Brain cells are starved of energy when autophagy malfunctions, new … – University of Birmingham

Research has major implications for neurodegenerative disease treatments

Neurodegeneration in brain cells may be happening when the natural cellular cleaning process malfunctions due to falling levels of a niacin-related coenzyme and leaves cells starved of energy, new research shows.

Brain cells die from malfunction of autophagy, a process by which cells get rid of cellular waste and generate energy for their survival. In new research published in Cell Reports, researchers have found that a metabolic failure arising from loss of autophagy is detrimental to brain cells called neurons. When autophagy stops working, the levels of a coenzyme called nicotinamide adenine dinucleotide (NAD) falls, causing the cells to not be able to get enough energy to maintain normal function and to survive.

Researchers led by Dr Sovan Sarkar at the University of Birmingham along with his PhD students, Ms Congxin Sun and Dr Elena Seranova, and in collaboration with Prof. Rudolf Jaenisch at the Whitehead Institute for Biomedical Research, developed a human embryonic stem cell (hESC) model with deletion of a key gene involved in autophagy.

They generated neurons from these hESCs to understand how loss of autophagy kills brain cells. In autophagy-deficient neurons, depletion of NAD was identified to mediate cell death. The researchers found that upon loss of autophagy, NAD was consumed by hyperactivation of naturally occurring enzymes such as Sirtuins and PARPs.

Critically for brain health, dropping NAD levels resulted in undesirable electrical changes to mitochondria, leading to them not being able to function effectively and cells arent able to metabolise energy to continue to maintain homeostasis.

The researchers say that the findings of this neurotoxic pathway provide new clues about a way to combat neurodegenerative diseases, by showing that compounds boosting NAD levels can improve the survival of neurons with loss of autophagy.

....identifying that NAD levels are being depleted when autophagy malfunctions is a very important step in thinking about a way to manage decline in brain health both in older age and among at-risk populations.

Dr Sovan Sarkar, a Birmingham Fellow in the Institute of Cancer and Genomic Sciences at the University of Birmingham and lead senior author of the paper said:

We have shown a new mechanism of how brain cells are dying when autophagy stops working properly by using a hESC-derived neuronal model of autophagy deficiency. Autophagy is a critical process across all cells, especially in neurons, and identifying that NAD levels are being depleted when autophagy malfunctions is a very important step in thinking about a way to manage decline in brain health both in older age and among at-risk populations.

NAD can be boosted through the use of targeted therapeutics such as supplementation with NAD precursors like nicotinamide (NAM), nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), as well as through the consumption of vitamin B3 also called niacin.

Our research also identifies the potential for drugs that slow down the NAD-eating enzymes in the PARP and Sirtuin families, all of which could support healthy ageing and reduced risk of neurodegeneration.

The results suggest that among the many roles that autophagy plays, helping maintain the levels of NAD that supports cell metabolism is an important process for staving off neurodegeneration. It also provides new potential targets for future treatments for neurodegenerative diseases, both by targeting the enzymes (SIRT1 and 2 and PARP1 and 2) that ate up NAD and by supplementing NAD precursors.

Dr Viktor Korolchuk, Associate Professor at Newcastle University and a senior co-author of the paper said:

Both autophagy and NAD levels decline in our cells and tissues as we get older contributing to age-related diseases. Our study helps to explain how these processes are interlinked: loss of autophagy also causes depletion of NAD.

Our recent paper demonstrated this in yeast and mouse cells, and the current study in human cells unequivocally shows that this intimate link between autophagy and NAD can trigger the death of human neurons. This finding significantly adds to our understanding of ageing and age-related neurodegeneration and opens new avenues to explore.

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Brain cells are starved of energy when autophagy malfunctions, new ... - University of Birmingham

Developing cells likely can ‘change their mind’ about their destiny – Phys.org

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A neural crest cell (a type of stem cell) begins with the ability to differentiate into any number of specialist cell types, but it also appears to retain the capacity to "change its mind" and differentiate anew when the circumstances are right, according to new research from the University of Bath. As a result of this hyper-flexibility, the possibilities for these cells in replacing damaged human tissue is likely to be even greater than previously thought.

Neural crest cellsfound in very young embryos, and vital for determining the color of hair and skinare highly flexible by nature, giving rise to many different types of vital cells, including neurons. New research from the University of Bath suggests their flexibility remains greater than previously thought, a finding that has significant implications for regenerative medicine.

Until now, it was assumed that neural crest cells became committed to becoming a particular cell type very early, after which their fate was sealed. However, studies led by Professor Robert Kelsh from the Department of Life Sciences at Bath suggest they retain their adaptability even after they have become visibly differentiated.

This newly discovered flexibility helps explain why neural crest stem cellsan important type of stem cell that can also be readily isolated from adult skinhave immense potential as treatments to replace and repair damaged body tissue in many parts of the body.

The finding that even after choosing a destiny (for instance, developing into skin pigment cells), neural crest cells might be able to "change their mind" and choose a new destiny (perhaps becoming cartilage cells) reconciles a long-standing debate among biologists over the nature of neural crest cell differentiation.

In humans, neural crest cells are multipotent, meaning they are capable of developing into many different types of cell, including cells of the peripheral nervous system, cardiac muscle, and cartilage, as well as pigment cells in the skin and hair. These are all cells with highly specific functions.

Until now, two rival theories have sought to explain how, exactly, they pull this off.

"The question of how the fate of these cells becomes decided and restricted has been unclear and much debated for over 40 years," said Professor Kelsh.

According to the first theory, neural crest cells begin to commit to a specific role in the young embryo before leaving the place from which they arisethe neural tube (which develops into the brain and spine). The thinking goes that by the time they start migrating to their final destinationbe that the gut, skin, or connective tissuetheir destiny is already partially limited (i.e., some options are already off the table) and that more and more options become eliminated as they migrate.

The second theory posits that neural crest cells remain multipotent when they leave the neural tube and only commit to a specific differentiation path once they reach their destination.

There has been a general feeling in the field that the first model was the more accurate of the two. The new study published in Nature Communications, however, finds that neither of these "static" theories is correct.

"It would appear that these cells are choosing their fate in a much more dynamic, mobile way and are not narrowing their options irreversibly until much later than we previously thought," said Professor Kelsh. "This provides experimental biologists with a new, updated model to help them understand the behavior of neural crest cells."

It has long been known that neural crest cells use molecular signals from their environments to turn into one type of cell or another. However, Professor Kelsh's genetic work on zebrafisha freshwater fish with many genetic similarities to humansshows these steps are likely reversible: remove the signals and the cells revert to a more primitive state, where their potential to differentiate differently is restored.

Professor Kelsh said, "Our work shows these cells become biased by their environment. Take them out of that environment and they relax back to a more broadly competent state, likely capable of becoming anything."

He added, "Our findings will be of interest to other stem-cell researchers, as they give us a theoretical understanding of how neural crest cells might be used in medicine to repair any number of defects, from skin-pigmentation defects such as vitiligo to defects of the nervous system."

More information: Tatiana Subkhankulova et al, Zebrafish pigment cells develop directly from persistent highly multipotent progenitors, Nature Communications (2023). DOI: 10.1038/s41467-023-36876-4

Journal information: Nature Communications

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Developing cells likely can 'change their mind' about their destiny - Phys.org

Map of spinal cord formation gives new knowledge on diseases of … – EurekAlert

Researchers at Karolinska Institutet in Sweden have mapped how cells in the human spinal cord are formed in the embryo and what genes control the process. Their findings can give rise to new knowledge on how injury to and diseases of the spinal cord arise and how they can be treated. The study has been published in the journal Nature Neuroscience.

The spinal cord is part of the central nervous system, serving as an important bridge for communication between the brain and the rest of the body. There are many different types of cells in the human spinal cord but much still remains to be understood about how these cells are formed from stem cells during embryonic development.

Many neurodegenerative diseases and injuries of the spinal cord are incurable because of the poor regeneration of human spinal cord cells, says the studys first author Xiaofei Li, assistant professor at the Department of Neurobiology, Care Sciences and Society, Karolinska Institutet. A better grasp of how the spinal cord is formed and how different genes control this development can lead to new therapies for spinal cord injuries and diseases such as ALS or cancer of the nervous system.

User-friendly online tool

The researchers have built up an extensive map of all the cell types of the human spinal cord, showing where the cells are and what genes they express during embryonic development. The information has been gathered in a user-friendly interactive online tool that researchers or other interested parties can use to search for genes that shape how the spinal cord develops.

The study identified key genes that affect how the stem cells migrate when the spinal cord is formed and what specialisations they have. A comparison with spinal cord development in mice revealed important differences between mice and humans.

These findings are very important because much of what we already know is based on mouse studies, says Dr Li.

The study was conducted using single-cell RNA sequencing and spatial transcriptomics, which enabled the researchers to map thousands of genes in each individual cell and analyse how they are expressed at different sites of the same tissue section.

Learning more about child cancer

The researchers also studied an unusual tumour type called ependymoma, which manifests as malignant brain tumours in children or benign spinal cord tumours in adults. On identifying genes that are specific to tumour development they were thus able to demonstrate how their findings can be used to increase understanding of diseases of the nervous system.

Well now be interrogating how stem cells form different cell types and change their properties both during embryonic development and later during maturity and ageing, as well as in different kinds of pathological conditions, says the studys last author Erik Sundstrm, senior researcher at the Department of Neurobiology, Care Sciences and Society, Karolinska Institutet.

The study was financed by the Erling Persson Foundation, the Knut and Alice Wallenberg Foundation, Karolinska Institutet and SciLifeLab. Co-authors Zaneta Andrusivova, Ludvig Larsson and Joakim Lundeberg are consultants at 10x Genomics Inc., for which Mats Nilsson is also an advisor.

Publication: Profiling spatiotemporal gene expression of the developing human spinal cord and implications for ependymoma origin. Xiaofei Li, Zaneta Andrusivova, Paulo Czarnewski, Christoffer Mattsson Langseth, Alma Andersson, Yang Liu, Daniel Gyllborg, Emelie Braun, Ludvig Larsson, Lijuan Hu, Zhanna Alekseenko, Hower Lee, Christophe Avenel, Helena Kopp Kallner, Elisabet kesson, Igor Adameyko, Mats Nilsson, Sten Linnarsson, Joakim Lundeberg, Erik Sundstrm. Nature Neuroscience, online 24 April 2023, doi: 10.1038/s41593-023-01312-9.

Nature Neuroscience

Experimental study

Human tissue samples

Profiling spatiotemporal gene expression of the developing human spinal cord and implications for ependymoma origin

24-Apr-2023

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Map of spinal cord formation gives new knowledge on diseases of ... - EurekAlert

Cell Therapy Market to Witness Rapid Growth, Driven by Growing Applications in Oncology and Regenerative Medic – openPR

Global Cell Therapy Market report from Global Insight Services is the single authoritative source of intelligence on Cell Therapy Market. The report will provide you with analysis of impact of latest market disruptions such as Russia-Ukraine war and Covid-19 on the market. Report provides qualitative analysis of the market using various frameworks such as Porters' and PESTLE analysis. Report includes in-depth segmentation and market size data by categories, product types, applications, and geographies. Report also includes comprehensive analysis of key issues, trends and drivers, restraints and challenges, competitive landscape, as well as recent events such as M&A activities in the market.

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Cell therapy is a type of treatment that uses living cells to treat a disease or condition. The cells can be from the patient's own body, or they can be from a donor. Cell therapy is also called cellular therapy, cell transplantation, or regenerative medicine.

Key Trends:

The major factors driving the growth of this market are the increasing prevalence of cancer and chronic diseases, and the growing demand for personalized medicine.

However, the high cost of cell therapy treatments and the lack of skilled professionals are the major factors restraining the growth of this market.

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Key Drivers:

The key drivers of the cell therapy market are the increasing incidence of cancer, the rise in the aging population, and the growing demand for minimally invasive treatments.

The aging population is also a major driver of the cell therapy market, as the risk of developing cancer increases with age.

The demand for minimally invasive treatments is also growing, as patients seek to avoid the side effects of traditional cancer treatments such as chemotherapy and radiation therapy.

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Market Segments:

The cell therapy market is segmented by therapy type, therapeutic area, end-user, and region. By therapy type, the market is classified into autologous, and allogenic. On the basis of therapeutic area, it is bifurcated into malignancies, autoimmune disorders, dermatology, and others. Based on end-use, it is divided into hospitals, clinics, academic, and others. Region-wise, the market is segmented into North America, Europe, Asia Pacific, and Rest of the World.

Key Players:

The global cell therapy market includes players such as Allosource, Cells for Cells, Holostem Terapie Avanzate Srl, JCR Pharmaceuticals Co Ltd, Kolon Tissuegene Inc, Medipost Co Ltd, Mesoblast Ltd, Nuvasive Inc, Osiris Therapeutics, Inc, Stemedica Cell Technologies Inc, and others.

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The first babies conceived with a sperm-injecting robot have been born – MIT Technology Review

I was calm. In that exact moment, I thought, Its just one more experiment, says Eduard Alba, the student mechanical engineer who commanded the sperm-injecting device.

The startup company that developed the robot, Overture Life, says its device is an initial step toward automating in vitro fertilization, or IVF, and potentially making the procedure less expensive and far more common than it is today.

Right now, IVF labs are staffed by trained embryologists who earn upwards of $125,000 a year to delicately handle sperm and eggs using ultra-thin hollow needles under a microscope.

But some startups say the entire process could be carried out automatically, or nearly so. Overture, for instance, has filed a patent application describing a biochip for an IVF lab in miniature, complete with hidden reservoirs containing growth fluids, and tiny channels for sperm to wiggle through.

Think of a box where sperm and eggs go in, and an embryo comes out five days later, says Santiago Munn, the prize-winning geneticist who is chief innovation officer at the Spanish company. He believes that if IVF could be carried out inside a desktop instrument, patients might never need to visit a specialized clinic, where a single attempt at getting pregnant can cost $20,000 in the US. Instead, he says, a patients eggs might be fed directly into an automated fertility system at a gynecologists office. It has to be cheaper. And if any doctor could do it, it would be, says Munn.

MIT Technology Review identified a half-dozen startups with similar aims, with names like AutoIVF, IVF 2.0, Conceivable Life Sciences, and Fertilis. Some have roots in university laboratories specializing in miniaturized lab-on-a-chip technology.

So far, Overture has raised the most: about $37 million from investors including Khosla Ventures and Susan Wojcicki, the former CEO of YouTube.

The main goal of automating IVF, say entrepreneurs, is simple: its to make a lot more babies. About 500,000 children are born through IVF globally each year, but most people who need help having kids dont have access to fertility medicine or cant pay for it.

How do we go from half a million babies a year to 30 million? wonders David Sable, a former fertility doctor who now runs an investment fund. You cant if you run each lab like a bespoke, artisanal kitchen, and that is the challenge facing IVF. Its been 40 years of outstanding science and really mediocre systems engineering.

While an all-in-one fertility machine doesnt yet exist, even automating parts of the process, like injecting sperm, freezing eggs, or nurturing embryos, could make IVF less expensive and eventually support more radical innovations, like gene editing or even artificial wombs.

But it wont be easy to fully automate IVF. Just imagine trying to make a robot dentist. Test-tube conception involves a dozen procedures, and Overtures robot so far performs only one of them, and only partially.https://wp.technologyreview.com/wp-content/uploads/2023/04/robot-procedure-notext.mp4An video showing robotic fertilization of an egg at Overture Life Sciences. A vibrating needle pierces the egg, depositing a single sperm cell.

OVERTURE

The concept is extraordinary, but this is a baby step, says Gianpiero Palermo, a fertility doctor at Weill Cornell Medical Center who is credited with developing the fertilization procedure known as intracytoplasmic sperm injection, or ICSI, in the 1990s. Palermo notes that Overtures researchers still relied on some manual assistance for tasks like loading a sperm cell into the injector needle. This is not yet robotic ICSI, in my opinion, he says.

Other doctors are skeptical that robots can, or should, replace embryologists anytime soon. You pick up a sperm, put it in an egg with minimal trauma, as delicately as possible, says Zev Williams, director of Columbia Universitys fertility clinic. For now, humans are far better than a machine, he says.

His center did develop a robot, but it has a more limited aim: dispensing tiny droplets of growth medium for embryos to grow in. Its not good for the embryos if the drop size differs, says Williams. Creating the same drops over and over againthat is where the robot can shine. He calls it a low risk way to introduce automation to the lab.

One obstacle to automating conception is that so-called microfluidicsanother name for lab-on-a-chip technologyhasnt lived up to its hype.

Jeremy Thompson, an embryologist based in Adelaide, Australia, says hes spent his career figuring out how to make the lives of embryos better as they grow in laboratories. But until recently, he says, his tinkering with microfluidic systems yielded an unambiguous result: Bollocks. It didnt work. Thompson says IVF remains a manual process in part because no one wants to trust an embryoa potential personto a microdevice where it could get trapped or harmed by something as tiny as an air bubble.

A few years ago, though, Thompson saw images of a minuscule Eiffel Tower, just one millimeter tall. It had been made using a new type of additive 3D printing, in which light beams are aimed to harden liquid polymers. He decided this was the needed breakthrough, because it would let him build a box or a cage around an embryo.

Since then, a startup he founded, Fertilis, has raised a couple of million dollars to print what it calls see-through pods or micro-cradles. The idea is that once an egg is plopped into one, it can be handled more easily and connected to other devices, such as pumps to add solutions in minute quantities.

Inside one of Fertiliss pods, an egg sits in a chamber no larger than a bead of mist, but the container itself is large enough to pick up with small tongs. Fertilis has published papers showing it can flash-freeze eggs inside the cradles and fertilize them there, too, by pushing in a sperm with a needle.

A human egg is about 0.1 millimeters across, at the limit of what a human eye can see unaided. Right now, to move one, an embryologist will slurp it up into a hollow needle and squirt it out again. But Thompson says that once inside the companys cradles, eggs can be fertilized and grow into embryos, moving through the stations of a robotic lab as if on a conveyor belt. Our whole story is minimizing stress to embryos and eggs, he says.

Thompson hopes someday, when doctors collect eggs from a womans ovaries, theyll be deposited directly into a micro-cradle and, from there, be nannied by robots until theyre healthy embryos. Thats my vision, he says.https://wp.technologyreview.com/wp-content/uploads/2023/04/better-injection.mp4A video taken through a microscope shows a microneedle penetrating eggs held in 3D-printed pods, or cradles. An egg is about 0.1 mm across.

FERTILIS

MIT Technology Review found one company, AutoIVF, a spinout from a Massachusetts General HospitalHarvard University microfluidics lab, that has won more than $4 million in federal grants to develop such an egg-collecting system. It calls the technology OvaReady.

Egg collection happens after a patient is treated with fertility hormones. Then a doctor uses a vacuum-powered probe to hoover up eggs that have ripened in the ovaries. Since theyre floating in liquid debris and encased in protective tissue, an embryologist needs to manually find each one and denude it by gently cleaning it with a glass straw.

An AutoIVF executive, Emre Ozkumur, declined to discuss the projectthe company wants to stay under the radar a little bit longer, he saysbut its grant and patent documents suggest it is testing a device that can spot and isolate eggs and then automatically strip them of surrounding tissue, perhaps by swishing them through something that resembles a microscopic cheese grater.

Once an egg is in hand, doctors need to match it with a sperm cell. To help them pick the right one, Alejandro Chavez-Badiola, a fertility doctor based in Mexico, started a company, IVF 2.0, that developed software to rank and analyze sperm swimming in a dish. Its similar to computer-vision programs that track sports players as they run, collide, and switch directions on a pitch.

The job is to identify healthy sperm by assessing their shape and seeing how well they swim. Motility, says Chavez-Badiola, is the ultimate expression of sperm health and normality. While a person can only keep an eye on a few sperm at one time, a computer doesnt face that limit. We humans are good at channeling our attention to a single point. We can assess five or 10 sperm, but you cant do 50, says Chavez-Badiola.

His IVF clinic is running a head-to-head study of human- and computer-picked sperm, to see which lead to more babies. So far, the computer holds a small edge.

We dont claim its better than a human, but we do claim its just as good. And it never gets tired. A human has to be good at 8 a.m., after coffee, after having an argument on the phone, he says.

Chavez-Badiola says such software will be the brains to command future automated labs. This year, he sold the rights to use his sperm-tracking program to Conceivable Life Sciences, another IVF automation startup being formed in New York where Chavez-Badiola will act as chief product officer. Also joining the company is Jacques Cohen, a celebrated embryologist who once worked at the British clinic where the first IVF baby was born in 1978.https://wp.technologyreview.com/wp-content/uploads/2023/04/Conceivable-720.mp4A computer system developed by IVF 2.0 tracks and grades sperm as they swim, using image-recognition software.

CONCEIVABLE

Conceivable plans to create an autonomous robotic workstation that can fertilize eggs and cultivate embryos, and it hopes to demonstrate all the key steps this year. But Cohen allows that automation could take a while to become reality. It will happen step by step, he says. Even things that seem obvious take 10 years to catch on, and 20 to become routine.

The investors behind Conceivable think they can cash in by expanding the use of IVF. Its nearly certain that the IVF industry could grow to five or 10 times its current size. In the US, fewer than 2% of kids are born this way, but in Denmark, where the procedure is free and encouraged, the figure is near 10%.

That is the true demand, says Alan Murray, an entrepreneur with a background in software and co-working spaces who cofounded Conceivable with his business partner, Joshua Abram. The challenge is that these wonderful rich and eccentric countries can do it, but the rest of the world cannot. But they have demonstrated the true human need, he says. What they have done with money, we need to do with technology.

Murray estimates the average IVF baby in the US costs $83,000 if you include failed attempts, which are common. He says his companys objective is to lower the cost by 70%, something he says can happen if success rates increase.

But its not a given that robots will reduce the cost of IVF or that any savings will be passed on to patients. Rita Vassena, an advisor to Conceivable and CEO at Fecundis, a fertility science company, says the field has a history of introducing innovations without appreciably increasing pregnancy rates. The trend [is] toward piling up tests and technologies rather than a true effort to lower access barriers, she says.

Last fall, the researchers at Overture and doctors at New Hope published a description of their work with the robot, claiming that two patients had become pregnant. That was done after gaining ethics approval for the study, says John Zhang, founder of New Hope and senior author of the report.

Both those children have now been born, says Jenny Lu, the egg donation coordinator at New Hope. MIT Technology Review was able to speak to the father of one of the children.

Its wild, isnt it, said the father, who asked to remain anonymous. They said up until now it had always been done manually.

He said he and his partner had tried IVF several times before, without success. Both cases of robot injection involved donor eggs, which were provided to the patients for free (they can cost $15,000 otherwise). In each case, after being fertilized and grown into embryos, they were implanted in the uterus of the patient.

Donor eggs are most often used when a patient is older, in her 40s, and cant get pregnant otherwise.

Since automation wont directly solve the problem of aging eggs, an IVF lab-in-a-box wont fix this intractable reason that fertility treatments fail. However, automation could let doctors begin precisely measuring what they do, allowing them to fine-tune their procedures. Even a small increase in success rates could mean tens of thousands of extra babies every year.

Kathleen Miller, chief scientist of Innovation Fertility, a chain of clinics in the southern US, says her centers are now using computer-vision systems to study time-lapse videos of growing embryos and trying to see if any data explain why some become babies and others dont. Were putting it into models, and the question is Tell me something I dont know, she says.

Were going to see an evolution of what an embryologist is, Miller predicts. Right now, they are technicians, but theyre going to be data scientists.

For some proponents of IVF automation, an even wilder future awaits. By giving over conception to machines, automation could speed the introduction of still-controversial techniques such as genome editing, or advanced methods of creating eggs from stem cells.

Although Munn says Overture Life has no plans to modify the genetic makeup of children, he allows it would be a simple matter to use the sperm-injecting robot for that purpose, since it could dispense precise amounts of gene-editing chemicals into an egg. It should be very easy to add to the machine, he says.

Even more speculative technology is on the horizon. Fertility machines could gradually evolve into artificial wombs, with children gestated in scientific centers until birth. I do believe we are going to get there, says Thompson. There is credible evidence that what we thought was impossible is not so impossible.

Others imagine that robots could eventually be shot into outer space, stocked with eggs and sperm held in a glassy state of stasis. After a thousand-year journey to a distant planet, such machines might boot up and create a new society of humans.

Its all part of the goal of creating more people, and not just here on Earth. There are people thinking that humankind should be an interplanetary species, and human lifetimes are not going to be enough to reach out to these worlds, says Chavez-Badiola. Part of the job of a scientist is to keep dreaming.

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The first babies conceived with a sperm-injecting robot have been born - MIT Technology Review

Loss of autism-linked gene dampens social interactions in animals – Spectrum – Autism Research News

Stranger danger: Unlike wildtype mice (top row), those lacking GIGYF1 (bottom row) avoid unfamiliar mice (right) in favor of those they know (left), position heat maps show.

Mice and zebrafish that lack the autism-linked gene GIGYF1 show atypical social behaviors, according to a new study. The findings tie variations in the gene to social traits in autistic people, the researchers say.

Among the genes strongly linked to autism, GIGYF1 ranks as the second most commonly mutated one in people with autism and related neurodevelopmental conditions. But little is known about the genes contribution to autism traits, says Bo Xiong, professor of forensic medicine at Huazhong University of Science and Technology in China. Initial findings point to a role in regulating social behavior: Deleting the gene blunts social memory in mice, through mechanisms thought to be mediated by impaired insulin signaling.

GIGYF1 is also implicated in other pathways including autophagy and mRNA regulation that are often altered in people with neurodevelopmental conditions, says Jeremy Veenstra-VanderWeele, professor of developmental psychiatry at Columbia University, who was not involved in the study. But it had not previously been rigorously studied for its impact on neurodevelopment and downstream behavior, he says.

Xiong and his colleagues combed sequencing data from SPARK, a project that aims to collect genetic and clinical information from 50,000 families that have at least one child with autism. (SPARK is funded by the Simons Foundation, Spectrums parent organization).

They identified seven new GIGYF1 mutations and pooled the data with 19 previously reported variants. Cross-referencing with clinical information revealed that 86 percent of people with GIGYF1 mutations have autism. A similar proportion have communication difficulties and social phobia, alongside sleep problems and delayed speech.

Zebrafish embryos edited via CRISPR to lack GIGYF1 develop more slowly than their wildtype counterparts, Xiong and his colleagues found. As adults, the fish are more anxious and less willing to socialize.

Zebrafish are typically highly sociable: They rarely swim alone, preferring to travel in clusters called shoals. When placed in a three-chambered enclosure with a fish at one end and an empty chamber at the other, wildtype fish will opt for company. But fish lacking GIGYF1 prefer solitude and appear anxious, frequently darting around the tank. Whats more, they form looser shoals, maintaining more distance between themselves and others.

Mice engineered to express just one copy of the GIGYF1 gene also display social deficits. When the researchers tested for social novelty a mouses inclination to investigate a stranger over those it already knows the mutant mice stayed near the familiar mouse. GIGYF1 deletion also triggered repetitive behaviors, one of the core traits of autism.

The study plays to the strengths of each model, says Julia Dallman, associate professor of biology at the University of Miami in Florida, who was not involved in the study. For example, delayed embryogenesis is easier to spot in zebrafish, which develop outside their mothers body, than in mice. These different models can provide complementary windows of insight into gene function, she says.

But the fish could be tweaked to better reflect the genetics of autism, says Dallman. The study used zebrafish lacking both copies of GIGYF1, but people with the condition have one mutated copy and one functional copy.

Disrupting both gene copies is a good way to understand the biological importance of GIGYF1 but does not model the human condition, Veenstra-VanderWeele agrees.

Mice missing a copy of the gene in only their excitatory neurons still showed repetitive behaviors and impairments in social novelty. Yet deleting a copy of GIGYF1 in only inhibitory neurons triggered a different set of traits, including heightened anxiety and poorer cognition, suggesting that GIGYF1 plays distinct roles in different cell types.

The findings were published 14 March in Biological Psychiatry.

Exactly how GIGYF1 variants cause changes in social behavior remains an open question. Right now, we only know a small piece of the whole picture. We still dont know the exact molecular mechanisms by which these mutations cause behavioral defects, Xiong says.

Initial findings hint at changes in neuronal communication. By screening for transcripts and proteins that bind to GIGYF1, the researchers identified hundreds of downstream targets, including several involved in synaptic transmission. They are now harnessing electrophysiology to see how GIGYF1 deletion in mice influences neuronal chatter.

Because GIGYF1s function appears to be conserved among animal models, it would be interesting to see whether similar effects are seen in organoids and stem cells, says Ctia Igreja, a researcher at the Max Planck Institute for Biology in Tbingen, Germany, who was not involved in the study. If so, scientists may be able to pinpoint the GIGYF1s molecular mechanisms and identify potential therapeutic interventions that alleviate GIGYF1 deficiency, she adds.

Cite this article: https://doi.org/10.53053/GPMX9020

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Loss of autism-linked gene dampens social interactions in animals - Spectrum - Autism Research News

A burst of genomic innovation at the origin of placental mammals … – Nature.com

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A burst of genomic innovation at the origin of placental mammals ... - Nature.com

expert reaction to study looking at creating embryo-like structures … – Science Media Centre

April 6, 2023

A study published in Cell Stem Cell looks at the generation of embryo-like structures from monkey embryonic stem cells.

Prof Magdalena Zernicka-Goetz, Bren Professor of Biology and Biological Engineering, California Institute of Technology; and Professor of Mammalian Development and Stem Cell Biology, University of Cambridge, said:

This is an exciting development building on work from our own and other labs showing the importance of establishing interactions between embryonic and extra-embryonic stem cells to establish models of the mammalian embryo at pre-and early post-implantation stages. The excitement of this study is not only that embryos generated from monkey stem cells provide a close model for human embryos, but monkeys are also experimentally tractable.

The authors follow approaches that have been previously used to direct embryonic stem cells into a naive state, and then use treatments that allow the nave monkey ES cells to form extra-embryonic cell types. Together these cells assemble into blastoids, structures resembling blastocysts, that are able to develop in vitro into structures with a striking resemblance to the embryonic disc at gastrulation, both in morphology and gene expression. The blastoids also appear to implant into foster monkey mothers but, in common with similar structures in the mouse, development appears restricted.

This study is a hugely encouraging development in the study of primate embryo models.

The paper is excellent and an important step forward but still the stem cell derived embryos have a limited developmental potential, as the authors state themselves. Nevertheless, it is an important step in the very exciting field of enormous potential for understanding how the embryo develops and why so many pregnancies fail.

Prof Roger Sturmey, Professor of Reproductive Medicine, Hull York Medical School, University of Hull, said:

The work by Li and colleagues is an impressive technical achievement that has demonstrated the possibility that embryonic stem cells from a primate can be persuaded to form structures that mirror many features of early embryos.

Similar achievements have already been reported in other species, however this work assesses the primate embryo-like structures in detail and gives new insights into how the cell lineages families of cells that constitute the early embryo can be generated from stem cells.

Remarkably, when cultured in a laboatory, the embryo-like structures are able to replicate a number of key developmental features, most notably the formation of cells that resemble the primordial germ cells the cells that can produce gametes as well as the formation of a structure similar to the so-called primitive streak. When transferred into a recipient macaque uterus, these embryo-like structures were able to generate components of a pregnancy response, but were unable to develop, indicating that while these structures do share many features with competent embryos, there are still aspects of early development that differ between competent embryos and stem-cell derived models, preventing full development.

The work by Li and colleagues will offer important new tools in our understanding of the earliest stages of embryo development, but also highlight the need for guidance in this area, something that scientists in the UK are actively working on.

Prof Alfonso Martinez Arias, ICREA Senior Research Professor, Department of Experimental and Health Sciences, Universitat Pompeu Fabra (UPF), said:

This is a timely study.

About half of human pregnancies fail during the proliferation of the zygote and the implantation of the blastocyst. Understanding the causes of this failure rate will impact human fertility and IVF success. In part to address this need, over the last few years, a number of Embryonic Stem (ES) cell models of early mammalian development have been created in the lab. Amidst these, mouse and human blastoids mimic mammalian blastocysts and as such can play an important role in understanding the process of implantation. Blastoids have been derived from mouse and human ES cells.

For these studies to go forward there is a need to develop a proper test for the function of the blastocyst: its implantation into the uterus. In the case of mouse blastoids this can be tested by implanting them into females. However, there is no such a test for human blastoids since, for obvious reasons, it is not possible to implant them into a human uterus. And yet there is a need to develop a system to study these structures in humans. Mouse reproductive biology and implantation are very different from human, which means that while an excellent system to find principles, the mouse is not useful for the specifics of this process; and this is what matters. It is this vacuum of a system to study human implantation and peri-implantation development that is addressed in the present study.

Following protocols established for human blastoids, macaque blastoids are made from nave stem cells and their potential is tested in two ways. One, by culturing them in vitro up to gastrulation stages and the other, by placing them in the uterus of a macaque foster mother. The idea behind this system is that it has reduced ethical barriers compared to human and therefore might provide an experimental system to test the potential of blastoids fully and, in the long term, to study infertility. The work is well conducted and the result is clear: although at the level of single cells macaque blastoids bear a strong resemblance to blastocysts, they do not behave as blastocysts. Although they implant and initiate gastrulation, they do not reach the end of this process. In vitro, blastoids cultured to form an epiblast and to undergo gastrulation, display progressive problems over time and, though they reach early stages of gastrulation, it is difficult to see in their data how faithful they are to an early gastrula. In one important experiment they implant some of these into female macaques and follow their progress with ultrasound. It appears as if they might perform well in the early stages of implantation, and the release of progesterone is a sign that something has gone well, but then, they disappear after about a week.

So, the important result of this work is that we are not close to generating blastoids that can be recognised as blastocysts by the mother. Definitely an important proof of principle but the lesson is that there is work to do.

An important difference between a blastoid and a blatocyst is their origin. The blastocyst in the egg, the blastoid in the ES cells. There might be elements in the oocyte that are important for the viability of the blastocysts and that will not be provided by the ES cells. Furthermore, if about 50% of conceptions fail at implantation, it is difficult to gauge whether the failure of the high level goal of the experiment (long term development in the womb) is due to defects in the blastoid system or whether the failure mirrors the natural situation; eight experimental subjects, the numbers of the experiment, are not sufficient to make a judgement. Only more experiments will decide and the one reported here, within well established ethical footprints, is definitely one to watch.

Dr Darius Widera, Associate Professor in Stem Cell Biology and Regenerative Medicine, University of Reading, said:

This is an interesting study that demonstrates the successful generation of embryo-like structures from monkey embryonic stem cells. These structures resembled natural early embryonic structures and could generate cell types of all three germ layers. Although similar studies have been conducted using human stem cells, this is the first report showing that (in this case, monkey) embryo-like structures can induce signs of pregnancy if transplanted into females. Therefore, the method could be used as a model of primate and human development and potentially provide new insights into certain factors that contribute to miscarriages in humans.

However, the study has some limitations. Only 3 out of 8 embryo-like structures were successfully implanted into female monkeys, and none of these persisted for more than one week. Thus, the structures do not have full developmental potential.

In addition, the ethical implications of embryonic stem cell research in monkeys are complex. Primates are intelligent, social animals with complex cognitive and emotional lives. Therefore, it is important to carefully consider both the potential benefits and the ethical impact of primate embryonic stem cell research.

Prof Robin Lovell-Badge FRS FMedSci, Group Leader, Francis Crick Institute, said:

The paper by Jie Li et al is another demonstration of the remarkable ability of pluripotent stem cells, in this case embryonic stem cells derived from early Macaque (non-human primate) embryos, to self-organise and begin a process of embryo formation in culture that mirrors that of normal Macaque embryos. However, the paper also shows that these stem cell-based embryo models are not entirely normal they could be implanted in female macaques, appear to initiate a pregnancy, but then fail soon after.

The authors were able to culture these stem cell-based embryo models, which they refer to as blastoids, through to gastrulation stages, equivalent to post-implantation embryos developing in a uterus, with good signs of development of all the main extraembryonic and embryonic tissues, where the latter included ectoderm, mesoderm and endoderm organised in a similar fashion to normal embryos. They could also demonstrate the presence of primordial germ cell-like cells and cells that are early progenitors of the blood system. These stages would be equivalent to those of human embryos at about 16 -18 days of development, beyond the 14 day limit (or the beginning of gastrulation) which is the maximum period normal human embryos are allowed to be cultured by law in the UK and some other countries.

It has been shown by others that human pluripotent stem cells can also be used to form blastoids, but to date such cultures have been stopped prior to gastrulation, but the paper by Li et al suggests that they could indeed be taken beyond this and provide valuable information about these early stages of human development that are otherwise very difficult to obtain. The data from the Macaque embryos and blastoid cultures may also help to understand aspects of human development, but without direct comparisons this will always be tentative, given how much mammalian embryos can vary at these stages.

These embryo models are referred to as integrated stem cell-based embryo models because they include extraembryonic tissues that normally give rise to the placenta and yolk sac that in a normal conceptus would permit implantation into the uterus and support the development of the embryo proper. So how much like a real embryo are these Macaque blastoids and could they implant and develop much further in a uterus? Although all the detailed comparisons presented in the paper of gene expression in the various cell types between normal Macaque embryos and the embryo models suggests that they can be very similar, the proportion of the blastoids reaching advanced stages was very low, indicating that most are not normal, and those that did still showed some differences. Moreover, while some could implant, begin to develop some complexity, and induce a typical response in the host uterus and lead to production of the typical pregnancy hormones, chorionic gonadotrophin and progesterone, the embryos all failed before gastrulation. This suggests that they failed to form fully functional extraembryonic tissues that could adequately support the embryo and that these could not give rise to a placenta, which would be essential for more complex development. It is likely that the same would be true for human integrated stem cell-based embryo models, although it would be unethical and illegal (in the UK) to attempt to implant these into a woman.

It seems likely that the culture methods for these integrated stem cell-based embryo models will be improved, and who knows it may eventually be possible to have them implant and develop normally, but the failure of this to happen as reported in this paper will give regulators some breathing space to develop appropriate rules for the culture of such human models, notably whether they can be taken beyond the equivalent of gastrulation stages, which would be of immense importance in helping to understand not just normal development of the human embryo, but what so often goes wrong and leads to embryo failure and congenital disorders.

Cynomolgus monkey embryo model captures gastrulation and early pregnancy by Jie Li et al. was published in Cell Stem Cell at 16:00 UK time on Thursday 6 April 2023.

DOI: 10.1016/j.stem.2023.03.009

Declared interests

Prof Magdalena Zernicka-Goetz: I have no conflict of interest to declare.

Prof Roger Sturmey: None.

Prof Alfonso Martinez Arias: I have no conflict of interests.

Dr Darius Widera: I have no conflict of interest to declare.

Prof Robin Lovell-Badge: I have no conflicts of interest to declare, except I do serve on the HFEAs Scientific and Clinical Advances Advisory Committee and I am a member of their Legislative Reform Advisory Group.

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expert reaction to study looking at creating embryo-like structures ... - Science Media Centre

NANOG (Part 1): Its Role In Aging And Cancer – Forbes

eternal youth and the mythological island that NANOG protein was named after.Patrick Lynch, URL: https://www.irishcentral.com/roots/history/tir-na-nog-legend-eternal-youth

This is the first article in a series on the NANOG protein. Please see my companion series on klotho, another protein that may be involved in aging. You can read more about klotho in parts 1 and 2 of my series.

In Celtic mythology, Tr na ng is an island paradise and supernatural realm filled with everlasting youth, beauty, health, abundance, and joy. The inhabitants of Tr na ng consist of warriors and gods who are known for their poetry, music, and entertainment. By participating in the feast of Goibniu, the inhabitants of the island are granted immortality, giving Tr na ng its nickname The Land of Youth.

Now, studies report that a protein named after this Celtic taleNANOG may play a role in anti-aging and cancer prevention, but what is NANOG and why do researchers believe that it may prevent aging?

What is NANOG?

The key to NANOG and its biological function lies in our embryonic stem cells. Stem cells are a unique cell type, containing two characteristics that make them very powerful: pluripotency and the ability for self-renewal.

Pluripotency is the ability of stem cells to develop into many different tissues or cell types. While all embryonic stem cells are essentially the same basic cell, each stem cell has the potential to grow into nearly any tissue or cell type in the body. In other words, a single stem cell has multiple fates and depending on the environmental and chemical cues the stem cell is given, it can become anything from a brain cell to a muscle cell.

This becomes an especially important property when considering that stem cells have the ability to self-renew. Unlike many other cells, embryonic stem cells can simply divide to create multiples of themselves, allowing them to exist perpetually in the body so long as they can continue to self-renew.

What allows these stem cells to not only constantly regenerate, but to maintain their pluripotency? In other words, when new stem cells are created, what prevents them from spontaneously maturing into some form of adult cell?

Both pluripotency and self-renewal have been linked to a few, core transcription factors. Transcription factors are proteins in the body that control whether genes are turned on or off. Previous studies have found that the core transcription factors controlling stemness are Oct4, Sox2, Klf4, and NANOG.

How NANOG maintains pluripotency and self-renewal

An interesting aspect of NANOG is that it does not exist in adult cells. Instead, NANOG is only detected in stem cells that are still pluripotentthey have not begun to differentiate or develop into any particular cell type. Once a stem cell begins to differentiate, the NANOG gene is turned off and NANOG protein is no longer produced in the cell. Due to this observation, scientists suggest that NANOG may play a role in maintaining the pluripotency of stem cells, essentially preventing the stem cells from differentiating and maturing into adult cells.

There are three NANOG proteins that influence the pluripotency of human embryonic stem cells. These are Nanog1, Nanog2, and NanogP8. Researchers have found that when Nanog1 is abundant, it can prevent embryonic stem cells from differentiating. When the protein is scarce, embryonic stem cells tend to mature and differentiate into other cell types, losing their pluripotency.

NanogP8 is similar to Nanog1 except that it is mainly found in cancer cells, suggesting that NanogP8 may have larger anti-cancer properties than anti-aging properties.

How exactly could NANOG prevent stem cells from differentiating? While it is currently unclear what the biological mechanisms of NANOG are, two proteins that might offer a clue are leukemia inhibitory factor and STAT3. Both leukemia inhibitory factor proteins and STAT3 are widely known to prevent the differentiation of stem cells.

Leukemia inhibitory factor plays an important role in a wide array of biological processes including the growth of leukemia cancer cells and inflammation. The protein works primarily by controlling the activity of other transcription factors and proteins including STAT3. Researchers have found that when leukemia inhibitory factor levels drop and STAT3 activity decreases, stem cells begin to differentiate.

Interestingly, more recent experiments have shown that when NANOG is deficient, stem cells also differentiate. This occurs even in the presence of STAT3 and leukemia inhibitory factor, suggesting that NANOG may help maintain the pluripotency of stem cells by controlling the production and release of leukemia inhibitory factor and STAT3.

Additional studies focus on how NANOG may interact with other core transcription factors like Oct4 to prevent the differentiation of stem cells and maintain pluripotency. Researchers have suggested that NANOG and Oct4 may work together to control certain genes and proteins related to the pluripotency of stem cells. Oct4 is a transcription factor that is critically involved in the self-renewal of embryonic stem cells. Studies have shown that NANOG and Oct4 exhibit very similar patterns of behavior and often regulate similar genes in the body. This has led to the suspicion that NANOG and Oct4 may play a combined role in maintaining the pluripotency and self-renewal of embryonic stem cells.

Conclusion: NANOG in aging and cancer

While the biological mechanisms of how NANOG maintains the pluripotency of stem cells are unclear, it is evident that this small protein has an unusual ability to determine whether or not cells mature into different cell types. In the next installments of this short series, I will detail some of the more recent studies on NANOG, how the protein may prevent cellular aging, and how it could play a role in minimizing the growth of cancerous tumors.

I am a scientist, businessman, author, and philanthropist. For nearly two decades, I was a professor at Harvard Medical School and Harvard School of Public Health where I founded two academic research departments, the Division of Biochemical Pharmacology and the Division of Human Retrovirology. I am perhaps most well known for my work on cancer, HIV/AIDS, genomics and, today, on COVID-19. My autobiography, My Lifelong Fight Against Disease, publishes this October. I am chair and president of ACCESS Health International, a nonprofit organization I founded that fosters innovative solutions to the greatest health challenges of our day. Each of my articles at Forbes.com will focus on a specific healthcare challenge and offer best practices and innovative solutions to overcome those challenges for the benefit of all.

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NANOG (Part 1): Its Role In Aging And Cancer - Forbes

Regenerative Medicine Market Investments, Share and Revenue … – GlobeNewswire

Jersey City, NJ, April 12, 2023 (GLOBE NEWSWIRE) -- InsightAce Analytic Pvt. Ltd. announces the release of a market assessment report on the "GlobalRegenerative Medicine Market Size, Share & Trends Analysis Report By Product (Therapeutics, Primary cell-based therapeutics, Stem Cell & Progenitor Cell-based therapeutics), By Therapeutic Category (Dermatology, Musculoskeletal, Immunology & Inflammation, and Oncology)- Market Outlook And Industry Analysis 2031"

The global Regenerative Medicine market is estimated to reach over USD 183.08 billion by 2031, exhibiting a CAGR of 15.02% during the forecast period.

In recent year, it has been determined that regenerative therapies can uniquely change the underlying pathological processes. Trial-stage regenerative medicines offer promising treatments for particular chronic diseases with unmet medical needs. Novartis announced the release of T-ChargeTM in December 2021, a next-generation CAR-T platform that would be used for cutting-edge investigational CAR-T cell treatments.

Free PDF Report Brochure @https://www.insightaceanalytic.com/request-sample/1687

The development of gene-based treatment, which uses targeted DNA delivery as a drug to combat numerous illnesses, results from significant effects in molecular therapeutics. With the restoration of gene function, gene therapy holds great promise for treating cancer and type 1 and type 2 diabetes. Gene-based medicines treat patients with conditions such as cancer, oncology, infectious diseases, cardiovascular disorders, monogenic diseases, genetic disorders, ophthalmological indications, and central nervous system illnesses. These elements have helped the market for regenerative medicine expand.

Recent Developments:

In April 2022, Obecabatagene autoleucel, a CD19-directed autologous chimeric antigen receptor T therapy being investigated in the ongoing FELIX Phase 2 study of leukaemia, has been given the Regenerative Medicine Advanced Therapy designation by the U.S. Food and Drug Administration (FDA). This was announced by Autolus Therapeutics plc.

List of Prominent Players in the Regenerative Medicine Market:

Get Customized Report @https://www.insightaceanalytic.com/customisation/1687

Regenerative Medicine Market Report Scope:

Market Dynamics:

Drivers- The ability of adult stem cells to proliferate or self-renew forever and to develop all the cell kinds of the organ from which they originate has propelled research into these cells, with the potential to regenerate the complete organ from a few cells. No embryo must be destroyed in order to produce adult stem cells. Furthermore, medical research on stem cells has been thoroughly examined and attracted much attention. ExCellThera Inc. and Ossium Health recently announced a partnership to explore and advance opportunities to use adult stem cells from deceased donors from Ossium Health's first-ever bone marrow bank in combination with ExCellThera's ECT-001 cell expansion and rejuvenation technology. This collaboration will take place in April 2021. These kinds of developments are anticipated to accelerate market expansion.

Challenges:The market for regenerative medicine is projected to be hampered by a lack of information and moral considerations surrounding the usage of embryonic stem cells for research and development. Since cell therapy is a crucial component of regenerative medicine, it has a significant impact on the market growth rate. One of the leading market inhibitors may be the high cost of investment, which might be followed by problems with assay sensitivity, robustness, and reproducibility; the challenge of culture/propagation; and finally, the challenge of handling.

Regional Trends:Due to the presence of big players, the rapid advancement of technology, significant investments in stem cell and oncology research, and the presence of major players, North America is predicted to have the largest revenue share. The largest market in North America is the United States. In the U.S., numerous stem cell therapies are increasingly being used to treat a growing number of ailments like cancer and diabetes. According to the Heart Disease & Stroke Statistics Fact Sheet 2020, congenital heart abnormalities are predicted to affect at least 40,000 infants annually in the United States.

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Segmentation of Regenerative Medicine Market-

By Product-

By Therapeutic Category-

By Region-

North America-

Europe-

Asia-Pacific-

Latin America-

Middle East & Africa-

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Regenerative Medicine Market Investments, Share and Revenue ... - GlobeNewswire