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New ‘time machine’ technique to measure cells — ScienceDaily

Using a new single-cell technique, WEHI researchers have uncovered a way to understand the programming behind how stem cells make particular cell types.

The research uncovered 30 new genes that program stem cells to make the dendritic cells that kick-start the immune response.

By uncovering this process, the researchers hope they will be able to find new immunotherapy treatments for cancer, and plan to expand this technique in other areas such as discovering new drug targets in tumour initiation.

At a glance

  • WEHI researchers have developed a new single cell method to understand the programming behind what causes stem cells to make particular cell types.
  • By testing daughters of a single stem cell in different parallel tests, researchers found 500 genes that predicted dendritic cell fate.
  • Using a CRISPR screen, they discovered 30 key genes amongst the 500 that program dendritic cell production.
  • Researchers intend to expand use of this technique to find the ‘big bang’ moment in cancer development to identify new drug targets to fight cancer.

Studying ‘sister’ cells

Led by Dr Shalin Naik, Dr Luyi Tian, Ms Sara Tomei and Mr Jaring Schreuder and published in Immunity, the research outlined the processes involved in kick-starting the generation of dendritic cells driven by the hormone Flt3 ligand, which is used in immunotherapy.

The research team developed a new technique to link the gene expression of a single cell with what cell types it made.

“We invented a technique called ‘SIS-seq’ in order to study ‘sister’ cells that descended in parallel from the ‘mother’ stem cell,” Dr Naik said.

“As RNA sequencing destroys the single stem cell, you are only able to measure the genetic contents of the cell but lose the chance to know what it would have made. So, there is no way of then going back in time to find that out.”

“By letting a single stem cell divide only a few times, not all the way, we were able to test the sisters separately. Some were tested for what they made, and others were tested for their genetic contents.”

“In this way, we have been able to link the genes with the cell types that are made.”

Discovery of 30 new genes

Dr Naik said the findings would not have been possible without advances in technology that enabled the team to answer multiple questions simultaneously.

“Using a CRISPR screen, we tested 500 genes that predicted dendritic cell fate and discovered 30 new genes that actually program dendritic cells to be made,” he said.

Dr Naik said the breakthrough could pave the way for new drug targets to fight cancer and improve immunotherapy treatment.

“We’ve now got a list of genes to try and generate or boost human dendritic cells in a petri dish for immunotherapy,” he said.

“And we are going to expand the use of this technology to find the genes that program the generation of each of the different human immune cell types.”

Finding the ‘big bang’ of cancer initiation

By examining cells at the single-cell level using this technique, researchers also intend to find the ‘big bang’ moment in cancer development in order to create new drug targets to fight cancer and improve immunotherapy.

“Using our time machine technique, we hope to be able to pinpoint which of the normal programs in tissue generation are hijacked by cancer causing genes in single cells and then use this information to find new targets for therapy,” Dr Naik said.

This work was made possible with funding from the National Health and Medical Research Council, the Australia Research Council, the Victorian Cancer Agency and the Victorian Government.

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Breakthrough discovery could speed up bone implant recovery — ScienceDaily

An international research team led by Monash University has uncovered a new technique that could speed up recovery from bone replacements by altering the shape and nucleus of individual stem cells.

The research collaboration involving Monash University, the Melbourne Centre for Nanofabrication, CSIRO, the Max Planck Institute for Medical Research and the Swiss Federal Institute of Technology in Lausanne, developed micropillar arrays using UV nanoimprint lithography that essentially ‘trick’ the cells to become bone.

Nanoimprint lithography allows for the creation of microscale patterns with low cost, high throughput and high resolution.

When implanted into the body as part of a bone replacement procedure, such as a hip or knee, researchers found these pillars — which are 10 times smaller than the width of a human hair — changed the shape, nucleus and genetic material inside stem cells.

Not only was the research team able to define the topography of the pillar sizes and the effects it had on stem cells, but they discovered four times as much bone could be produced compared to current methods.

The findings were published in Advanced Science.

“What this means is, with further testing, we can speed up the process of locking bone replacements with surrounding tissue, in addition to reducing the risks of infection,” Associate Professor Jessica Frith from Monash University’s Department of Materials Science and Engineering said.

“We’ve also been able to determine what form these pillar structures take and what size they need to be in order to facilitate the changes to each stem cell, and select one that works best for the application.”

Researchers are now advancing this study into animal model testing to see how they perform on medical implants.

Engineers, scientists and medical professionals have known for some time that cells can take complex mechanical cues from the microenvironment, which in turn influences their development.

However, Dr Victor Cadarso from Monash University’s Department of Mechanical and Aerospace Engineering says their results point to a previously undefined mechanism where ‘mechanotransductory signalling’ can be harnessed using microtopographies for future clinical settings.

“Harnessing surface microtopography instead of biological factor supplementation to direct cell fate has far-reaching ramifications for smart cell cultureware in stem cell technologies and cell therapy, as well as for the design of smart implant materials with enhanced osteo-inductive capacity,” Dr Cadarso said.

Professor Nicolas Voelcker from the Monash Institute of Pharmaceutical Sciences and Director of the Melbourne Centre for Nanofabrication said the study results confirm micropillars not only impacted the overall nuclear shape, but also changed the contents of the nucleus.

“The ability to control the degree of deformation of the nucleus by specifying the architecture of the underlying substrate may open new opportunities to regulate gene expression and subsequent cell fate,” Professor Voelcker said.

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New insight into formation of the human embryo — ScienceDaily

Pioneering research led by experts from the University of Exeter’s Living Systems Institute has provided new insight into formation of the human embryo.

The team of researchers discovered an unique regenerative property of cells in the early human embryo.

The first tissue to form in the embryo of mammals is the trophectoderm, which goes on to connect with the uterus and make the placenta. Previous research in mice found that trophectoderm is only made once.

In the new study, however, the research team found that human early embryos are able to regenerate trophectoderm. They also showed that human embryonic stem cells grown in the laboratory can similarly continue to produce trophectoderm and placental cell types.

These findings show unexpected flexibility in human embryo development and may directly benefit assisted conception (IVF) treatments. In addition, being able to produce early human placental tissue opens a door to finding causes of infertility and miscarriage.

The study is published in the leading international peer-review journal Cell Stem Cell on Wednesday, April 7th 2021.

Dr Ge Guo, lead author of the study from the Living Systems Institute said: “We are very excited to discover that human embryonic stem cells can make every type of cell required to produce a new embryo.”

Professor Austin Smith, Director of the Living Systems Institute and co-author of the study added, said: “Before Dr Guo showed me her results, I did not imagine this should be possible. Her discovery changes our understanding of how the human embryo is made and what we may be able do with human embryonic stem cells”

Human naïve epiblast cells possess unrestricted lineage potential is published in Cell Stem Cell. The research was funded by the Medical Research Council (MRC) .

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PANDORA sequencing method can detect once-undetectable small RNAs — ScienceDaily

A team led by a biomedical scientist at the University of California, Riverside, has developed a new RNA-sequencing method — “Panoramic RNA Display by Overcoming RNA Modification Aborted Sequencing,” or PANDORA-seq — that can help discover numerous modified small RNAs that were previously undetectable.

RNA plays a central role in decoding the genetic information in DNA to sustain an organism’s life. It is generally known as the intermediate molecule used to synthesize proteins from DNA. Cells are full of RNA molecules in complex and diverse forms, two main types being ribosomal RNA, or rRNA; and transfer RNA, or tRNA; which are involved in the synthesis of proteins.

Small RNAs play essential roles in health and diseases, including cancer, diabetes, neurological diseases, and infertility. Examples of small RNAs are microRNA; piwi-interacting RNA, or piRNA; and tRNA-derived small RNA, or tsRNA. Small RNAs can get modified by chemical groups and thus acquire new functions.

The development of high-throughput RNA sequencing technologies — useful for examining the quantity and sequences of RNA in a biological sample — has uncovered an expanding repertoire of small RNA populations that fine-tune gene expression and protect genomes.

“PANDORA-seq can be widely used to profile small RNA landscapes in various physiological and disease conditions to facilitate the discovery of key regulatory small RNAs involved in these conditions,” said Qi Chen, an assistant professor of biomedical sciences in the UCR School of Medicine, who led the study published today in Nature Cell Biology. “Modified small RNAs wear an ‘invisibility cloak’ that prevents them from being detected by traditional RNA-sequencing methods. How many such modified RNAs are there? What is the origin of their sequences? And what exactly is their biological function? These are questions PANDORA-seq may be able to answer.”

PANDORA-seq employs a stepwise enzymatic treatment to remove key RNA modifications, which then takes off the invisibility cloak used by the modified small RNAs.

“PANDORA-seq has opened Pandora’s box of small RNAs,” said Tong Zhou, a bioinformatician at the University of Nevada, Reno School of Medicine and a co-corresponding author of the study. “We can now dance with these once invisible partners in the RNA ballroom.”

According to Chen, PANDORA-seq uncovers a surprising small-RNA landscape that is dominated by tsRNAs and rRNA-derived small RNAs, or rsRNAs, rather than microRNAs, which were previously believed to dominate many mammalian tissues and cells.

“With PANDORA-seq, we found unprecedented microRNA/tsRNA/rsRNA dynamics when somatic cells are reprogrammed to induced pluripotent stem cells, which are generated by adult cells and have properties similar to those of embryonic stem cells, making them capable of differentiating into all cell types of the body,” said Sihem Cheloufi, an assistant professor of biochemistry at UCR and a co-corresponding author of the paper. “Some tsRNAs and rsRNAs can impact protein synthesis and even affect embryonic stem cell lineage differentiation in embryonic stem cells.”

Chen explained the current best-studied classes of small RNAs in mammals are microRNAs, which are abundant in mammalian somatic cells and control the kind and amount of proteins the cells make; and piRNAs, which are mainly expressed in the testis and modulate germ cell development.

“Currently, these small RNAs can be comprehensively profiled by high-throughput methods such as RNA sequencing,” he said. “However, the widely used small RNA sequencing protocols have intrinsic limitations, which prevent certain modified small noncoding RNAs from being detected during RNA sequencing. PANDORA-seq overcomes these limitations.”

Junchao Shi, a doctoral student working in Chen’s lab and the research paper’s first author is enthusiastic about the use of PANDORA-seq.

“The new method could revolutionize the view of small RNA landscapes,” he said. “Frankly, all previous studies using traditional RNA-sequencing may now need to be revisited.”

Cheloufi said the team now wants to understand how tsRNA/rsRNA are generated, how they function in stem cells, and how they orchestrate cell fate decisions during development.

“Answers to these questions are timely to develop diagnostic tools, identify therapeutic targets, and advance regenerative medicine,” she said.

While developing PANDORA-seq, Chen was reminded of the parable of the blind men and the elephant, which teaches truth is only revealed when various parts come together.

“We sometimes forget the big picture, being focused on just a small part of it,” he said. “Perhaps the only way to arrive at total truth — the big picture — is to push against our boundary of knowledge and confirm the revealed truth with newly devised technology.”

“It is fascinating to observe down the lenses of a microscope in the lab the profound cell fate change during cellular reprogramming and differentiation,” said Reuben Franklin, a doctoral student in Cheloufi’s lab and a coauthor on the study. “But PANDORA-seq allows us to eavesdrop on the molecular players during these processes.”

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Tadpole nerve regeneration capacity provides clue to treating spinal cord injury — ScienceDaily

Nagoya University researchers have identified a gene that plays a crucial role in regenerating neurons of African clawed frog tadpoles, which has an unusually high capacity for nerve regeneration. Their study, recently published in the journal iScience, showed that introducing the gene into mice with spinal cord injury (SCI) led to a partial recovery of their lost motor functions. These findings could contribute to the development of a new therapy for SCI, which often causes a person to experience permanent and severe physical and neurological disabilities.

Repairing spinal cord injuries in humans and other mammals is difficult, partly because of their limited ability to repair and regenerate neural tissues in the spinal cord. In contrast, there are animals with a high capacity for nerve regeneration, such as the African clawed frog. “As a tadpole, it is fully capable of functional recovery after a spinal cord injury,” said Drs. Dasfne Lee-Liu and Juan Larrain from the P. Universidad Catolica de Chile in their study, “Genome-wide expression profile of the response to spinal cord injury in Xenopus laevis reveals extensive differences between regenerative and non-regenerative stages,” published in 2014.

In this context, the Nagoya University research team conducted a collaborative study with Drs. Lee-Liu and Larrain to identify transcription factors that regulate nerve regeneration in the African clawed frog tadpole, with the aim of inducing regenerative effects in mammals. The team comprehensively analyzed the gene expression profiles of tadpoles in response to SCI, and found that a gene called Neurod4 was expressed predominantly during nerve regeneration. The team thus hypothesized that this gene is a key factor in the regeneration of neural tissues after an injury.

In this study, the team also focused on the fact that in mammals, neural stem cells (known as self-renewing cells) derived from the ependymal cells lining the central canal of the spinal cord are activated and proliferate in the early stage of SCI, although these types of neural stem cells eventually transform into astrocytes — a type of cell that forms rigid glial scars.

“Taking these things together, we thought that introducing Neurod4 into activated neural stem cells may help regenerate neurons,” said Associate Professor Atsushi Natsume of the Nagoya University Graduate School of Medicine, the corresponding author of the study.

To that end, the team conducted experiments in which the Neurod4 gene was introduced to activated neural stem cells in mice just after SCI. The researchers observed that the neural stem cells were successfully converted into neurons and, interestingly, the mice occasionally moved their paralyzed hind legs. Dr. Natsume explained, “Neurod4 introduced into activated neural stem cells facilitates the production of relay neurons, which project to motor neurons of the hind legs. As a secondary effect, glial scar formation was suppressed after the subacute phase of spinal cord injury. This effect allows an environment that was conducive for axons to elongate beyond the injury site and form synapses, thereby improving the motor function of the hind legs.”

“Our method is to introduce a neuro regenerative gene directly into neural stem cells that are already present in the spinal cord. This could lessen the problems of rejection and tumor formation, which often occur in conventional stem cell transplantation methods. We believe this study will contribute to the development of new therapeutic approaches to spinal cord injury,” he added.

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Regenerating hair follicle stem cells — ScienceDaily

Harvard University researchers have identified the biological mechanism of how chronic stress impairs hair follicle stem cells, confirming long-standing observations that stress might lead to hair loss.

In a mouse study published in the journal Nature, the researchers found that a major stress hormone causes hair follicle stem cells to stay in an extended resting phase, without regenerating the hair follicle and hair. The researchers identified the specific cell type and molecule responsible for relaying the stress signal to the stem cells, and showed that this pathway can be potentially targeted to restore hair growth.

“My lab is interested in understanding how stress affects stem cell biology and tissue biology, spurred in part by the fact that everyone has a story to share about what happens to their skin and hair when they are stressed. I realized that as a skin stem cell biologist, I could not provide a satisfying answer regarding if stress indeed has an impact — and more importantly, if yes, what are the mechanisms,” said Ya-Chieh Hsu, Ph.D., the Alvin and Esta Star Associate Professor of Stem Cell and Regenerative Biology at Harvard and senior author of the study. “The skin offers a tractable and accessible system to study this important problem in depth, and in this work, we found that stress does actually delay stem cell activation and fundamentally changes how frequently hair follicle stem cells regenerate tissues.”

The hair follicle is one of the few mammalian tissues that can undergo rounds of regeneration throughout life, and has become a paradigm that informs much of our fundamental understanding of mammalian stem cell biology. The hair follicle naturally cycles between growth and rest, a process fueled by hair follicle stem cells. During the growth phase, hair follicle stem cells become activated to regenerate the hair follicle and hair, and hairs grow longer each day. During the resting phase, the stem cells are quiescent and hairs can shed more easily. Hair loss can occur if the hairs shed and the stem cells remain quiescent without regenerating new tissue.

The researchers studied a mouse model of chronic stress and found that hair follicle stem cells stayed in a resting phase for a very long time without regenerating tissues. A major stress hormone produced by the adrenal glands, corticosterone, was upregulated by chronic stress; providing corticosterone to mice was able to reproduce the stress effect on the stem cells. The equivalent hormone in humans is cortisol, which is also upregulated under stress and is often referred to as the “stress hormone.”

“This result suggests that elevated stress hormones indeed have a negative effect on hair follicle stem cells,” Hsu said. “But the real surprise came when we took out the source of the stress hormones.”

Under normal conditions, hair follicle regeneration slows over time — the resting phase becomes longer as the animals age. But when the researchers removed the stress hormones, the stem cells’ resting phase became extremely short and the mice constantly entered the growth phase to regenerate hair follicles throughout their life, even when they were old.

“So even the baseline level of stress hormone that’s normally circulating in the body is an important regulator of the resting phase. Stress essentially just elevates this preexisting ‘adrenal gland-hair follicle axis,’ making it even more difficult for hair follicle stem cells to enter the growth phase to regenerate new hair follicles,” Hsu said.

After establishing the link between the stress hormone and hair follicle stem cell activity, the researchers looked for the biological mechanism underlying the connection.

“We first asked whether the stress hormone was regulating the stem cells directly and checked by taking out the receptor for corticosterone, but this turned out to be wrong. Instead, we found that the stress hormone actually acts on a cluster of dermal cells underneath the hair follicle, known as the dermal papilla,” said Sekyu Choi, Ph.D., the lead author of the study.

Dermal papilla is known to be critical for activating hair follicle stem cells, but none of the previously identified factors secreted from dermal papilla changed when stress hormone levels were altered. Rather, the stress hormone prevented dermal papilla cells from secreting Gas6, a molecule that the researchers showed can activate the hair follicle stem cells.

“Under both normal and stress conditions, adding Gas6 was sufficient to activate hair follicle stem cells that were in the resting phase and to promote hair growth,” Choi said. “In the future, the Gas6 pathway could be exploited for its potential in activating stem cells to promote hair growth. It will also be very interesting to explore if other stress-related tissue changes are related to the stress hormone’s impact on regulating Gas6.”

These initial findings in mice need to be further studied before they can be safely applied to humans. Harvard’s Office of Technology Development has protected the intellectual property relating to this work and is exploring opportunities for collaboration on its further development and eventual commercialization.

Last year, Hsu’s group discovered how stress affects another type of stem cell located in the hair follicle, the melanocyte stem cells that regenerate hair pigment. The researchers found that stress activates the sympathetic nervous system and depletes melanocyte stem cells, leading to premature hair graying. Now with the new study, the two findings together demonstrate that although stress has detrimental impacts on both hair follicle stem cells and melanocyte stem cells, the mechanisms are different. Stress depletes melanocyte stem cells directly via nerve-derived signals, while stress prevents hair follicle stem cells from making new hairs indirectly via an adrenal-gland-derived stress hormone’s impact on the niche. Because hair follicle stem cells are not depleted, it might be possible to reactivate stem cells under stress with mechanisms such as the Gas6 pathway.

Beyond the potential application of the Gas6 pathway in promoting hair growth, the study’s results also have broader implications for stem cell biology.

“When looking for factors that control stem cell behaviors, normally we would look locally in the skin. While there are important local factors, our findings suggest that the major switch for hair follicle stem cell activity is actually far away in the adrenal gland and it works by changing the threshold required for stem cell activation,” Hsu said. “You can have systemic control of stem cell behavior located in a different organ that plays a really important role, and we are learning more and more examples of these ‘cross-organ interactions.’ Tissue biology is interconnected with body physiology. We still have so much to learn in this area, but we are constantly reminded by our findings that in order to understand stem cells in the skin, we often need to think beyond the skin.”

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Scientists use nanotechnology to detect bone-healing stem cells — ScienceDaily

Researchers at the University of Southampton have developed a new way of using nanomaterials to identify and enrich skeletal stem cells — a discovery which could eventually lead to new treatments for major bone fractures and the repair of lost or damaged bone.

Working together, a team of physicists, chemists and tissue engineering experts used specially designed gold nanoparticles to ‘seek out’ specific human bone stem cells — creating a fluorescent glow to reveal their presence among other types of cells and allow them to be isolated or ‘enriched’.

The researchers concluded their new technique is simpler and quicker than other methods and up to 50-500 times more effective at enriching stem cells.

The study, led by Professor of Musculoskeletal Science, Richard Oreffo and Professor Antonios Kanaras of the Quantum, Light and Matter Group in the School of Physics and Astronomy, is published in ACS Nano — an internationally recognised multidisciplinary journal.

In laboratory tests, the researchers used gold nanoparticles — tiny spherical particles made up of thousands of gold atoms — coated with oligonucleotides (strands of DNA), to optically detect the specific messenger RNA (mRNA) signatures of skeletal stem cells in bone marrow. When detection takes place, the nanoparticles release a fluorescent dye, making the stem cells distinguishable from other surrounding cells, under microscopic observation. The stem cells can then be separated using a sophisticated fluorescence cell sorting process.

Stem cells are cells that are not yet specialised and can develop to perform different functions. Identifying skeletal stems cells allows scientists to grow these cells in defined conditions to enable the growth and formation of bone and cartilage tissue — for example, to help mend broken bones.

Among the challenges posed by our ageing population is the need for novel and cost-effective approaches to bone repair. With one in three women and one in five men at risk of osteoporotic fractures worldwide, the costs are significant, with bone fractures alone costing the European economy €17 billion and the US economy $20 billion annually.

Within the University of Southampton’s Bone and Joint Research Group, Professor Richard Oreffo and his team have been looking at bone stem cell based therapies for over 15 years to understand bone tissue development and to generate bone and cartilage. Over the same time-period, Professor Antonios Kanaras and his colleagues in the Quantum, Light and Matter Group have been designing novel nanomaterials and studying their applications in the fields of biomedical sciences and energy. This latest study effectively brings these disciplines together and is an exemplar of the impact collaborative, interdisciplinary working can bring.

Professor Oreffo said: “Skeletal stem cell based therapies offer some of the most exciting and promising areas for bone disease treatment and bone regenerative medicine for an aging population. The current studies have harnessed unique DNA sequences from targets we believe would enrich the skeletal stem cell and, using Fluorescence Activated Cell Sorting (FACS) we have been able to enrich bone stem cells from patients. Identification of unique markers is the holy grail in bone stem cell biology and, while we still have some way to go; these studies offer a step change in our ability to target and identify human bone stem cells and the exciting therapeutic potential therein.”

Professor Oreffo added: “Importantly, these studies show the advantages of interdisciplinary research to address a challenging problem with state of the art molecular/cell biology combined with nanomaterials’ chemistry platform technologies.”

Professor Kanaras said: “The appropriate design of materials is essential for their application in complex systems. Customizing the chemistry of nanoparticles we are able to program specific functions in their design.

“In this research project, we designed nanoparticles coated with short sequences of DNA, which are able to sense HSPA8 mRNA and Runx2 mRNA in skeletal stem cells and together with advanced FACS gating strategies, to enable the assortment of the relevant cells from human bone marrow.

“An important aspect of the nanomaterial design involves strategies to regulate the density of oligonucleotides on the surface of the nanoparticles, which help to avoid DNA enzymatic degradation in cells. Fluorescent reporters on the oligonucleotides enable us to observe the status of the nanoparticles at different stages of the experiment, ensuring the quality of the endocellular sensor.”

Both lead researchers also recognise that the accomplishments were possible due to the work of all the experienced research fellows and PhD students involved in this research as well as collaboration with Professor Tom Brown and Dr Afaf E-Sagheer of the University of Oxford, who synthesised a large variety of functional oligonucleotides.

The scientists are currently applying single cell RNA sequencing to the platform technology developed with partners in Oxford and the Institute for Life Sciences (IfLS) at Southampton to further refine and enrich bone stem cells and assess functionality. The team propose to then move to clinical application with preclinical bone formation studies to generate proof of concept studies.

The work has been possible through a BBSRC project grant to Professor Oreffo and Professor Kanaras.

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Opening the door for hematopoiesis research — ScienceDaily

Most people have heard of stem cells, cells from which all other cells with specialized functions are generated. Hematopoietic stem cells (HSCs) are the architects of blood cell development and are responsible for blood cell formation throughout the life of an organism. HSCs are also used in the treatment of cancer and immune disturbances.

Previous research into HSC transplantation has involved the use of adult and fetal mice. This has involved the removal of recipient HSCs using approaches including irradiation and the administration of DNA damaging drugs. In a first of its kind, researchers from the University of Tsukuba devised a novel approach for HSC deletion in mouse embryos. This report provides the first description of embryonic HSC depletion and transplantation of donor HSCs into the embryo via the placenta.

In describing their approach, Assistant Professor Michito Hamada says: “We were able to exploit the genetics of HSC development in mice to generate mice that completely lack HSCs in the fetal liver, making these mice the perfect recipients for HSC transplantation.” Mice lacking the Runx1 gene do not survive into adulthood and die at embryonic day 12.5, in part because they lack HSCs. The recipient mice developed by this team have Runx1 transgenes that partially restore the effects of Runx1 absence, and while these mice still lack HSCs, they can develop until embryonic day 18.5.

Using these recipient mice, the research team explored the effects of transplanting HSCs from the same species (allogenic) or from a different species (xenogeneic). The placentas of recipient mice were injected with donor HSCs at embryonic day 11.5, before the development of the immune system. Excitingly, over 90% the HSCs of recipient fetuses were from the donor, irrespective of species.

Analysis of the HSCs that developed in recipient mice after transportation revealed that they contributed to the development of both white and red blood cells. Furthermore, additional transplant of these cells into adult recipients revealed that the HSCs were functional and had retained normal abilities.

“These results are really exciting,” explains Professor Satoru Takahashi. “These mice represent a new tool that can be used to advance HSC research. The ability to perform HSC transplants at an earlier developmental stage really allows us to explore fetal hematopoiesis and, in the future, this model could be ‘humanized’ using human HSCs. The applications appear endless.”

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The advance could lead to the development of stem cell-based therapies for muscle loss or damage due to injury, age or disease — ScienceDaily

A UCLA-led research team has identified a chemical cocktail that enables the production of large numbers of muscle stem cells, which can self-renew and give rise to all types of skeletal muscle cells.

The advance could lead to the development of stem cell-based therapies for muscle loss or damage due to injury, age or disease. The research was published in Nature Biomedical Engineering.

Muscle stem cells are responsible for muscle growth, repair and regeneration following injury throughout a person’s life. In fully grown adults, muscle stem cells are quiescent — they remain inactive until they are called to respond to injury by self-replicating and creating all of the cell types necessary to repair damaged tissue.

But that regenerative capacity decreases as people age; it also can be compromised by traumatic injuries and by genetic diseases such as Duchenne muscular dystrophy.

“Muscle stem cell-based therapies show a lot of promise for improving muscle regeneration, but current methods for generating patient-specific muscle stem cells can take months,” said Song Li, the study’s senior author and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

Li and his colleagues identified a chemical cocktail — a combination of the root extract forskolin and the small molecule RepSox — that can efficiently create large numbers of muscle stem cells within 10 days. In mouse studies, the researchers demonstrated two potential avenues by which the cocktail could be used as a therapy.

The first method uses cells found in the skin called dermal myogenic cells, which have the capacity to become muscle cells. The team discovered that treating dermal myogenic cells with the chemical cocktail drove them to produce large numbers of muscle stem cells, which could then be transplanted into injured tissue.

Li’s team tested that approach in three groups of mice with muscle injuries: adult (8-week-old) mice, elderly (18-month-old) mice and adult mice with a genetic mutation similar to the one that causes Duchenne in humans.

Four weeks after the cells were transplanted, the muscle stem cells had integrated into the damaged muscle and significantly improved muscle function in all three groups of mice.

For the second method, Li’s team used nanoparticles to deliver the chemical cocktail into damaged muscle tissue. The nanoparticles, which are about one one-hundredth the size of a grain of sand, are made of the same material as dissolvable surgical stitches, and they are designed to release the chemicals slowly as they break down.

The second approach also produced a robust repair response in all three types of mice. When injected into injured muscle, the nanoparticles migrated throughout the injured area and released the chemicals, which activated the quiescent muscle stem cells to begin dividing.

While both techniques were successful, the key benefit of the second one is that it eliminated the need for growing cells in the lab — all of the muscle stem cell activation and regeneration takes place inside the body.

The team was particularly surprised to find that the second method was effective even in elderly mice, in spite of the fact that as animals age, the environment that surrounds and supports muscle stem cells becomes less effective.

“Our chemical cocktail enabled muscle stem cells in elderly mice to overcome their adverse environment and launch a robust repair response,” said Li, who is also chair of bioengineering at the UCLA Samueli School of Engineering and professor of medicine at the David Geffen School of Medicine at UCLA.

In future studies, the research team will attempt to replicate the results in human cells and monitor the effects of the therapy in animals for a longer period. The experiments should help determine if either approach could be used as a one-time treatment for patients with serious injuries.

Li noted that neither approach would fix the genetic defect that causes Duchenne or other genetic muscular dystrophies. However, the team envisions that muscle stem cells generated from a healthy donor’s skin cells could be transplanted into a muscular dystrophy patient’s muscle — such as in the lungs — which could extend their lifespan and improve their quality of life.

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New bioink brings 3D-printing of human organs closer to reality — ScienceDaily

Researchers at Lund University in Sweden have designed a new bioink which allows small human-sized airways to be 3D-bioprinted with the help of patient cells for the first time. The 3D-printed constructs are biocompatible and support new blood vessel growth into the transplanted material. This is an important first step towards 3D-printing organs. The new study has been published in Advanced Materials.

Chronic lung diseases are the third leading cause of death worldwide with an EU cost of more than €380 billion annually. For many chronic diseases there is no cure and the only end-stage option for patients is lung transplantation. However, there are not enough donor lungs to meet clinical demand.

Therefore, researchers are looking at ways to increase the amount of lungs available for transplantation. One approach is fabricating lungs in the lab by combining cells with a bioengineered scaffold.

“We started small by fabricating small tubes, because this is a feature found in both airways and in the vasculature of the lung. By using our new bioink with stem cells isolated from patient airways, we were able to bioprint small airways which had multiple layers of cells and remained open over time,” explains Darcy Wagner, Associate Professor and senior author of the study.

The researchers first designed a new bioink (a printable material with cells) for 3D-bioprinting human tissue. The bioink was made by combining two materials: a material derived from seaweed, alginate, and extracellular matrix derived from lung tissue.

This new bioink supports the bioprinted material over several stages of its development towards tissue. They then used the bioink to 3D-bioprint small human airways containing two types of cells found in human airways. However, this bioink can be adapted for any tissue or organ type.

“These next generation bioinks also support the maturation of the airway stem cells into multiple cell types found in adult human airways, which means that less cell types need to be printed, simplifying the nozzle numbers needed to print tissue made of multiple cell types,” says Darcy Wagner.

Wagner notes that the resolution needs to be improved to 3D-bioprint more distal lung tissue and the air sacks, known as alveoli, that are vital for gas exchange.

“We hope that further technological improvements of available 3D printers and further bioink advances will allow for bioprinting at a higher resolution in order to engineer larger tissues which could be used for transplantation in the future. We still have a long way to go,” she says.

The team used a mouse model closely resembling the immunosuppression used in patients undergoing organ transplantation. When transplanted, they found that 3D-printed constructs made from the new bioink were well-tolerated and supported new blood vessels.

“The development of this new bioink is a significant step forward, but it is important to further validate the functionality of the small airways over time and to explore the feasibility of this approach in large animal models,” concludes Martina De Santis, the first author of the study.

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

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