By Arthur Hirsch

Sure, you know how old you are, but what about your cells? Are they the same age? Are they older, younger? Why does it matter?

Led by scientists at Johns Hopkins University, a team of researchers is reporting progress in developing a method to accurately determine the functional age of cells, a step that could eventually help clinicians evaluate and recommend ways to delay some health effects of aging and potentially improve other treatments, including skin graft matching and predicting prospects for wound healing.

The more accurate system could eventually enable clinicians to see aging in cells before a patient experiences age-related health decline, or help clinicians produce more successful skin grafts by matching cell characteristics of the donor and the graft site.

In the current issue of Nature Biomedical Engineering, lead author Jude M. Phillip, who conducted this research while completing his doctorate in chemical and biomolecular engineering at Johns Hopkins, reports success in creating a system that considers a wide array of cellular and molecular factors in one comprehensive aging assessment.

These results show that the biophysical qualities of cells, such as cell movements and structural features, make better measures of functional age than other factors, including cell secretions and cell energy.

The multidisciplinary team of engineers and clinicians examined dermal cells from just underneath the surface of the skin taken from both males and females between the ages of 2 and 96.

The researchers from Johns Hopkins, Yale University, and the National Cancer Institute of the National Institutes of Health hoped to devise a system that, through computational analysis, could take the measure of various factors of cellular and molecular functions. From that information, they hoped to determine the biological age of individuals more accurately using their cells, in contrast to previous studies, which makes use of gross physiology, or examining cellular mechanisms such as DNA methylation.

"We combined some classic biomolecular hallmarks of aging, and sought to further elucidate the role of biophysical properties of aging cells, all in one study," said Phillip, now a post-doctoral fellow at Weill Cornell Medicine.

Researchers trying to understand aging have, up until now, focused on factors such as tissue and organ function and on molecular-level studies of genetics and of epigenetics, meaning heritable traits that are not traced to DNA. The level in betweencellshas received relatively little attention, the researchers wrote.

This research was meant to correct for that omission by considering the biophysical attributes of cells, including such factors as the cells' ability to move, maintain flexibility, and structure. This focus emerges from the understanding that changes associated with aging at the physiological levelsuch as diminished lung capacity, grip strength, and mean pressure in the arteries"tend to be secondary to changes in the cells themselves, thus advocating the value of cell-based technologies to assess biological age," the research team wrote.

Older cells, for example, are more rigid and do not move as well as younger cells, which, among other consequences, most likely contributes to the slower wound healing commonly seen in older people.

For example, older cells are more rigid and do not move as well as younger cells, which, among other consequences, most likely contributes to the slower wound healing commonly seen in older people, said Denis Wirtz, the senior author and Johns Hopkins' vice provost for research. Wirtz and Phillip conducted their research in the Johns Hopkins Institute for NanoBioTechnology.

From the analysis, they were able to stratify individuals' samples into three groups: those whose cells roughly reflected their chronological age, those whose cells were functionally older, and those whose cells were functionally younger. The results also showed that the so-called biophysical factors of cells determined a more accurate measure of age than biomolecular factors such as cell secretions, cell energy, and the organization of DNA.

Phillip explained that this better accuracy from the biophysical factors most likely results from the orchestration of many biomolecular factors. He compared it to the more complete picture you get looking at a forest from a distance without binoculars.

"With binoculars you can see details about the individual trees, the color and shapes of the leaves, the roughness of the bark, the type of tree, but without the binoculars you can now see the density of the trees, and whether there is a barren plot, or a group or dying trees," Phillip said. "This is something you may miss with the binoculars, unless you are looking at the correct spot."

The more accurate system could eventually enable clinicians to see aging in cells before a patient experiences age-related health decline. This in turn could allow doctors to recommend treatments or changes in life habits, such as exercise or diet changes, Wirtz said. Phillip said the work could potentially help clinicians produce more successful skin grafts by matching cell characteristics of the donor and the graft site. Other potential applications range from toxicology screening for cosmetics and topical therapeutics to predicting progression of some age-related diseases.

The researchers acknowledge that the system needs further testing with a larger cell sample, but the results are robust and encouraging. Conducted along with clinicians such as Jeremy Walston, the Raymond and Anna Lublin Professor of Geriatric Medicine, and co-director of the Biology of Healthy Aging program at the Johns Hopkins School of Medicine, this work promises to allow clinicians to measure a person's health in the present and the future.

"It opens the door to finally be able to track how a person is doing at the cellular level," Wirtz said.

Added Phillip: "This platform is also more than just a cellular age predictor; it has the ability to do so much more in terms of assessing an individual's cellular health."

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How old are your cells? New method determines cell age more accurately, could help elderly patients - The Hub at Johns Hopkins

When the Japanese researcher Shinya Yamanaka managed to reprogram adult cells into an embryonic-like state to yield induced pluripotent stem cells (iPSCs), this was supposed to herald a revolution in regenerative medicine. But 10 years after their discovery, a therapeutic breakthrough is still outstanding.

The overall stem cell therapy field has failed today to show a very clear cut clinical benefit, told me Georges Rawadi, VP for Business Development at Celyad. The field now needs some significant success to attract attention.

Even though investors prefer placing their bets on the hot T cell therapies these days, some stem cell technologies such as iPSCs are starting to get traction as big industry players are exploring the territory. Last year, Bayer and Versant threw $225M into the pot to launch BlueRock Therapeutics, a regenerative medicine company that plans to develop iPSC-based therapies. A year before, Fujifilm spent $307M to acquire the iPSC company Cellular Dynamics.

Although a big success story is still lagging behind, recent advances in the field argue that stem cells indeed have the potential to translate into effective therapies for currently intractable diseases. Heres an overview of what biotechs stem cells are up to!

Stem cell treatment is not a new concept hematopoietic stem cells (HSCs) were described as early as the 1960s and bone marrow transplants have been used to treat blood cancer for decades.

The reason that we get excited about stem cell therapies comes from our experience with the hematopoietic stem cells. If you want to see what a mature stem cell therapy is like, you only need to look at bone marrow transplantation explained James Peyer, Managing Partner at Apollo Ventures, who has a Ph.D. in stem cell biology.

According to Peyer, the hematopoietic stem cell field is one of the most active areas in the stem cell world right now, mainly fueled by our advances in the gene editing space. Tools like CRISPR and TALEN allow for the genetic modification of a patients own bone marrow stem cells, which can then be expanded and returned to the patient for the correction of a genetic defect.

Last year, regulators gave green light to one of the first therapies of this kind. Strimvelis, developed by GSK, consists of an ex vivo stem cell gene therapy to treat patients with the very rare type of Severe Combined Immunodeficiency (SCID). Using the patients own cells avoids the risk of graft versus host disease (GvHD), which still affects around 30% of people receiving a bone marrow transplant.

Small wonder that the CRISPR companies, CRISPR Therapeutics, Editas, and Intellia are all active in this field, with preclinical programs in a number hematological diseases.

To date, the most prominent stem cells in the clinic are mesenchymal stem cells (MSCs), which are moving through more than 300 registered clinical trials for a wide array of diseases. These cells are able to form a variety of tissues including bone, cartilage, muscle or fat, and can be readily harvested from patients or donors for use in autologous or allogeneic therapies.

While MSCs have deluded the biotech scene with good safety profiles in clinical trials, their actual regenerative potential remains controversial, and there have been a great number of clinical failures, which many blame on a lack of demonstrated mechanisms of action.

As Peyer explained, The problem here is that, as opposed to other adult stem cells, the MSC has been unclearly defined. We know roughly what it does but we dont fully understand the molecular mechanisms driving these cells. On top of being unclearly defined, the regenerative powers of MSCs have been massively over-claimed in the past.

Another reason for the lack of clinical benefit has also been attributed to the use of undifferentiated MSCs, as Rawadi explained to me. The Belgian biotech Celyad, which has been pioneering cell therapy in the cardiovascular space, is using bone-marrow derived autologous MSCs and differentiates them into cardiomyocyte precursors to produce new heart muscle in patients with heart failure.

Although the company missed its primary endpoint in a phase III trial last year, Celyad has staked out a patient subpopulation that showed significant improvement. Its technology still has the confidence of the FDA, which just handed out a Fast Track designation and Celyad is now planning a refined Phase III trial.

One of Celyads major competitors, Australian Mesoblast, is forging ahead using allogeneic MSCs with Phase III programs in heart failure, chronic low back pain (CLBP) due to disc degeneration, as well as a range of inflammatory conditions including GvHD and rheumatoid arthritis.

Although the ability of MSCs to regenerate tissues remains questionable, the Mesoblasts approach hinges on a body of evidence showing that MSCs can suppress inflammation and mobilize endogenous repair mechanisms through indirect effects on immune cells.

Indeed, the first-ever approved stem cell therapy, Prochymal, also depends on this mechanism. Prochymal was developed by US-based Osiris Therapeutics and in 2012 received Canadian approval to treat acute GvHD. But after Sanofi opted to shelve its partnership with Osiris prior to FDA approval, the biotech sold out its off-the-shelf stem cell platform to Mesoblast in a $100M deal.

In Belgium, companies like TiGenix and Promethera are also banking on the immunomodulatory properties of MSCs. The companies are developing treatments for patients with Crohns disease and liver diseases, respectively.

The ultimate hope for stem cell therapies has been to regenerate damaged or diseased tissues as found in diabetes, heart failure or blindness. Holostem Terapie Avanzate, a spin-off from the University of Modena and Reggio Emilia was the first company to move towards this goal.

Building on 20 long years of research, the biotech has developed Holoclar, the first and only autologous stem cell therapy (apart from bone marrow transplants) to enter the European market. Holoclar is based on limbal stem cells, located in a part of the eye called the limbus, which can be used to restore eyesight in patients that have lost sight due to burn injuries.

Meanwhile, UK-based Reneuron is developing off-the-shelf therapies that aim to restore the cognitive function of patients following a stroke. Backed by no other than Neil Woodford, the company recently raised an impressive 100M to advance its lead therapy to the market.

The biotechs fetal-derived neural stem cell line CTX was able to significantly reduce the disability of post-stroke patients in a Phase II trial and ReNeuron is now planning to push its candidate into pivotal trials.

A major question in the space a decade ago was safety. Today, theres been a lot of trials done that show that safety is not an issue. I think safety is kind of off the table but efficacy is still a question mark. And thats what were trying to deliver now, Olav Helleb, CEO of ReNeuron, told me.

While neural stem cells and other tissue-specific stem cells are able to regenerate the cells of a particular tissue, Embryonic Stem Cells (ESCs) and their engineered counterparts, iPSCs, are capable of making every cell type in the body, a property known as pluripotency. Pluripotent stem cells can also expand indefinitely in culture and their identification unlocked massive expectations for these cells to transform the regenerative medicine field.

Yet, these cells come with significant challenges associated with the safety of the final preparation. Apart from ethical issues surrounding ESCs, today, a lot of companies have been cautious about using these cells for therapy, because undifferentiated pluripotent cells can drive tumor formation, explained Rawadi. Since ESCs can, in principle, form every cell type, they can lead to the formation of teratomas.

A major reason for the fairly slow progress in the field is based on the difficulties of directing a pluripotent cell to exactly the cell type that is needed for cell therapy. We can readily drive the cells from the undifferentiated state to the differentiated state. However, getting those cells to pause anywhere in the middle of this continuum to yield progenitor cells is incredibly challenging, Peyer explained. Another challenge, he says, is to engraft the cells in the right place to enable them to become fully integrated.

Besides initial hurdles, companies like US-based Asterias or ViaCyte are now running the first Phase I/II trials with ESC-derived cells to treat patients with spinal cord injuries and to restore the beta cells in type I diabetes. So far, the eye has been the the dominant organ for many of the first human clinical trials with pluripotent stem cells, where the cells are assessed in diseases such as age-related macular degeneration (AMD) to restore the loss of the retinal epithelium.

Deriving retinal epithelium from pluripotent cells is relatively easy and in fact, researchers in Japan are now running the very first clinical trial using donor-derived iPSCs to treat patients with AMD. For reasons of safety and standardization, the trial is based on an allogeneic approach. However, since this doesnt offer an exact genetic match, allogeneic therapies raise the prospect of immune rejection, an issue that has been plaguing the use of ESCs.

But the scientists in Japan have contended that iPSC banks could potentially solve this problem. The team in Japan is currently establishing an iPSC bank, consisting of HLA-characterized cell lines from 5-10 different donors, which should match 3050% of Japans population.

Such haplobanks have the benefits of allogeneic cell therapy, namely cost-effectiveness and standardization, but you still have matching immune systems, Peyer agrees.

For now, this remains a vision for the future, but the potential seems enormous. As Julian Howell, CMO of ReNeuron, told me, iPSCs have still got an awful long way to go. For the iPSC program running in Japan, they recently acknowledged that it took about $1.5M and 6 months to treat each patient. Its a great idea but its still got some way to go before it reaches the scale that could get into the clinic.

Images via nobeastsofierce,Natali_ Mis,vchal/ Shutterstock

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Regenerating the Body With Stem Cells Hype or Hope? - Labiotech.eu (blog)

Irvine, Calif., July 11, 2017 To paraphrase the classic poem, no hair is an island entire of itself.

Instead, University of California, Irvine scientists have discovered that all hairs can communicate with each other and grow in coordination across the entire body. This is regulated by a single molecular mechanism that adjusts by skin region to ensure efficient hair growth so no bald patches form and enable distinct hair densities in different body areas.

Study co-leader Maksim Plikus is an assistant professor of developmental & cell biology. Daniel A. Anderson / UCI

In animals, this regulatory process is important for survival in the wild. In humans, these findings could lead to new ways of addressing both balding and unwanted hair growth and further understanding of how regions of faster and slower regeneration work in coordination in other fast-renewing tissues, such as the intestines and bone marrow.

For the study, the researchers used the first mouse model of poor hair growth to analyze human-like hair behavior that leads to baldness. Their results appear in eLife, an open-access journal focusing on the life and biomedical sciences. UCIs Maksim Plikus, assistant professor of developmental & cell biology, and Qing Nie, professor of mathematics, led the effort. Ji Won Oh from Plikus lab and Qixuan Wang from Nies lab contributed equally to this work.

How skin regions communicate

The researchers focused on the interaction of the Wnt signaling pathway, which is important in embryonic development and regeneration, and bone morphogenetic proteins, which are hair growth inhibitory factors.

Study co-leader Qing Nie is professor of mathematics. UCI

While previous studies have shown that Wnt-BMP signals regulate hair growth in certain body areas, it was not known how different skin regions communicate with one another to coordinate hairs across their borders. By combining expertise in mathematical modeling from Nies lab and expertise in skin studies from Plikus lab, Wnt-BMP regulation was found to be ubiquitous across all skin.

In analogy with languages spoken in two neighboring countries, it was unclear how the back skin talks with the belly skin to coordinate the tasks of growing hairs, Plikus said. We showed that although different signaling dialects may exist between belly and back skin, for instance, all hairs can understand one another through the use of similar words and sentences.

The roots of hair growth problems

A breakdown of this complex signaling could uncover the roots of human hair growth irregularities and point to solutions.

For example, common male pattern baldness affects frontal and crown regions but not the back of the head. In adult humans, messaging among scalp hairs appears to stop, and every hair follicle is thought to grow independently.

If communication between nonbalding and balding regions can be reactivated, hair growth signals can then start spreading across the entire head skin, preventing regional baldness, Plikus said.

Just like scalp skin can show hair growth deficiency, skin in other body sites such as the face, arms and legs can often show excessive hair growth that can be cosmetically undesirable, he added. Our findings suggest that increased signaling crosstalk among hair follicles could be one major reason for this.

Whats next?

Plikus said that Wnt and BMP signaling activities can be regulated pharmacologically. Our study identified the types of Wnt-BMP signaling levels that are very favorable for hair growth and the types that prevent it, he said. It provides the road map for optimizing Wnt-BMP levels to achieve enhanced hair growth.

He added that the findings point toward additional signaling factors besides Wnt and BMP positively correlated with robust hair growth. Studying these will be the researchers next step.

Nie noted that laboratory experiments can be insufficient to study complex biological functions, such as hair growth across the entire skin. In such cases, mathematical modeling can greatly assist in the discovery process, he said. Our new mathematical model predicted details of signaling communications between hairs, otherwise difficult to reveal with standard biological experiments alone.

Scientists from UCI, the University of Southern California and Indiana University, as well as research centers in Australia, Poland, South Korea and China, contributed to the study, which received support from the National Institutes of Health, the National Science Foundation, the Edward Mallinckrodt Jr. Foundation, the Pew Charitable Trusts and UCIs Center for Complex Biological Systems.

About the University of California, Irvine: Founded in 1965, UCI is the youngest member of the prestigious Association of American Universities. The campus has produced three Nobel laureates and is known for its academic achievement, premier research, innovation and anteater mascot. Led by Chancellor Howard Gillman, UCI has more than 30,000 students and offers 192 degree programs. Its located in one of the worlds safest and most economically vibrant communities and is Orange Countys second-largest employer, contributing $5 billion annually to the local economy. For more on UCI, visit http://www.uci.edu.

Media access: Radio programs/stations may, for a fee, use an on-campus ISDN line to interview UCI faculty and experts, subject to availability and university approval. For more UCI news, visit news.uci.edu. Additional resources for journalists may be found at communications.uci.edu/for-journalists.

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UCI study sheds light on regulation of hair growth across the entire body - UCI News

July 11, 2017 NASA immunologist Hawley Kunz performs a microgravity evaluation of the pipetting steps necessary for terrestrial purification of cells. Credit: NASA

Just like early explorers, NASA Twins Study investigators are venturing into new territory. Conducting human omics research on twin astronauts as part of the One Year Mission that took place aboard the International Space Station is one such venture. As technology evolves so does the research. NASA is evaluating more efficient and innovative research techniques to prepare for the journey to Mars.

Innovative thinking could improve the way biological samples are processed and transported from space back to research labs on Earth for future studies. This thinking was prompted by researchers in NASA's Human Research Program (HRP) and Twins Study investigators at Johns Hopkins Medicine.

Freshly isolated samples yield better results than cells isolated from frozen samples returned to Earth from the orbiting laboratory. Pipetting fresh samples at ambient temperature and performing cell isolation on the space station also eliminates the need for expeditious transportation logistics, and allows for more frequent sampling. Once cells are isolated, the samples can be viably frozen and return on any transfer vehicle at any time for further analysis.

On an aircraft that is used as a parabolic flight analog to create short periods of simulated microgravity, Twins Study Investigators Dr. Andrew Feinberg and Lindsay Rizzardi of Johns Hopkins Medicine tested a theory that liquids could be transferred safely in microgravity using a pipettor, which is a slender, graduated measurement tube. Previously researchers thought transferring biological fluids in space could pose risks to precisely controlling the sample.

"This analog demonstrated that pipetting of open fluids is relatively simple and easily controlled and that all fluid transfer steps associated with centrifugation can be replicated in microgravity," Feinberg said. "When dealing with genetic material, research requires precise transfer of liquids among different types of tubes in order to purify DNA, RNA or protein from biological samples to perform molecular analyses."

Coinciding with the fluid transfer research was cell isolation research being conducted by NASA immunologists Brian Crucian, Clarence Sams, Hawley Kunz and NASA astronaut and molecular biologist Kate Rubins. NASA researchers tested terrestrial protocols for cell purification in microgravity using the parabolic flight analog. They found that cell isolation and purification could both be performed in microgravity. Rubins also confirmed some of these findings in space. They published their research with Feinberg and Rizzardi in the July 2016 issue of NPJ Microgravity.

Crucian said, "Laboratory procedures for isolating and purifying cells typically require sensitive gradient centrifugation, careful extraction of isolated cells, and general open pipetting of liquids for washing and transferring the isolated cells."

Being able to transfer fluids and isolate cells in space is significant for a variety of reasons. Mars is a challenging distance from Earth if diagnostics are ever needed of a crewmember. Enabling astronauts to conduct more human research independently could help diagnose an illness more quickly, possibly saving a life in a medical emergency.

As NASA prepares for its journey to Mars, the way researchers handle and processes biological samples in space could change. The protocols validated by the Johns Hopkins and NASA investigators demonstrate that standard cell isolation protocols may indeed be performed in space, something which may enable certain types of genetic, or 'omics', research onboard the space station. Molecular biology technologies such as hand-held sequencers continue to evolve pushing the boundaries of scientific research. HRP will continue to adapt its methodologies to support novel research that protects and ensures the safety of future crews on long-duration missions while opening the door for innovative opportunities.

Explore further: Study examines effects of spaceflight on immune system

More information: Lindsay F Rizzardi et al, Evaluation of techniques for performing cellular isolation and preservation during microgravity conditions, npj Microgravity (2016). DOI: 10.1038/npjmgrav.2016.25

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Squeezing innovation out of the NASA Twins study: Pipetting and cell isolation in space - Phys.Org