It Isn’t All In The Genes – Are We Inheriting More Than We Think?

Scientists have made a groundbreaking discovery about the mechanisms of healthy development in embryos, which could change our understanding on what we inherit from parents and how they shape us. The new research suggests that mothers may be passing on more of their DNA than we thought, with an epigenetic legacy for future generations.

It’s a recently discovered phenomenon called “epi-genetics”. The study, led by researchers from WEHI in Melbourne, Australia has significantly broadened our understanding of which genes have information passed down through generations and what proteins control this unusual process.

We all know that our genetics determine who we are, but what if there were other factors involved? DNA contains the instructions for producing all cells in your body. It’s really hard to change yourself and pass on these new changes because they happen through alterations of chromatin structure around genes which cause them not to be read by protein-coding regions any longer – so no products get made! This means you can have different versions or “epigenes” depending how much nutrition improves during development.

And it turns out that mothers can pass on their genes through epigenetics to a tiny extent. This means we need more research into how this works and what other factors come in play when determining whether or not an individual will have certain traits based off the DNA they’ve been given at birth. The new research has shown that a mother’s supply of protein can affect the genes which drive skeletal patterning in their offspring.

The discovery that mother’s DNA contains information passed on through generations has a deep impact on how we view ourselves. With this new understanding, there are many more questions than answers about what other types of environmental factors can affect our development and future health risks.

Researchers have recently discovered a new link between the mother’s eggs and her developing baby. This study focused on one protein, SMCHD1; it was found by Professor Blewitt back in 2008! The researchers wanted to see what would happen if they decreased or increased this level within an ovo- fertilized embryo before birth via maternal transfer. They monitored how many different types of Hox genes were activated throughout development as well because these play important roles during patterning for elegant structural formation.

It has been shown that mothers pass on their epigenetic information, rather than just the blueprint of genes. This is fascinating knowledge that we can now put to use. While there are more than 20,000 genes in our genome-the average human possesses around 150 of these coding regions which carry genetic information produced by mutation or choice over time. “This is the first time that we’ve seen this type of inheritance happen in human beings,” said Dr. Benetti, “and it gives us an idea about how few genes really matter over long periods.”

Research has shown that a gene called SMCHD1, which only exists in the fertilized egg after two days of conception and is unique to humans as well as other animals, can have an impact on life-long health problems. This discovery could help women with these variants live more comfortable lives by providing them opportunities for treatment options through our drug design efforts at WEHI.

To view the original scientific study click below:
Maternal SMCHD1 regulates Hox gene expression and patterning in the mouse embryo

Growing Transplantable Arteries From Stem Cells

From the early 1900’s blood banks have been crucial in medical care. A team is now wanting to take the concepts a step further by utilizing stem cells in creating new arteries for people that have cardiovascular diseases. They have discovered a drug that might help decrease complications in people who undergo bypass surgery.

There are 2 cellular building blocks of arteries that are functional, one of which is smooth muscle cells. A team was able to perfect the process of building them by using pluripotent stem cells along with a drug called RepSox. The identical compound may additionally lower the risk of a possibly dangerous complication that is frequently seen in people who undergo restorative surgeries like stents, balloon angioplasty and arterial disease bypass surgery.

The team used single cell CRISPR-Cas9 and single cell RNA sequencing to determine the pathways that can control differentiation of arterial endothelial cells, which are pillars of arteries. From manipulation of the pathways they were successful at generating arterial cells that were functional. They focused on cells that are smooth muscle.

Growth factors that have been widely used for production of smooth muscle cells from stem cells can account for an irregular thickening known as intimal hyperplasia. Initial hyperplasia can lead to blood vessel narrowing known as restenosis. It is a frequent problem in differentiation of smooth muscle cells and if you want an artery that is useful, you do not want this risk.

Restoring the contractile ability of cells that are smooth muscle and hence facilitate better flow of blood, the team utilized high throughput screening in order to find small molecules that can overcome the problem. RepSox emerged from 4,804 different drugs. In comparison to frequently used growth factors, they discovered that RepSox inhibited intimal hyperplasisa in a rat balloon model of injury and it is less expensive and more stable.

The team thinks RepSox may additionally serve as a medication to treat restenosis in people after surgery. At the present, there are 2 FDA approved medications to address the problems and they are not cell type specific leading to side effects. The team found that RepSox suppresses intimal hyperplasia with fewer side effects.

It is hard to repair the cardiac system when damages occur, therefore, scientists are looking into various regenerative methods. One team discovered a protein known as CXCL12 could grow ancillary arteries when the major arteries of the heart are blocked. It has been found that the Hippo signaling pathway, which controls the size of organs and cell death, can prevent damage to heart muscles from repairing themselves. When the team silenced it, the heart’s ability to pump in mouse models that had heart failure was restored.

From this study the team is now nearing their goal of building arteries, but there is still lots of work ahead. This cell type is an improvement from earlier efforts, but it still isn’t mature. The team needs to generate these cells to become more mature which would make them like a native artery and make it more functional.

To view the original scientific study click below:
A Human Pluripotent Stem Cell-Based Screen for Smooth Muscle Cell Differentiation and Maturation Identifies Inhibitors of Intimal Hyperplasia

New Way to Generate Human Heart Cells from Stem Cells

A new study is trying to understand early heart disease and development in relation to the mechanisms that determine cell fate. PSCs, or human pluripotent stem cells can conceivably produce a tissue the human body needs for repair. But developing technology for this to happen for a specialized cell, for example a beating heart muscle cell, has required intricate knowledge of developmental pathways and regulatory factors.

Although there has been important technological advances, types of cells that are obtained from human PSCs are still functionally immature. For example, in a human beating heart muscle cell (cardiomyocyte), the applications are limited in disease modeling and regenerative medicine. The cells that are generated don’t fully portray those that are found in the adult heart but are instead more similar to a fetal heart that is 20-weeks old.

The team utilized mouse embryo and cardiomyocytes to look into mechanisms that determine the fate of cells by modulating the peroxisome proliferator activated receptor (PPAR) signaling pathway. It plays a vital role in the development of cardiomyocytes to repeat in culture, and the cell in the womb to maturate and to progress to its specialization.

They were able to identify a response from isoform specific maturation, where PPARdelta signaling activation had the ability to augment the structural, metabolic and contractile maturation of hPSC-CMs. This being the first incident where PPAR signaling has been decoded in such an isoform specific way.

The specificity of PPARdelta, however, not PPARalha to show such an efficient effect on cardiac maturation was unexpected. The new strategy for maturation provided an easy and robust way to generate in culture mature heart cells. These can be used for a variety of applications such as disease modeling, drug screening or therapy for cell replacement in failing hearts.

The researchers were able to identify how the protein PPARdelta played a role by inducing a metabolic receptor from glycolysis to fatty acid oxidation in a heart muscle that was lab generated. This is a vital step in the controls and maturation no matter if these cells produce energy from fatty acids or glucose.

They showed that the signaling of PPARdelta plays an important role. It has the ability to turn on gene regulatory networks which increase the organization and number of mitochondria and peroxisomes, fatty acid oxidation, myofibril lay out, the contractility and the size of heart muscle cells.

To purify hPSC-CMs they are exposed to lactate and this treatment will trigger an independent molecular reaction for maturation of heart cells. In the study, the team exhibited lactate treatment along with activation of PPARdelta that increased further oxidative metabolism which allows energy generation from both fatty acids and carbohydrates.

The team developed a publicly and comprehensive accessible gene expression dataset of transcriptomic changes in hPSC-CMs which might be valuable to scientists studying PPAR lactate selection, PPAR signaling, or screening targets for drug or research testing.

The team is interested in analyzing disorders of fatty acid oxidation. This will depend on having CMs that primarily utilize fatty acid oxidation as a source of energy. They will investigate using the mature hPSC-CMs in transplants following an infarct.

The work will expand opportunities to further research biology of the human heart through multi-disciplinary avenues that incorporate transcriptomics, developmental biology, drug testing, and contractile measurements. They are headed to understanding how to use their knowledge of human development in order to improve access to human cell types that are mature.

To view the original scientific study click below:
PPARdelta activation induces metabolic and contractile maturation of human pluripotent stem cell-derived cardiomyocytes

How the Intestine Repairs and Replaces Itself

It is known that the intestinal lining needs to regenerate daily to be a powerful barrier to counter pathogens while allowing nutrients to be absorbed. The responsibility for this comes from the intestine’s stem cells. They need to meet a level of constant replenishment and repair. But, for this to happen, the stem cell needs to decide if the conditions of the intestine are receptive. If the stem cell makes the wrong decision or coordinates it poorly, intestinal cancer or diseases could occur.

From new research, it has been suggested that intestinal stem cells get cues from the surrounding area to decide what to do. They can then coordinate their activity over tissue through vasculature networks in the same area.

The team discovered that lymphatic capillaries, which are fine vessels responsible for transporting immune cells and draining tissue fluids, are a signaling station that communicate to the stem cell in order to control their action. From lymphatic molecular guidance, the stem cell produces daughter cells that can either self-renew to add to the reserve of stem cells or repopulate the intestinal lining.

The discoveries help understand how primary intestinal components communication disruption may add to intestinal disorders such as inflammation of the bowel. The solution to treating various diseases will be to find out who communicates with whom in this ecosystem and how it is able to reset communication networks.

Stem cells of the intestine live in crypts that reside at the bottom of thickly packed depressions in the lining of the intestine. The stem cells can stay in the crypt through renewal, or form into cells that are differentiated into specialized cells that can migrate out of the crypt replenishing the lining of the gut. In order to discern how a stem cell can balance self renewal with differentiation, there needs to be a complete profile of crypt niches.

In order to analyze the crypt, the researchers utilized various techniques which included single cell and spatial transcriptomics, allowing the team to identify types of cells at certain locations to study their signaling molecules. Results indicated that lymphatic capillaries will assemble a personal connection to the stem cells contained in the crypt and produce a variety of proteins which are crucial for their function.

One earlier protein, REELIN, appeared to be the main candidate for negotiating communication between stem cells and lymphatics. Through manipulation of the amount of REELN in laboratory grown organoid cultures in some of the experiments and genetically suppressing it in mice in other experiments, the team found the REELIN specifically controls the regenerative behavior of the stem cells in the intestine.

The lymphatic system involvement of the stem cells function is a new concept. An earlier study by the team disclosed that lymphatics are also involved closely with skin stem cells and play a crucial role in their regeneration. This leads to the suggestion that the lymphatics could be a core feature of niches of stem cells, however, their relationship to stem cells are probably tailored to the requirements of each tissue.

To view the original scientific study click below:
Lymphatics act as a signaling hub to regulate intestinal stem cell activity

People Generate Their Own Oxidation Field Changing Air Chemistry

The indoor environment is usually more dangerous than the outdoors, with 90% of people’s time spent indoors. Chemicals from a variety of sources such as outdoor pollutants can seep into your home and cause problems for you there too! When it comes to health risks our bodies are constantly being bombarded by new chemicals – some good (like oxygen), others bad such as viruses or bacteria which want nothing better then an opportunity to live off of us. You might be surprised to learn that we are extremely harmful traveling emission sources of chemicals, including those found in our skin and breath.

The answer to why our atmosphere bothers cleaning up after us is that it’s a living thing. Atmospheric chemicals react with each other and rain to disappear. The sun UV light and water vapor in the air react with each other, forming molecules which then attach themselves (and any dirt) onto these reactive ingredients as “detergents.” These detergent-like components are mostly made when solar radiation strikes oxygen or hydrogen gas present amongst other things found on earth.

Indoor air is affected by rain and direct sunlight. UV rays are mainly filtered out through glass windows, so it’s been assumed that concentration of OH radicals in indoor environments isn’t as high compared to outdoor ones. This may be due mostly because there are no strong sources like solar radiation or wild fires burning nearby which can produce abundant quantities of ultra-violet light (which we know cause damage). It also seems likely than any ozone leaking into a building from outdoors will combine with other chemicals found inside a building.

OH radicals are a byproduct of skin oils and the ozone, which can be created indoors just due to people. It has now been discovered that humans are able to transform these reactive chemicals themselves- meaning we have even more control than previously thought over how much damage will be done or protective measures taken against it! The shape and strength of its oxidation field can be determined by things like ventilation patterns or space configuration. The research team found that even outside daytime concentrations of OHs were comparable.

The reaction of unsaturated fats and oil with ozone can be quite harmful to your skin, releasing a host of squalene degradation products. One type in particular is double-bonded gas phase chemicals that react further when exposed to the airfield generating OH radicals which have been shown as an important factor for aging signs such as wrinkles or age spots due their ability to damage DNA molecules by breaking apart hydrogen bonds between bases pairs. This study measured each individual level while also determining how much total reactivity there was so we could quantify what impact this has overall over time.

When scientists tested four different people to see how well they responded in an environment with higher indoor levels of ozone, they found that not only did all participants experience adverse effects such as headaches and difficulty breathing but even those who arrived without any pre-existing medical conditions experienced these same symptoms. The team monitored each individual’s OH value before their stay began along side assessments made at regular intervals during it.

To understand how the human activated OH field compared under a variety of conditions, results from an elaborate multiphase chemical kinetic model were connected with computational fluid dynamics models. The modeling team found that the human generated field varied under a variety of conditions, beyond those tested in lab. From their results it is clear OH radicals are abundant and present forming durable spatial gradients.

The model developed by this team has been the first of its kind that can accurately predict chemical processes happening at both molecular scales (in terms of individual molecules) as well room-sized regions. It does make sense why OH would be generated from your skin reaction when reacting with air particles; they’re essentially just small versions of you!

The team’s work has found that OH can oxidize many more spaces than ozone, which creates a myriad of products right in our immediate surroundings. These impacts on health are unknown as they have not yet been studied experimentally or clinically but could be serious due to how much time we spend near chemical signals like those present from plastics and other chemicals.

The research published today has implications for our health. Chemical emissions from a variety of furniture and materials are being tested before they can be approved to sell. It would also be wise to conduct tests in the presence of ozone because oxidation processes may generate respiratory irritants such as 4-oxopentanal or other OH radical generated oxygenated species that could have negative effects, especially on children.

To view the original scientific study click below:
The human oxidation field

Eating More Protein Will Not Enlarge Muscles Without Exercise

It has been found from reviewing 49 studies from 1800 weightlifters that increasing protein intake by double the amount increased strength by 9% and added about 1 lb of muscle growth. The participants worked out for 6 weeks and lifted weights at least twice per week.

The amount of protein used in the studies was the recommended dietary allowance (RDA), which is 0.4 grams for the average person per pound of body weight. When working out with strength training and increasing protein intake it was found that any additional gain in muscle strength levels off at 0.7 grams. The extra protein consumed presented less muscle growth with aging.

The researchers found that the type of protein consumed, whether dietary or from supplements, made no difference in the amount of muscle gained. You do need more protein when trying to increase muscle growth, but consuming more than double the RDA did not change the outcome.

To add additional muscle growth, it was found that going to the gym and performing resistance exercises is what increases muscle growth. It could be beneficial to consume up to twice the protein but any extra amounts of protein from any source did not grow larger muscles. Maximum muscle can be gained from eating protein up to 50-70 grams per day.

From 15 previous studies it was shown the supplementing protein for older weightlifters offered no benefit. You cannot just eat extra protein and expect to increase muscle. With aging, almost any person will lose muscle strength and size. But you can decrease this loss brought on by aging with performing resistance exercises on a regular basis.

When you work a muscle it breaks down. In order for it to heal and grow any combination of foods that contain protein and sugar will promote healing. Protein can be found in nuts and seeds, beans and all animal products such as dairy products, eggs, fish, poultry and meat. A variety of these foods can meet the protein needs for muscle growth.

To view the original scientific study click below:
A systematic review, meta-analysis and meta-regression of the effect of protein supplementation on resistance training-induced gains in muscle mass and strength in healthy adults

Regenerating Muscle Repair with Hyaluranic Acid

New research has identified how cells communicate to repair muscle damage. When a muscle is damaged, stem cells and immune cells work together to repair the damage. But how these cells interact to complete the removal process of dead tissue and make new muscle fibers had been a mystery. Scientists have discovered that hyaluranic acid is the essential molecule that contributes to this interaction.

Hyaluranic acid is a natural substance and is currently used in beauty treatments and osteoarthritis injections. The new study shows it is the secret ingredient that communicates to muscle cells when to start repair. When muscle cells are damaged, it is critical for immune cells to rapidly enter the tissue to remove any damage so that stem cells can begin the repair process.

The research shows that the stem cells in muscles are prepared to begin repair instantly, but the immune cells keep the stem cells in a state of rest while they complete the cleanup job. This takes approximately 40 hours. Once this process is complete there is an internal alarm that wakes up the muscle stem cells and communicates to them to begin the repair process.

The damaged muscle stem cells must work in unison with immune cells to complete the process of repair. It is important for immune cells to quickly enter the tissue to remove the damage before stem cells can begin repair. When damage to muscles occur, stem cells begin coating and producing themselves with hyaluranic acid. When this coating is thick enough, it shuts down the immune cells sleep signal and wakes up the muscle stem cells.

From the use of human and mouse tissues, the team additionally discovered how stem cells in muscle control production of hyaluranic acid using epigenetic marks on the Has2 gene.

Aging is linked with muscle weakness, chronic inflammation, and a decreased ability of muscle stem cells to start the repair of any damage. If a way can be found to enhance the production of hyaluranic acid in the muscle stem cells of aged adults it might assist with repairing the muscle.

The team notes that the regenerative benefit of hyaluranic acid might depend on its production by the stem cells in the muscle. They are now examining drugs that can regulate the epigenetics of stem cells in muscle that may be used to increase the production of hyaluranic acid.

To view the original scientific study click below:
JMJD3 activated hyaluronan synthesis drives muscle regeneration in an inflammatory environment

Hip Implants from Cartilage Grown from Stem Cells

A new study has found a way to program stem cells in order to grow new cartilage on a 3-D template of the hip joint ball. This cartilage releases anti-inflammatory molecules that assist in fending off new arthritis occurrences. The new technology could supply an alternative to traditional hip replacement surgery and could remove the need for surgery for joint replacement surgery in some people.

The team has developed a means to resurface an arthritic joint with a person’s very own stem cells to grow new cartilage. When combined with gene therapy it can release molecules that are anti-inflammatory in an effort to stave off arthritis. Hopefully this could delay or prevent the normal plastic or metal prosthetic joint replacement.

The cartilage is made with the person’s own stem cells which are taken from fat found beneath the skin. A 3-D biodegradable synthetic scaffold is then molded into the shape of the joint of the patient. It is then covered with the cartilage and implanted onto the arthritic joint surface. The process helps to alleviate pain from arthritis and might delay or remove the necessity for hip replacement surgery.

Utilizing gene therapy, the developers were able to place anti-inflammatory molecules in the hip to fend off arthritis reoccurrence. As inflammatory molecules rise, cartilage in joints can be destroyed leading to an increase in pain, which this gene therapy can help deter.

If a patient has inflammation, they can be given a simple drug activating the gene that has been implanted, to decrease the joint inflammation. The drug can be stopped at any moment, which will turn off the gene.

The scaffold is made utilizing a weave of about 600 biodegradable fiber bundles. The weaving pattern gives the scaffold the properties and structure that can be found in normal cartilage. The implants have the ability to load up to 10 times a person’s body weight.

Currently, customized implants are being tested in lab animals using the stem cell based tissue. If they are successful, we could see some devices ready for human testing in 3 to 5 years.

To view the original scientific study click below:
Anatomically shaped tissue-engineered cartilage with tunable and inducible anticytokine delivery for biological joint resurfacing

New Discovery For Hair Follicle Life and Death

Hair follicle cells divide and die. But a new study has discovered a single chemical called TGF-beta that determines when this happens. It could ultimately treat baldness and may speed wound healing. Since follicles are a stem cell source they have the unique capability to be able to turn into other types of cells. This stem cell adaptability creates a path for repair of tissues and organs that have been damaged.

Hair follicles are the one organ in the human body that automatically regenerate periodically without injury. Therefore, this was the ideal organ for the research team to study. They determined how TGF-beta, which is a type of protein, controls the division of hair follicles or orchestrates its death.

TGF-beta has two roles at play in the hair follicle. The first role is to divide and produce new life in the hair follicle and the second is that it helps orchestrate cell death. The team found that the amount of this chemical is what makes the difference in life or death of the hair follicle. A certain amount and the cell divides, but too much and it causes apoptosis, or death.

But the death of a hair follicle does not kill the stem cell reservoir. The cell eventually receives a signal to regenerate and then it divides, makes a new cell and a new follicle is developed. If the scientists can figure out how TGF-beta activates cell division through communicating with other distinct genes, there is the possibility to activate follicle stem cells and stimulate hair growth.

The researchers hope in the future they can precisely determine how the TGF-beta activates the cell to divide. It could potentially lead to a cure of baldness and a variety of other problems.

To view the original scientific study click below:
A probabilistic Boolean model on hair follicle cell fate regulation by TGF-B

Relational Memory Benefits From Sleep

While we sleep there are brain circuits and neuron learning connections that are active. They help us establish differences between items that are unrelated. The ability to remember indirect or arbitrary links between people, objects or events is called relational memory. This is what helps you put names with faces, find your keys or remember to turn off the stove before you leave the house.

It has been established that human and animal memory receives benefits from quality and sufficient sleep. New research is showing the hidden mechanisms that create or strengthen new relational memories while you sleep.

The researchers made an artificial model of 2 different areas of the brain. The cortical, which is involved in learning, memory and making decisions, and the thalamic, which has to do with prior sensory processing. The model simulated 2 major states of the brain. The first is awake, when the neurons are automatically optimized and active to generate sensory input. The second is deep sleep, when inherent oscillations of electrical activity is processed, such as waves that are slow.

The network model properties were able to be changed to generate transitions from asleep activity and awake activity comparable to brain activity every day.

In the region that is cortical, the neuron connections were able to become weaker or stronger dependent on their activity. This is called synaptic plasticity, and reflects the primary biological mechanism of the way memories are erased or formed.

The team modeled the cortex following visual processing, with one cortical layer which represented primary visual cortex and another layer which represented associative cortex. Each time one sees the exact object, the same neurons in the cortex that was visual was active. If someone sees two objects in the exact context, then these links might be learned in the cortex that is associative through strengthening connections between neurons that represent the two objects.

The team trained the network in the awake mode to determine direct links, such as A+B or B+C but not A+C, then found that in sleep, the model made indirect associations of A+C.

This occurred because during sleep the neurons which represented all three related items (A, B & C), automatically fired in close order that was temporal. This phenomenon is known as sleep replay and triggers synaptic plasticity and leads to the formation of powerful synaptic connections between all the neurons. This means that following sleep, activating any one of the groups such as A, activated all the other related groups – B and C.

The work is primarily conceptual, but the team states the work has implications that are real world. One that is important in the study is in informing studies of disease in the future – such as autism spectrum disorder and schizophrenia. Studies show that people who have these conditions do worse on relational memory tasks and also have sleep that is disrupted and that is slow wave.

The study has suggested the focus on improving sleep that is slow wave, which would alleviate some of the symptoms that are cognitive and associated with theses conditions, might be a more fruitful forward path rather than focusing exclusively on the cognitive symptoms.

The team notes that sleep quality and memory function do decline with the aging process, however current or even new technologies that augment sleep oscillations might help improve and protect functions of memory in the older population.

To view the original scientific study click below:
Role of Sleep in Formation of Relational Associative Memory

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