Stem Cell Clinic

Turning Back the Clock on Aging Cells – The New York Times

Researchers at Stanford University report that they can rejuvenate human cells by reprogramming them back to a youthful state. They hope that the technique will help in the treatment of diseases, such as osteoarthritis and muscle wasting, that are caused by the aging of tissue cells.

A major cause of aging is thought to be the errors that accumulate in the epigenome, the system of proteins that packages the DNA and controls access to its genes. The Stanford team, led by Tapash Jay Sarkar, Dr. Thomas A. Rando and Vittorio Sebastiano, say their method, designed to reverse these errors and walk back the cells to their youthful state, does indeed restore the cells vigor and eliminate signs of aging.

In their report, published on Tuesday in Nature Communications, they described their technique as a significant step toward the goal of reversing cellular aging and could produce therapies for aging and aging-related diseases.

Leonard P. Guarente, an expert on aging at M.I.T., said the method was one of the most promising areas of aging research but that it would take a long time to develop drugs based on RNA, the required chemical.

The Stanford approach utilizes powerful agents known as Yamanaka factors, which reprogram a cells epigenome to its time zero, or embryonic state.

Embryonic cells, derived from the fertilized egg, can develop into any of the specialized cell types of the body. Their fate, whether to become a skin or eye or liver cell, is determined by chemical groups, or marks, that are tagged on to their epigenome.

In each type of cell, these marks make accessible only the genes that the cell type needs, while locking down all other genes in the DNAs. The pattern of marks thus establishes each cells identity.

As the cell ages, it accumulates errors in the marking system, which degrade the cells efficiency at switching on and off the genes needed for its operations.

In 2006 Dr. Shinya Yamanaka, a stem-cell researcher at Kyoto University, amazed biologists by showing that a cells fate could be reversed with a set of four transcription factors agents that activate genes that he had identified. A cell dosed with the Yamanaka factors erases the marks on the epigenome, so the cell loses its identity and reverts to the embryonic state. Erroneous marks gathered during aging are also lost in the process, restoring the cell to its state of youth. Dr. Yamanaka shared the 2012 Nobel Prize in medicine for the work.

But the Yamanaka factors are no simple panacea. Applied to whole mice, the factors made cells lose their functions and primed them for rapid growth, usually cancerous; the mice all died.

In 2016, Juan Carlos Izpisua Belmonte, of the Salk Institute for Biological Studies in San Diego, found that the two effects of the Yamanaka factors erasing cell identity and reversing aging could be separated, with a lower dose securing just age reversal. But he achieved this by genetically engineering mice, a technique not usable in people.

In their paper on Tuesday, the Stanford team described a feasible way to deliver Yamanaka factors to cells taken from patients, by dosing cells kept in cultures with small amounts of the factors.

If dosed for a short enough time, the team reported, the cells retained their identity but returned to a youthful state, as judged by several measures of cell vigor.

Dr. Sebastiano said the Yamanaka factors appeared to operate in two stages, as if they were raising the epigenomes energy to one level, at which the marks of aging were lost, and then to a higher level at which cell identity was erased.

The Stanford team extracted aged cartilage cells from patients with osteoarthritis and found that after a low dosage of Yamanaka factors the cells no longer secreted the inflammatory factors that provoke the disease. The team also found that human muscle stem cells, which are impaired in a muscle-wasting disease, could be restored to youth. Members of the Stanford team have formed a company, Turn Biotechnologies, to develop therapies for osteoarthritis and other diseases.

The study is definitively a step forward in the goal of reversing cellular aging, Dr. Izpisua Belmonte said.

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Turning Back the Clock on Aging Cells - The New York Times

A New Way to Study HIV’s Impact on the Brain – Global Health News Wire

By culturing astrocytes, microglia, and neuronsall derived from human-induced pluripotent stem cellsin one dish, researchers have created an effective model to study the cognitive impacts of HIV and other diseases. (Image: Sean Ryan)

Though many negative repercussions of human immunodeficiency virus infection can be mitigated with the use of antiretroviral therapy (ART), one area where medical advances havent made as much progress is in the reduction of cognitive impacts. Half of HIV patients have HIV-associated neurocognitive disorders (HAND), which can manifest in a variety of ways, from forgetfulness and confusion to behavior changes and motor deficiencies.

To better understand the mechanisms underlying HAND, researchers from Penns School of Dental Medicine and Perelman School of Medicine and from the Childrens Hospital of Philadelphia (CHOP) brought together their complementary expertise to create a laboratory model system using three of the types of brain cells thought to be involved. Led by doctoral student Sean Ryan, who was co-mentored by Kelly Jordan-Sciutto of Penn Dental Medicine and Stewart Anderson of CHOP and Penn Medicine, the model recapitulates important features of how HIV infection and ART affect the brain.

Frankly the models we generally use in the HIV field have a lot of weaknesses, says Jordan-Sciutto, co-corresponding author on the paper, which appears in the journalStem Cell Reports. The power of this system is it allows us to look at the interaction between different cell types of human origin in a way that is more relevant to patients than other models.

In addition to studying HIV, members of the team plan to use the same model to shed light on the neurological mechanisms that underlie other conditions, such as schizophrenia, Alzheimers, and even normal aging.

Were collaborating with a variety of colleagues to use this system to study Alzheimers disease as well as schizophrenia, says Anderson, co-corresponding author on the paper. We have the components in a dish that we know are interacting in these diseases, and this gives us a new mix-and-match way to understand how certain cells are contributing to neuronal damage.

Indeed, the impetus to create the model grew not out of HIV research but work that Ryan was pursuing in Andersons lab on schizophrenia.

We had been looking at the role of microglia, the resident immune cells of the central nervous system, says Ryan, first author on the work. We wanted to see if we could see the mechanistic changes that occur with microglia in schizophrenia.

To do so, Ryan and Anderson were interested in using human-induced pluripotent stem cellsadult cells that are reprogrammed to resemble embryonic stem cellswhich can be coaxed into differentiating into a variety of different cell types.

But schizophrenia is a complicated disease with a variety of contributing genetic and environmental factors and a broad spectrum of presentations. Rather than looking at something complex, they sought to apply their new system to a disease that likewise causes neurological damage but does so in a more dramatic way and in which microglia are also implicated: HIV/AIDS infection.

They reached out to Jordan-Sciutto, who has deep experience investigating the mechanisms of HAND and was eager for the opportunity to develop a model superior to those currently available. Together, the scientists identified the three cell types they were most interested in studying: neurons, astrocytes, and microglia.

Neurons arent directly infected by HIV but are known to be damaged during infection. Meanwhile astrocytes are believed to interact with neurons, causing damage by sending pro-inflammatory factors into the spaces between cells, called synapses. And microglia, which are responsible for maintaining a healthy environment in the absence of disease, are seen to expand and contribute to inflammation during HIV infection.

After nailing the technical challenge of creating this tractable model in which each cell type is generated independently and then mixed together, the team used it to probe how HIV infection and ART impact the cells, both alone and in combination.

A lot of people are taking PreEP [pre-exposure prophylaxis] if theyre in a situation where their risk of contracting HIV is heightened, says Ryan. Just as we want to understand the cognitive impacts of HIV, we also want to see whether these drugs alone are impacting the brain health of otherwise healthy people.

The researchers looked at RNA expression in their cultures to get a sense of what proteins and signaling pathways were becoming activated in each scenario. During infection, they saw inflammatory pathways that had previously been implicated in HIV in earlier research. When they introduced the antiretroviral drug EFZ, which is not in common use in the United States but remains a frontline therapy in many other areas of the world, with an infection, the activity of most of these pathways was reduced.

But this scenario involved its own unique response, says Ryan. Certain pathways associated with inflammation and damage remained despite the introduction of EFZ.

EFZ treatment of the tri-cultures that included HIV-infected microglia reduces inflammation by around 70%, Ryan says. Interestingly, EFZ by itself also triggered inflammation, though to a lesser extent than infection.

It seems a combination of infection and ART is creating its own unique response that is different from the sum of its parts, Ryan says. Knowing what pathways are still active due to ART could help us appropriately target additional therapies so patients dont develop HAND.

Many features of infection seen in the three-cell culture mirror what is known from HIV infection and ART treatment in people, giving the researchers confidence in the reliability of their model.

Just looking at the microglia, says Anderson, we see in our system that they are taking on both of their normal roles in keeping key signaling systems balanced during their normal state and activating and causing damage when theyre fighting infection. Were able to model normality and abnormality in a way we havent been able to before.

For Jordan-Sciutto, the new system is really going to change the way my lab operates going into the future. Shes hopeful many other HIV scientists will take it up to further their studies as she also explores more aspects of HIVs impact on the brain, such as how it navigates through the blood-brain barrier that normally protects the central nervous system from inflammation and infection.

The study authors give credit to the collaborative environment at Penn for this cross-disciplinary project. Tentacles of this project extend from CHOP to the dental school to the vet school to the medical school, says Anderson. Penn is a very special place where people seem to be more likely to share their technologies around and let other people work with and develop them. This project is a great example of that.

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A New Way to Study HIV's Impact on the Brain - Global Health News Wire

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Human Embryonic Stem Cell Market Analysis and Forecasts to 2027 By Recent Trends, Developments In Manufacturing Technology And Regional Growth...

Laboratory model looking at how a HIV infection impacts the brain – Health Europa

The Human Immunodeficiency Virus (HIV) infection impacts the human body in a variety of ways, however medical advances have made progress in mitigating the impact of the infection using antiretroviral therapy (ART). One area of impact which is yet to see much progress is the impact of the infection on cognition.

Half of HIV patients have HIV-associated neurocognitive disorders (HAND), which can manifest in a variety of ways, from forgetfulness and confusion to behaviour changes and motor deficiencies.

To better understand the mechanisms underlying HAND, researchers from Penns School of Dental Medicine and Perelman School of Medicine and from the Childrens Hospital of Philadelphia (CHOP) brought together their complementary expertise to create a laboratory model system using three of the types of brain cells thought to be involved.

Led by doctoral student Sean Ryan, who was co-mentored by Kelly Jordan-Sciutto of Penn Dental Medicine and Stewart Anderson of CHOP and Penn Medicine, the model recapitulates important features of how HIV infection and ART affect the brain.

The research was published in the journal Stem Cell Reports.

Jordan-Sciutto, co-corresponding author on the paper, said: Frankly the models we generally use in the HIV field have a lot of weaknesses. The power of this system is that it allows us to look at the interaction between different cell types of human origin in a way that is more relevant to patients than other models.

Anderson, co-corresponding author on the paper, said: Were collaborating with a variety of colleagues to use this system to study Alzheimers disease as well as schizophrenia.

We have the components in a dish that we know are interacting in these diseases, and this gives us a new mix-and-match way to understand how certain cells are contributing to neuronal damage.

We had been looking at the role of microglia, the resident immune cells of the central nervous system, says Ryan. We wanted to see if we could see the mechanistic changes that occur with microglia in schizophrenia.

Ryan and Anderson were interested in using human-induced pluripotent stem cells, which are adult cells that are reprogrammed to resemble embryonic stem cells, and which can be coaxed into differentiating into a variety of different cell types.

The scientists identified the three cell types they were most interested in studying: neurons, astrocytes, and microglia.

Neurons arent directly infected by HIV but are known to be damaged during infection. Meanwhile astrocytes are believed to interact with neurons, causing damage by sending pro-inflammatory factors into the spaces between cells, called synapses. Microglia, which are responsible for maintaining a healthy environment in the absence of disease, are seen to expand and contribute to inflammation during HIV infection.

A lot of people are taking PreEP [pre-exposure prophylaxis] if theyre in a situation where their risk of contracting HIV is heightened, says Ryan. Just as we want to understand the cognitive impacts of HIV, we also want to see whether these drugs alone are impacting the brain health of otherwise healthy people.

The researchers looked at RNA expression in their cultures to see what proteins and signalling pathways were becoming activated in each scenario. During infection, they saw inflammatory pathways that had previously been implicated in HIV in earlier research. When they introduced the antiretroviral drug EFZ, which is not in common use in the United States but remains a frontline therapy in many other areas of the world, with an infection, the activity of most of these pathways was reduced.

Ryan said: EFZ treatment of the tri-cultures that included HIV-infected microglia reduces inflammation by around 70%.

It seems a combination of infection and ART is creating its own unique response that is different from the sum of its parts. Knowing what pathways are still active due to ART could help us appropriately target additional therapies so patients dont develop HAND.

Many features of infection seen in the three-cell culture mirror what is known from HIV infection and ART treatment in people, giving the researchers confidence in the reliability of their model.

Just looking at the microglia, says Anderson, we see in our system that they are taking on both of their normal roles in keeping key signalling systems balanced during their normal state and activating and causing damage when theyre fighting infection. Were able to model normality and abnormality in a way we havent been able to before.

For Jordan-Sciutto, the new system is really going to change the way my lab operates going into the future.

She is hopeful many other HIV scientists will take it up to further their studies as she also explores more aspects of HIVs impact on the brain, such as how it navigates through the blood-brain barrier that normally protects the central nervous system from inflammation and infection.

In addition to studying HIV, members of the team plan to use the same model to shed light on the neurological mechanisms that underlie other conditions, such as schizophrenia, Alzheimers, and even normal ageing.

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Laboratory model looking at how a HIV infection impacts the brain - Health Europa