem cells to desired location, improving their ability to heal — ScienceDaily

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Scientists at Sanford Burnham Prebys Medical Discovery Institute have created a drug that can lure stem cells to damaged tissue and improve treatment efficacy — a scientific first and major advance for the field of regenerative medicine. The discovery, published in the Proceedings of the National Academy of Sciences (PNAS), could improve current stem cell therapies designed to treat such neurological disorders as spinal cord injury, stroke, amyotrophic lateral sclerosis?(ALS) and other neurodegenerative disorders; and expand their use to new conditions, such as heart disease or arthritis.

Toxic cells (green) disappeared when mice with a neurodegenerative condition received both therapeutic stem cells (red) and the drug SDV1a-which corresponded with longer lives and delayed symptom onset. These results suggest that SDV1a can be used to improve the efficacy of stem cell treatments.

“The ability to instruct a stem cell where to go in the body or to a particular region of a given organ is the Holy Grail for regenerative medicine,” says Evan Y. Snyder, M.D. Ph.D., professor and director of the Center for Stem Cells & Regenerative Medicine at Sanford Burnham Prebys and senior author of the study. “Now, for the first time ever, we can direct a stem cell to a desired location and focus its therapeutic impact.”

Nearly 15 years ago, Snyder and his team discovered that stem cells are drawn to inflammation — a biological “fire alarm” that signals damage has occurred. However, using inflammation as a therapeutic lure isn’t feasible because an inflammatory environment can be harmful to the body. Thus, scientists have been on the hunt for tools to help stem cells migrate — or “home” — to desired places in the body. This tool would be helpful for disorders in which initial inflammatory signals fade over time — such as chronic spinal cord injury or stroke — and conditions where the role of inflammation is not clearly understood, such as heart disease.

“Thanks to decades of investment in stem cell science, we are making tremendous progress in our understanding of how these cells work and how they can be harnessed to help reverse injury or disease,” says Maria T. Millan, M.D., president and CEO of the California Institute for Regenerative Medicine (CIRM), which partially funded the research. “Dr. Snyder’s group has identified a drug that could boost the ability of neural stem cells to home to sites of injury and initiate repair. This candidate could help speed the development of stem cell treatments for conditions such as spinal cord injury and Alzheimer’s disease.”

A drug with only the “good bits”

In the study, the scientists modified CXCL12 — an inflammatory molecule which Snyder’s team previously discovered could guide healing stem cells to sites in need of repair — to create a drug called SDV1a. The new drug works by enhancing stem cell binding and minimizing inflammatory signaling — and can be injected anywhere to lure stem cells to a specific location without causing inflammation.

“Since inflammation can be dangerous, we modified CXCL12 by stripping away the risky bit and maximizing the good bit,” says Snyder. “Now we have a drug that draws stem cells to a region of pathology, but without creating or worsening unwanted inflammation.”

To demonstrate that the new drug is able to improve the efficacy of a stem cell treatment, the researchers implanted SDV1a and human neural stem cells into the brains of mice with a neurodegenerative disease called Sandhoff disease. This experiment showed SDV1a helped the human neural stem cells migrate and perform healing functions, which included extending lifespan, delaying symptom onset, and preserving motor function for much longer than the mice that didn’t receive the drug. Importantly, inflammation was not activated, and the stem cells were able to suppress any pre-existing inflammation.

Next steps

The researchers have already begun testing SDV1a’s ability to improve stem cell therapy in a mouse model of ALS, also known as Lou Gehrig’s disease, which is caused by progressive loss of motor neurons in the brain. Previous studies conducted by Snyder’s team indicated that broadening the spread of neural stem cells helps more motor neurons survive — so the scientists are hopeful that strategic placement of SDV1a will expand the terrain covered by neuroprotective stem cells and help slow the onset and progressive of the disease.

“We are optimistic that this drug’s mechanism of action may potentially benefit a variety of neurodegenerative disorders, as well as non-neurological conditions such as heart disease, arthritis and even brain cancer,” says Snyder. “Interestingly, because CXCL12 and its receptor are implicated in the cytokine storm that characterizes severe COVID-19, some of our insights into how to selectively inhibit inflammation without suppressing other normal processes may be useful in that arena as well.”

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Boosting stem cell activity can enhance immunotherapy benefits — ScienceDaily

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Immune-system T cells have been reprogrammed into regenerative stem cell-like memory (TSCM) cells that are long-lived, highly active “super immune cells” with strong antitumor activity, according to new research from Georgetown Lombardi Comprehensive Cancer Center.

The reprogramming involves a novel approach the researchers developed that inhibits the activity of proteins known as MEK1/2. Currently, several MEK inhibitors are used to effectively treat melanoma, but this study demonstrates that MEK inhibitors don’t just target certain types of cancer cells, but rather, more broadly, reprogram T cells to fight many types of cancer.

The finding appears November 23, 2020, in Nature Immunology.

“Although immunotherapies have improved survival for cancer patients over recent years, survival rates remain sub-optimal. Therefore, there is an urgent need to develop novel, more effective anti-cancer immunotherapies,” says Samir N. Khleif, MD, director of The Jeannie and Tony Loop Immuno-Oncology Laboratory and head of the team that conducted this research. “Our research shows that using drugs that have already been approved for human use may significantly enhance currently available immune therapeutic approaches, thereby leading to better and more durable anti-cancer responses.”

The researchers performed experiments with human cells in the lab and then confirmed the effects of such an approach in mice. The investigators were able to not only identify a novel strategy to reprogram T cells into TSCM cells by using MEK1/2 inhibition, they were able to identify a novel molecular mechanism by which the TSCMs were induced.

The scientists found that reprograming T cells into TSCM can significantly improve T cell therapies for cancer patients. T cell therapy is a process that is widely used in specific cancers and in clinical trials, where immune-system T cells are separated out from a patient’s blood, engineered and expanded with special tumor-targeting capabilities and infused back into the patient to fight cancer. In their experiments, human T cells were reprogrammed with MEK inhibitors into TSCM; additionally, when treating mice with MEK inhibitors, the reprogramming of T cells was also found to induce effective TSCMs.

“Stem cell research has played a vital role this century in enhancing the progress against many diseases. Recent public and private support for stem cell therapy is very gratifying,” says Khleif. “Having stem cell research-specific funding from both governmental and private funders will greatly help accelerate the development of this under-utilized area of research.”

Now that MEK inhibitors have been shown to enhance an anti-tumor immune response, the researchers are starting to look into designing clinical trials to test their research approach in cancer patients. “Our approach is quite novel and we’re anxious to see it put to use in the clinical arena as soon as possible,” concludes Khleif.

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Materials provided by Georgetown University Medical Center. Note: Content may be edited for style and length.

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Neural crest study results could boost stem cell therapies — ScienceDaily

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Last year, researchers at the University of California, Riverside, identified the early origins of neural crest cells — embryonic cells in vertebrates that travel throughout the body and generate many cell types — in chick embryos. Now the researchers have used a human model to figure out when neural crest cells acquire distinctive molecular and functional attributes.

The study, published in Stem Cell Research, provides new insight into the formation of neural crest cells and outlines transient prospective stages in their development. It also shows the neural crest lineage is distinct from pluripotent stem cells.

The neural crest is an important embryonic cell population in the developing embryo that generates cells such as neurons, glia, and melanocytes, along with cells that make up bone and cartilage. Its improper development is linked to a wide range of pathologies, from craniofacial malformations such as palate clefts to aggressive cancers such as melanoma and neuroblastoma.

“Defining the molecular signature required for the formation of the neural crest better equips us to understand human neural crest related pathologies and develop diagnostic and therapeutic efforts,” said lead study author Maneeshi S. Prasad, an assistant project scientist in the lab of Martin I. Garcia-Castro, an associate professor of biomedical sciences at the UC Riverside School of Medicine. “The knowledge of the precise time and molecular signals involved, when exactly the neural crest acquires the potential to form jaw and tooth cells, for example, will enable scientists to replicate and modulate their potential in stem cell therapies designed to aid regenerative craniofacial repair approaches, among many others.”

The study used a robust human model of neural crest formation to demonstrate a fast transition from the pluripotent stem cell state to the neural crest precursor state. According to this model, a sequential loss of pluripotency markers occurs during the pluripotent stem cell state as cells transition to neural crest cells.

“We address the precise timing when pluripotent stem cells diverge toward the neural crest cell lineage by exploring the distinctive molecular and functional attributes of early neural crest cells — something that had never been established,” Prasad said. “We also identified unique molecular signatures during the transition stages of neural crest formation from pluripotent stem cells.”

The researchers provide a high-resolution temporal map of gene expression and epigenetic changes with well-defined stages of neural crest formation they say should be a valuable resource for scientists identifying and studying the role of various genes involved in human neural crest formation.

Neural crest cells have been thought to originate in the ectoderm, one of the three germ layers formed in the earliest stages of embryonic development, but their capacity to form derivatives, such as bone- and tooth-forming cells, are in conflict with fundamental concepts in developmental and stem cell biology.

Garcia-Castro noted the study also establishes a novel in vitro specification test to determine the differentiation capacity of specified neural crest cells into other germ layers such as mesoderm and endoderm cell types. The specification test involves exposing the potentially specified cells to precise level of signals that stimulate the formation of other germ layers such as mesoderm and endoderm from pluripotent embryonic stem cells.

“Our work demonstrates that neural crest cells depart from the pluripotent stem cell state soon after the activation of Wnt signaling, an ancient and evolutionarily conserved pathway that regulates crucial aspects of the cell,” he said. “Importantly, using our novel specification test we found that prospective neural crest cells lose the mesodermal and endodermal potential characteristic of pluripotent stem cells just hours upon their induction.”

Garcia-Castro and Prasad were joined in the research by postdoctoral fellow Rebekah M. Charney and undergraduate researcher Lipsa J. Patel.

The research was funded by the National Institutes of Health.

The title of the research paper is “Distinct molecular profile and restricted stem cell potential defines the prospective human cranial neural crest from embryonic stem cell state.”

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Materials provided by University of California – Riverside. Original written by Iqbal Pittalwala. Note: Content may be edited for style and length.

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Undesirable rejection mechanism identified — ScienceDaily

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The term leukemia is used to describe a group of malignant diseases of the haematopoietic system, in which precursors of the white blood cells (leucocytes) proliferate uncontrollably. Chemotherapy and radiotherapy are used to destroy the abnormal blood cells, which are then replaced by means of a stem cell transplant. In leukemia, the transplantation of healthy bone marrow stem cells or haematopoietic stem cells is often the only hope of recovery for patients. The process involves “replacing” all the recipient’s blood cells that were previously destroyed by the treatment with donor cells.

However, the MedUni Vienna dermatologists have now found that there are so-called skin-resident and inactive T cells in the endogenous immune system that survive chemotherapy and radiotherapy intact and go on to survive for a further ten years between and beneath the epithelial cells of the skin, while the circulating T cells are destroyed.

“We were able to demonstrate that T cells surviving in the skin tissue are responsible for the inflammatory reaction following a stem cell transplant. These phenomena often occur within the first 100 days and can cause anything from mild eczema through to extensive fibrosis, hardening of the tissue, or blistering on the surface of the skin. In other words, the endogenous T cells attack the recipient (host) following stem cell transplantation.” In specialist jargon, the condition is also referred to as Graft versus Host Disease (GvHD), and, for the first time, this study identified an inverse “Host-versus-graft reaction.”

There were also cases in which the donor T cells further “supported,” and thus intensified, this reaction. Affected patients are treated with cortisone, which causes an additional burden for patients who are already immunosuppressed following the transplantation. The study found that in patients who do not develop graft-versus-host disease, tissue-resident T cells remaining after treatment even proved to be beneficial to the recipient, in that they assumed their role in immune defence and protecting against infection.

In the future, the exemplary study results could lead to new treatment strategies that help to avoid, or at least to minimise, undesirable and violent inflammatory reactions following stem cell transplants by manipulating the recipient’s inactive T cells in advance. In addition, the manipulation of tissue-resident T cells might lead to new therapeutic approaches for other chronic inflammatory skin diseases, such as psoriasis or neurodermatitis.

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

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Study reveals how smoking worsens COVID-19 infection in the airways — ScienceDaily

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UCLA researchers using a model of airway tissue created from human stem cells have pinpointed how smoking cigarettes causes more severe infection by SARS-CoV-2, the virus that causes COVID-19, in the airways of the lungs.

The study, led by scientists at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA and published in Cell Stem Cell, will help researchers better understand COVID-19 risks for smokers and could inform the development of new therapeutic strategies to help reduce smokers’ chances of developing severe disease.

Cigarette smoking is one of the most common causes of lung diseases, including lung cancer and chronic obstructive pulmonary disease, and most demographic studies of COVID-19 patients have indicated that current smokers are at increased risk of severe infection and death. But the reasons why have not been entirely clear.

To help understand how smoking affects SARS-CoV-2 infection on a cellular and molecular level, Dr. Brigitte Gomperts partnered with co-senior authors Vaithilingaraja Arumugaswami, an associate professor of molecular and medical pharmacology, and Kathrin Plath, a professor of biological chemistry, to recreate what happens when the airways of a current smoker are infected with SARS-CoV-2.

The team utilized a platform known as an air-liquid interface culture, which is grown from human airway stem cells and closely replicates how the airways behave and function in humans. The airways, which carry air breathed in from the nose and mouth to the lungs, are the body’s first line of defense against airborne pathogens like viruses, bacteria and smoke.

“Our model replicates the upper part of the airways, which is the first place the virus hits,” said Gomperts, a professor pulmonary medicine and member of the UCLA Jonsson Comprehensive Cancer Center. “This is the part that produces mucus to trap viruses, bacteria and toxins and contains cells with finger-like projections that beat that mucus up and out of the body.”

The air-liquid interface cultures used in the study were grown from airway stem cells taken from the lungs of five young, healthy, nonsmoking tissue donors. To replicate the effects of smoking, the researchers exposed these airway cultures to cigarette smoke for three minutes per day over four days.

“This type of model has been used to study lung diseases for over a decade and has been shown to mimic the changes in the airway that you would see in a person who currently smokes,” said Gomperts, who is also vice chair of research in pediatric hematology-oncology at the UCLA Children’s Discovery and Innovation Institute.

Next, the group infected the cultures exposed to cigarette smoke — along with identical cultures that had not been exposed — with live SARS-CoV-2 virus and the two groups were compared. In the models exposed to smoke, the researchers saw between two and three times more infected cells.

Digging further, the researchers determined that smoking resulted in more severe SARS-CoV-2 infection, at least in part, by blocking the activity of immune system messenger proteins called interferons. Interferons play a critical role in the body’s early immune response by triggering infected cells to produce proteins to attack the virus, summoning additional support from the immune system, and alerting uninfected cells to prepare to fight the virus. Cigarette smoke is known to reduce the interferon response in the airways.

“If you think of the airways like the high walls that protect a castle, smoking cigarettes is like creating holes in these walls,” Gomperts said. “Smoking reduces the natural defenses and that allows the virus to set in.”

Co-first authors of the study are Arunima Purkayastha, Chandani Sen, Gustavo Garcia Jr. and Justin Langerman, all of UCLA.

This work was supported by the National Institutes of Health, the UCLA Medical Scientist Training Program, a UCLA David Geffen School of Medicine — Broad Stem Cell Research Center COVID-19 Research Award, the California Institute for Regenerative Medicine, the UCLA Clinical and Translational Science Institute (supported by National Institutes of Health’s National Center for Advancing Translational Sciences), the Tobacco-Related Disease Research Program and the Ablon Scholars Program at the UCLA Jonsson Comprehensive Cancer Center and UCLA Broad Stem Cell Research Center.

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Repetitive elements trigger RIG-I-like receptors to enhance hematopoietic stem cell formation — ScienceDaily

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Hematopoietic stem cells can replenish all the different cell types of our blood system. For this reason, hematopoietic stem cells are the cells used in many blood diseases when patients need transplantations. Thus, our ability to generate, amplify and maintain these cells is important for human health. The lab of Eirini Trompouki at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg, in collaboration with scientists the Albert Einstein College of Medicine, the University of Trento and the Chinese Academy of Sciences, discovered a novel mechanism that enhances hematopoietic stem cell formation during development. They showed that RNA from repetitive elements, remnants of viruses integrated through evolution into the genome of many animals, is produced during hematopoietic development. Repetitive element RNAs activate innate immune receptors to induce inflammation — the good kind — and increase the formation of embryonic hematopoietic stem cells.

Hematopoietic stem cells are the foundation of the blood system from fish to humans and give rise to leukocytes for fighting off pathogens, erythrocytes for transferring oxygen to tissues, and every other cell type that can be found in our blood. Importantly, hematopoietic stem cells born during development are also the foundation of our blood system when we are adults and their improper function can lead to multiple blood diseases. Therefore, hematopoietic stem cells are precious both in sickness and in health and understanding the mechanisms that govern their formation during development can help simply: “make blood.”

Repetitive element RNA enhances HSC formation

During the process of embryonic hematopoiesis in zebrafish, the lab of Eirini Trompouki found small bits of RNA expressed from a part of the genome considered as “junk DNA.” “Contrary to what many people believe, genes only comprise a very small part of our genome. The largest part of it contains other sequences, among which many are the remnants of viruses accumulated within the vertebrate genome through years of infections and evolution. Such sequences are for example several types of the so-called repetitive elements that usually remain repressed,” explains Eirini Trompouki, Max Planck group leader and member of the Centre for Integrative Biological Signalling Studies, Cluster of Excellence at the University of Freiburg.

To investigate the possible role of these RNA molecules in hematopoietic stem cell formation, the team used chemicals that enhance the expression of repetitive elements or injected a repetitive element copy RNA in zebrafish embryos. These experiments resulted in an increase in hematopoietic stem cell numbers generated within injected embryos. The next question of the team was how do repetitive elements exert their function in hematopoietic development? They hypothesized that, since these RNAs are viral remnants, they might be sensed by cell proteins that are normally used to sense everyday viral infections.

One of the key sensors of viral infection is the RIG-I-like receptor (RLR) family, which establishes a host response once activated by such a pathogen. Eirini and her team thought that in order to prove that repetitive elements are sensed by RLRs they needed to show that the increase in HSC numbers, observed upon chemical induction or overexpression of repetitive elements should not happen if RLRs are missing from the cells. Indeed, the team showed that injection of the same repetitive element RNA copy could not enhance hematopoietic stem cell development in RLR-deficient zebrafish embryos, which proved that the influence of these RNAs on hematopoietic stem cell generation depends on the presence and function of RLRs.

Functions of RLRs in hematopoiesis

The researchers then reasoned that if the function of repetitive elements in hematopoiesis depends on RLRs, then ablation of RLRs should have an impact on hematopoietic stem cell biology. The RLR family includes three different members, namely RIG-I, MDA5 and LGP2. In their experiments, the team showed that the absence of either Rig-I or Mda5 severely reduced the numbers of hematopoietic stem cells born in zebrafish embryos.

On the contrary, the absence of the third family member, Lgp2, increased the numbers of hematopoietic stem cells. “In every organism, for every process to be maintained within normal healthy boundaries and especially during development, we always need a switch setting the process on, but also a switch setting the process off or containing it. In this case, it seems that the RLR family can function as an independent system that involves both the positive and negative regulatory mechanisms,” says Stelios Lefkopoulos on the dual role of the receptor family in hematopoiesis.

Repetitive RNA activates viral sensors

Knowing the role of RLRs in hematopoiesis, the team next tackled the question how these receptors regulate hematopoietic stem cell generation. They found that when they reduced the levels of either Rig-I or Mda5 in their experiments, inflammatory signals beneficial for hematopoietic stem cells were downregulated, whereas when they reduced the Lgp2 levels these signals were upregulated. These observations explained how Rig-I or Mda5 normally induce, whereas Lgp2 impairs developmental hematopoiesis.

“All these events constitute a novel mechanism modulating hematopoiesis. Hematopoietic stem cells originate in embryos from endothelial cells of the aorta. It therefore seems that during the transition from one cell type to the other, different repetitive elements are expressed. One can speculate that while this transition is happening, newly expressed repetitive elements are sensed by RLRs and thus, actively participate in shaping the developmental fate by orchestrating inflammation signals,” says Eirini Trompouki.

A universal mechanism of tissue generation and integrity?

Since repetitive elements and RLRs are also expressed in other non-blood cells, it could be possible that a similar mechanism can be pertinent in more setups and conditions such as other tissues, stem cells or for adult hematopoiesis. “Nature never maintains through evolution something that is of no use; these repetitive elements have been maintained within vertebrate genomes for a reason, and we now know that activating RLRs and regulating developmental hematopoiesis is one of them,” says Stelios Lefkopoulos.

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The natural artistry of disease: A wintry landscape in the eye

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Researchers report a case of frosted branch angiitis in a woman presenting years after being treated for leukemia-lymphoma with allogeneic human stem cell transplant. The relevance of this ocular finding is discussed and its value as an early warning sign of immune activation following therapeutic immunological interventions is highlighted.

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‘Monster tumors’ could offer new glimpse at human development — ScienceDaily

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Finding just the right model to study human development — from the early embryonic stage onward — has been a challenge for scientists over the last decade. Now, bioengineers at the University of California San Diego have homed in on an unusual candidate: teratomas.

Teratomas — which mean “monstrous tumors” in Greek — are tumors made up of different tissues such as bone, brain, hair and muscle. They form when a mass of stem cells differentiates uncontrollably, forming all types of tissues found in the body. Teratomas are generally considered an undesired byproduct of stem cell research, but UC San Diego researchers found an opportunity to study them as a model for human development.

Researchers report their work in a paper published Nov. 4 in Cell.

“We’ve been fascinated with the teratoma for quite a while,” said Prashant Mali, a professor of bioengineering at the UC San Diego Jacobs School of Engineering. “Not only is the teratoma an intriguing tumor to look at in terms of the diversity of cell types, but it also has regions of organized tissue-like structures. This prompted us to explore its utility in both cell science and cell engineering contexts.”

“There’s no other model like it. In just one tumor, you can study all of these different lineages, all of these different organs, at the same time,” said Daniella McDonald, an M.D/Ph.D. candidate in Mali’s lab and co-first author of the study. “Plus, it’s a vascularized model, it has a three-dimensional structure and it’s human-specific tissue, making it the ideal model for recreating the context in which human development happens.”

The team used teratomas grown from human stem cells injected under the skin of immunodeficient mice. They analyzed the teratomas with a technique called single-cell RNA sequencing, which profiles the gene expression of individual teratoma cells. The researchers were able to map 20 cell types, or “human lineages” (brain, gut, muscle, skin, etc.) that were consistently present in all the teratomas they analyzed.

The researchers then used the gene editing technology CRISPR-Cas9 to screen and knock out 24 genes known to regulate development. They found multiple genes that play roles in the development of multiple lineages.

“What’s remarkable about this study is that we could use the teratoma to discover things in a much faster way. We can study all of these genes on all of these human lineages in a single experiment,” said co-first author Yan Wu, who worked on this project as a Ph.D. student in the labs of Mali and UC San Diego bioengineering professor Kun Zhang. “With other models, like organoids, that separately model one lineage at a time, we would have had to run many different experiments to come up with the same results as we did here.”

“Teratomas are a very unique type of human tissue. When examined through the lens of single-cell sequencing, we can see that they contain most major representative cell types in the human body. With that understanding, we suddenly have an extremely powerful platform to understand, manipulate and engineer human cells and tissues in a far more sophisticated way than what was previously possible,” Zhang said.

The researchers also showed that they can “molecularly sculpt” the teratoma to be enriched in one lineage — in this case, neural tissue. They accomplished this feat using a microRNA gene circuit, which acts like a molecular chisel by carving away unwanted tissues — these are selectively killed off using a suicide gene — and leaving behind the lineage of interest. The researchers say this has applications in tissue engineering.

“We envision that this study will set a new foundation in the field. Hopefully, other scientists will be using the teratoma as a model for future discoveries in human development,” McDonald said.

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Materials provided by University of California – San Diego. Original written by Liezel Labios. Note: Content may be edited for style and length.

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