A candidate cancer drug currently in development has been also shown to stimulate regeneration of damaged nerves after spinal trauma. Four weeks after spinal cord injury, animals treated with the candidate drug, AZD1390, were “indistinguishable” from uninjured animals, according to the researchers.
The study, published in Clinical and Translational Medicine, demonstrated in cell and animal models that the candidate drug, AZD1390, can block the response to DNA damage in nerve cells and promote regeneration of damaged nerves. This restored sensory and motor function after spinal injury.
The announcement comes weeks after the same research team showed a different investigational drug, AZD1236, can reduce damage after spinal cord injury, by blocking the inflammatory response.
AZD1390 is also under investigation by AstraZeneca to block ATM-dependent signalling and repair of DNA double strand breaks (DSBs), an action which sensitises cancer cells to radiation treatment. The ATM protein kinase pathway – a critical biochemical pathway regulating the response to DNA damage. The DNA Damage Response system (DDR) is activated by DNA damage, including DSBs in the genome, which also happen in several common cancers and also after spinal cord injury.
Professor Zubair Ahmed, from the University’s Institute of Inflammation and Ageing and Dr Richard Tuxworth from the Institute of Cancer and Genomic Sciences hypothesised the persistent activation of this system may prevent recovery from spinal cord injury, and that blocking it would promote nerve repair and restore function after injury.
Their initial studies found that AZD1390 stimulated nerve cell growth in culture, and inhibited the ATM protein kinase pathway – a critical biochemical pathway regulating the response to DNA damage.
AZD1390 was tested in animal models following spinal cord injury. Oral treatment with AZD1390 significantly suppressed the ATM protein kinase pathway, stimulated nerve regeneration beyond the site of injury, and improved the ability of these nerves to carry electrical signals across the injury site.
Professor Ahmed commented: “This is an exciting time in spinal cord injury research with several different investigational drugs being identified as potential therapies for spinal cord injury. We are particularly excited about AZD1390 which can be taken orally and reaches the site of injury in sufficient quantities to promote nerve regeneration and restore lost function.
“Our findings show a remarkable recovery of sensory and motor functions, and AZD1390-treated animals being indistinguishable from uninjured animals within 4 weeks of injury.”
Dr Tuxworth added: “This early study shows that AZD1390 could be used as a therapy in life-changing conditions. In addition, repurposing this existing investigational drug potentially means we can reach the clinic significantly faster than developing a new drug from scratch.”
A new mouse study published in Nature showed that intermittent fasting changes gut bacteria, and increases the ability to recover from nerve damage.The fasting led to gut bacteria increasing production of 3-Indolepropionic acid (IPA), a metabolite which is required for regenerating axons.
The bacteria that produces IPA, Clostridium sporogenesis, is found naturally in the guts of humans as well as mice and IPA is found in human bloodstreams too, the researchers said.
“There is currently no treatment for people with nerve damage beyond surgical reconstruction, which is only effective in a small percentage of cases, prompting us to investigate whether changes in lifestyle could aid recovery,” said study author Professor Simone Di Giovanni at Imperial College London.
“Intermittent fasting has previously been linked by other studies to wound repair and the growth of new neurons – but our study is the first to explain exactly how fasting might help heal nerves.”
The study assessed nerve regeneration of mice where the sciatic nerve, the longest nerve running from the spine down the leg, was crushed. Half of the mice underwent intermittent fasting (one day with food, one day without), while the other half ate freely. These diets continued for a period of 10 days or 30 days before their operation, and the mice’s recovery was monitored 24 to 72 hours after the nerve was severed. The regrown axons were about 50% greater in mice that had been fasting.
Prof Di Giovanni said, “I think the power of this is that opens up a whole new field where we have to wonder: is this the tip of an iceberg? Are there going to be other bacteria or bacteria metabolites that can promote repair?”
The researchers also studied how fasting led to this nerve regeneration. They found that there were significantly higher levels of specific metabolites, including IPA, in the blood of diet-restricted mice.
To confirm whether IPA led to nerve repair, the mice were treated with antibiotics to remove gut bacteria. They were then given gene-edited of Clostridium sporogenesis that could or could not produce IPA.
“When IPA cannot be produced by these bacteria and it was almost absent in the serum, regeneration was impaired. This suggests that the IPA generated by these bacteria has an ability to heal and regenerate damaged nerves,” Prof Di Giovanni said.
Importantly, when IPA was administered to the mice orally after a sciatic nerve injury, regeneration and increased recovery was observed between two and three weeks after injury.
The next step is investigating spinal cord injuries in mice, along with seeing if more frequent IPA administrations increase its efficacy.
“One of our goals now is to systematically investigate the role of bacteria metabolite therapy.” Prof Di Giovanni said.
More studies will need to investigate whether IPA increases after fasting in humans and the efficacy of IPA and intermittent fasting as a potential treatment in people.
He said: “One of the questions that we haven’t explored fully is that, since IPA lasts in blood for four to six hours in high concentration, would administering it repeatedly throughout the day or adding it to a normal diet help maximise its therapeutic effects?”
Researchers have reported that they have successfully fused human retinal cells with adult stem cells, in a novel potential regenerative therapy to treat retinal damage and visual impairment.
The resulting hybrid cells stimulate the regenerative potential of human retinal tissue, something previously only thought to be found in cold-blood vertebrates.
Cell fusion events, where two different cells combine into one single entity, are known to be a possible mechanism contributing to tissue regeneration. These cell fusions result in four sets of chromosomes instead of the usual two. Though a rare phenomenon in humans, it has been reliably detected in the liver, brain, and gastrointestinal tract. Now, cell fusion events have been found also take place in the human retina, as reported in eBioMedicine.
Seeking to see if cell fusion events could differentiate into neurons, the researchers fused Müller glia, cells that play a secondary but important role in maintaining the structure and function of the retina, with adult stem cells.
“We were able to carry out cell fusion in vitro, creating hybrid cells. Importantly, the process was more efficient in the presence of a chemical signal transmitted from the retina in response to damage, resulting in rates of hybridisation increasing twofold. This gave us an important clue for the role of cell fusion in the retina,” said first author Sergi Bonilla.
The hybrid cells were injected into a growing retinal organoid, a model that closely resembles the function of the human retina. The researchers found that the hybrid cells successfully engrafted into the tissue and differentiated into cells that closely resemble ganglion cells, a type of neuron essential for vision.
“Our findings are important because they show that the Müller Glia in the human retina have the potential to regenerate neurons,” said lead researcher Professor Pia Cosma. “Salamanders and fish can repair damage caused to the retina thanks to their Müller glia, which differentiate into neurons that rescue or replace damaged neurons. Mammalian Müller glia have lost this regenerative capacity, which means retinal damage or degradation can lead to visual impairment for life. Our findings bring us one step closer to recovering this ability.”
Further work will be to understand why these hybrid cells, which have four complete sets of chromosomes, don’t result in chromosomal instability and cancer development. The authors of the study believe the retina may have a mechanism regulating chromosome segregation similar to the liver, which contains tetraploid cells that act as a genetic reservoir, undergoing mitosis in response to stress and injury.
In a significant advance for the field of tissue engineering, researchers have used sound waves to turn stem cells into bone cells, a technology which may help regrow bone lost by cancer or disease.
Described in the journal Small, the innovative stem cell treatment from researchers at RMIT University offers a smart way forward for overcoming some of the field’s biggest challenges, through the precision power of high-frequency sound waves.
Tissue engineering is an emerging field that aims to rebuild bone and muscle by harnessing the human body’s natural ability to heal itself. A key challenge in regrowing bone is having sufficient amounts of bone cells that can thrive once implanted in the target area.
So far, turning stem cells into bone cells has needed complicated and expensive equipment, making widespread clinical use unrealistic.
The few clinical trials trying to regrow bone mostly used stem cells painfully extracted from a patient’s bone marrow.
In a new study published in the journal Small, the RMIT research team showed stem cells treated with high-frequency sound waves turned into bone cells quickly and efficiently.
Importantly, the treatment was effective on multiple types of cells including fat-derived stem cells, which are far less painful to extract from a patient.
Co-lead researcher Dr Amy Gelmi said the new approach was faster and simpler than other methods.
“The sound waves cut the treatment time usually required to get stem cells to begin to turn into bone cells by several days,” said Dr Gelmi. “This method also doesn’t require any special ‘bone-inducing’ drugs and it’s very easy to apply to the stem cells.
“Our study found this new approach has strong potential to be used for treating the stem cells, before we either coat them onto an implant or inject them directly into the body for tissue engineering.”
The high-frequency sound waves used in the stem cell treatment were generated on a low-cost microchip device developed by RMIT.
Co-lead researcher Distinguished Professor Leslie Yeo and his team have spent over a decade researching the interaction of sound waves at frequencies above 10MHz with different materials.
The sound wave-generating device they developed can be used to precisely manipulate cells, fluids or materials.
“We can use the sound waves to apply just the right amount of pressure in the right places to the stem cells, to trigger the change process,” Prof Yeo said.
“Our device is cheap and simple to use, so could easily be upscaled for treating large numbers of cells simultaneously – vital for effective tissue engineering.”
The next stage in the research is investigating methods to upscale the platform, working towards the development of practical bioreactors to drive efficient stem cell differentiation.
Researchers have developed new way to get bone to regenerate with messenger RNA, which promises to be cheaper and less expensive while having fewer side effects than the current treatment.
Although fractures normally heal, bone will not regenerate under several circumstances. When bone does not regenerate, major clinical problems could result, including amputation.
One treatment is recombinant human bone morphogenetic protein-2, or BMP-2. However, it is expensive and only moderately effective. It also produces side effects, which can be severe.
Researchers at Mayo Clinic, along with colleagues in the Netherlands and Germany, may have a viable, less risky alternative: messenger RNA.
A study conducted on rats and published in Science Advances, shows that messenger RNA can be used at low doses to regenerate bone – and without side effects. The resulting new bone quality and biomechanical properties are also superior to that of BMP-2. Additionally, messenger RNA is a good choice for bone regeneration because it may not need repeat administrations.
Human bone develops in one of two ways: direct formation of bone cells from mesenchymal progenitor cells, or through endochondral ossification, in which cartilage forms first and then converts to bone. The BMP-2 therapy uses the former method, and the messenger RNA approach uses the latter. In general, the researchers say their work proves that this method “can heal large, critical-sized, segmental osseous defects of long bones in a superior fashion to its recombinant protein counterpart.”
Further studies are required in larger animals than rats before any translation can be considered for clinical trials.
Using a mix of drugs and a regenerative seal, scientists were able to successfully regrow frog legs, as reported in Science Advances. This represents an eventual step towards possibly regrowing limbs in humans.
On adult frogs, which are naturally unable to regenerate limbs, the researchers were able to trigger regrowth of a lost leg using a five-drug cocktail applied in a silicone wearable bioreactor dome that seals in the treatment over the stump for just 24 hours. That brief treatment sets in motion an 18-month period of regrowth that restores a functional, near-complete leg.
In humans and mammals loss of a large and structurally complex limb cannot be restored by any natural process of regeneration in humans or mammals. In fact, we tend to cover major injuries with an amorphous mass of scar tissue, protecting it from further blood loss and infection and preventing further growth.
The Tufts University researchers triggered the regenerative process in African clawed frogs by enclosing the wound in a silicone cap, which they call a BioDome, containing a silk protein gel loaded with the five-drug cocktail.
Each drug fulfilled a different purpose, including tamping down inflammation, inhibiting collagen production which would lead to scarring, and encouraging the new growth of nerve fibres, blood vessels, and muscle. The combination and the bioreactor provided a local environment and signals that tipped the scales away from the natural tendency to close off the stump, and toward the regenerative process.
A dramatic growth of tissue was observed in many of the treated frogs, re-creating an almost fully functional leg which was able to respond to stimuli, though the “toes” grown had no bones.
“It’s exciting to see that the drugs we selected were helping to create an almost complete limb,” said Nirosha Murugan, research affiliate at the Allen Discovery Center at Tufts and first author of the paper. “The fact that it required only a brief exposure to the drugs to set in motion a months-long regeneration process suggests that frogs and perhaps other animals may have dormant regenerative capabilities that can be triggered into action.”
Within the first few days after treatment, they detected the activation of known molecular pathways that are normally used in a developing embryo. Activation of these pathways could allow the burden of growth and organisation of tissue to be handled by the limb itself, similar to that in an embryo, rather than require ongoing therapeutic intervention over the many months it takes to grow the limb.
Animals naturally capable of regeneration live mostly in an aquatic environment. The first stage of growth after loss of a limb is the formation of a blastema, a mass of stem cells at the end of the stump, which is used to gradually reconstruct the lost body part. The wound is rapidly covered by skin cells within the first 24 hours after the injury, protecting the reconstructing tissue underneath.
“Mammals and other regenerating animals will usually have their injuries exposed to air or making contact with the ground, and they can take days to weeks to close up with scar tissue,” said Tufts University Professor David Kaplan, co-author of the study. “Using the BioDome cap in the first 24 hours helps mimic an amniotic-like environment which, along with the right drugs, allows the rebuilding process to proceed without the interference of scar tissue.”
Previous work using just progesterone with the BioDome resulted in a spike-like limb.
The five-drug cocktail is a major step toward the restoration of fully functional frog limbs and suggests further exploration of drug and growth factor combinations could lead to regrown limbs that are even more functionally complete.
“We’ll be testing how this treatment could apply to mammals next,” said corresponding author Professor Michael Levin at Tufts University.
“Covering the open wound with a liquid environment under the BioDome, with the right drug cocktail, could provide the necessary first signals to set the regenerative process in motion,” he said. “It’s a strategy focused on triggering dormant, inherent anatomical patterning programs, not micromanaging complex growth, since adult animals still have the information needed to make their body structures.”
Researchers at the Chinese Academy of Sciences have developed an innovative scaffold that regulates the immune microenvironment following a spinal cord injury, thereby reduces secondary injury effects. Their work is reported in Biomaterials.
By modifying a hydrogel with a cationic polymer, polyamidoamine, and interleukin-10 (IL-10; an anti-inflammatory cytokine), the scaffold could enhance tissue remodelling and promote axonal regeneration.
Spinal cord injuries cause axon damage and neural cell death, leading to dysfunction. A secondary stage of injury follows the primary stage and lasts for several weeks. Infiltration and activation of immune cells triggered by a spinal cord injury creates an inflammatory microenvironment characterised with damage-associated molecular patterns (DAMPs) that exacerbates secondary damage and impairs neurological functional recovery.
With the capabilities of effective scavenging of DAMPs and sustained release of IL-10, such a dual-functional immunoregulatory hydrogel not only reduced pro-inflammatory responses of macrophages and microglia, but also enhanced neurogenic differentiation of neural stem cells.
In a mouse model of spinal cord injury, the scaffold suppressed cytokine production, counteracting the inflammatory microenvironment and regulating immune cell activation, resulting in neural regeneration and axon growth without scar formation.
The dual-functional immunoregulatory scaffold with neuroprotection and neural regeneration effects significantly promoted electrophysiological enhancement and motor function recovery after spinal cord injury.
This study suggests that functional scaffold reconstruction of the immune microenvironment is a promising and effective method for treating severe spinal cord injury.
ESA astronaut Matthias Maurer is shown during preflight training for the BioPrint First Aid investigation, which tests a bioprinted tissue patch for enhanced wound healing. Credit: ESA
A suitably advanced piece of wound care technology will be sent into orbit to the space station in the next few days: a prototype for portable bioprinter that can cover a wound area on the skin by applying a tissue-forming bio-ink that acts like a patch, and accelerates the healing process.
While the aim is to provide a effective wound treatment for astronauts millions of kilometres from the nearest hospital, such a personalised wound healing patch would also have a great benefit on Earth. Since the cultured cells are taken from the patient, immune system rejection is unlikely, allowing a safe regenerative and personalised therapy. Other advantages are the possibilities of treatment and greater flexibility regarding wound size and position. In addition, due to its small size and portability, physicians could take the device anywhere to an immobile patient if their cells were cultivated in advance.
“On human space exploration missions, skin injuries need to be treated quickly and effectively,” said project manager Michael Becker from the German Space Agency. “Mobile bioprinting could significantly accelerate the healing process. The personalised and individual bioprinting-based wound treatment could have a great benefit and is an important step for further personalised medicine in space and on Earth.”
The use of bioprinting for skin reconstruction following burns is one growing application for the technology. However, it presently requires large bioprinters that first print the tissue, allow it to mature, before it is implanted onto the patient. By testing it in the gravity-free environment of space, Bioprint FirstAid will help optimise of bioprinting materials and processes. Microgravity-based 3D tissue models are important for greater understanding of the bioengineering and bio-fabrication requirements that are essential to achieve highly viable and functional tissues. Under microgravity conditions, the pressure of different layers containing cells is absent, as well as the potential sedimentation effect of living cell simulants. The stability of the 3D printed tissue patch, and the potentially gravity-dependent (electrolyte to membrane interface) crosslinking process, can be analysed for future applications.
The Bioprint FirstAid prototype contains no cells at this point. The surprisingly simple prototype is a robust, purely mechanical handheld bioprinter consisting of a dosing device in the handle, a print head, support wheels, and an ink cartridge. The cartridge contains a substitution (in total two different substitutions, both without skin cells) and a crosslinker, which serves as a stabilising matrix. To test it out, the simulant will be applied to the arm or leg of a crew member wrapped in foil, or alternatively at any other surface wrapped in foil. On Earth, a printed sample with human cells will be tested, and the distribution pattern will be compared to the cell-free sample that was printed in space.
Twenty years ago, clinicians first attempted to regenerate a failing human heart by injecting muscle myoblasts into the heart during a bypass operation. Despite high initial hopes and multiple studies since then, attempts to remuscularise an injured heart have met with little, if any, success.
Yet, there is hope that a therapy will be developed, according to experts in a Journal of the American College of Cardiology state-of-the-art review. The challenge is this: A heart attack kills heart muscle cells, leading to a scar that weakens the heart, often causing eventual heart failure. The lack of muscle repair is due to the very limited ability of mammalian heart muscle cells to proliferate, except during a brief period around birth.
In the review, the experts focus on three topics. First are several recent clinical trials with intriguing results. Second is the current trend of using cell-derived products like exosomes rather than muscle cells to treat the injured heart. For the third topic, authors discuss likely future experiments to replace a myocardial scar with heart muscle cells by ‘turning back the clock’ of the existing cardiomyocytes, rather than trying to inject exogenous cells. These efforts try to reverse the inability of mature mammalian heart muscle cells to proliferate.
Clinical trials One of the clinical trials reviewed involved giving cardiosphere-derived cells to patients with Duchenne muscular dystrophy, which affects both heart and skeletal muscles.
Cardiosphere-derived cells are a type of heart stromal/progenitor cell that has potent immunomodulatory, antifibrotic and regenerative activity in both diseased hearts and skeletal muscle. The HOPE-2 trial gave repeated intravenous doses of cardiosphere-derived cells to patients with advanced Duchenne disease, most of whom were unable to walk. Preliminary results showed safety, as well as major improvements in heart parameters such as left ventricle ejection fraction and reduced left ventricle size.
The HOPE-2 trial evaluated a repeated sequential dosing regimen of cell therapy for any cardiac indication, evaluated intravenous cardiosphere-derived administration, and clinically benefitted Duchenne patients.
Two features of the trial may bode well: a move away from invasive cardiac-targeted cell delivery and toward easily administered intravenous cell delivery, and the use of sequential repeated cell doses.
Cell-derived products Few cells transplanted into the heart survive, though some functional benefits in heart performance have been seen despite physical clearance of grafted cells. It could be possible that the cells were acting not as replacements but rather boosters of endogenous repair pathways through the release of a wide array of tissue-repairing biomolecules. This led to investigation of using cell-derived products rather than transplanting cells. Most of these biomolecules – proteins and non-coding nucleic acids – are enclosed in tiny vesicles that cells release naturally. When the vesicles, including exosomes, merge into recipient cells, the biomolecules can modulate signaling pathways. Using vesicles or exosomes involves a simpler manufacturing process compared with live cells, the ability to control quality and potency, and being able to refrigerate the vesicles to make administration simpler.
An alternative approach to the vesicle cell-derived products was the finding that injected stem cells can promote cardiac repair through release of biologically active molecules acting as short-range, paracrine hormones. These molecules are distinct from the biomolecules in vesicles or exosomes.
However, before use of any of these cell-derived products for heart repair in early trials, the reviewers say, more experiments are needed in purification of the products, potential modes of delivery and the suitability of repeated doses.
Proliferation of endogenous heart cells The final review topic looked ahead toward endogenous generation of cardiomyocytes – in other words, forcing existing native cardiomyocytes to divide, or other cells to become cardiomyocytes.
Pigs can regenerate heart muscle for only a few days after birth. But in one remarkable study, researchers injured the heart by removing part of the apex of the left ventricle one day after birth, and then induced heart attack 28 days after birth. Control pigs without the Day 1 resection showed no repair of heart attack damage at Day 56. In contrast, the pigs that had a resection one day after birth, and then had experimental heart attacks at Day 28, showed heart repair by Day 56 – notably an absence of dead heart muscle, known as an infarction. Furthermore, these pigs had more cardiomyocytes throughout their left ventricles.
This study showed that heart muscle cells in large mammals can be induced to proliferate and regenerate by inducing a heart injury at Day 1 to extend the neonatal regneration window. “If this cardiomyocyte cell-cycle activation can be activated in neonates, the same signaling pathways may be activated in adults as well,” the authors wrote, “which is highly impactful and significant.”
Another possible approach to endogenous generation is the direct programming of cardiac fibroblasts into cardiomyocytes. Inducing proliferation of cardiomyocytes will also need ways to promote growth of heart blood vessels to supply the new cardiomyocytes.
In conclusion, the authors believe that short-term approaches to clinical trials of post heart-attack therapies will use cells like cardiospheres or cell products. The longer-term approach, the reviewers said, will target “a more direct remuscularisation of the injured left ventricle by ‘turning back the clock’ of the cardiomyocyte cell-cycle or generating new cardiomyocytes from other cell types such as fibroblasts.”
“However, the efficiency and safety of these strategies, particularly their ability to generate cardiomyocytes seamlessly coupled with their native counterparts and to allow a regulation of these induced proliferative events preventing an uncontrolled and harmful cardiac growth, still need to be appropriately addressed before moving to clinical applications.”
A new wound dressing technology that can stop bleeding while preventing infection and scarring using a single material, has been developed. This technology also has potential applications in drug delivery, among other areas.
“Scarring is one of the worst consequences of severe wounds,” said Xiaoyang Wu, an associate professor in the Ben May Department of Cancer Research at the University of Chicago, noting that scar tissue formation is particularly common in human skin.
The researchers used a material science approach to develop a new method to overcome scarring, by impeding collagen synthesis by blocking transforming growth factor beta (TGF-β) – a cytokine that plays an important role in cell signaling, both in skin wound repair and tissue fibrosis.
“Increasing evidence suggests TGF-β is important in early phase wound repair for wound closure. But, later on, the signal may promote and enhance scarring,” Prof Wu said. This makes timing crucial. “We cannot simply block the signal, because that would slow down wound healing and would be dangerous for the patient,” he explained.
To get around this, the researchers came up with a delayed-release system combining a sutureless wound closure hydrogel material with a biodegradable microcapsule system, enabling them to control the release of the TGF-β inhibitor. “In this way, we can enhance skin wound repair and after 7-14 days can release the inhibitor that blocks the skin scarring process at the same time by using one material,” Prof Wu added.
At present, treatment of scarring is not ideal with little besides cosmetic surgery, and little can be done to prevent scar formation if a patient experiences a deep or messy wound. “The system we developed is very convenient for application,” said Wu, adding that the system has many possible future applications, such as drug delivery.
“We believe the novel system will have potential clinical importance in the future,” he said. To this end, the next steps include filing an investigational new drug (IND) application with the US Food and Drug Administration (FDA). Consistent manufacturing of the material is necessary and the researchers are exploring collaborations with pharmaceutical companies to move the research forward.
Since the system is a biocompatible material with adhesive properties, Wu said it has internal applications as well, adhering to and closing bleeding arteries and cardiac walls after irradiation with UV light. This was demonstrated in animal models, suggesting significant advantages as a traumatic wound sealant.
“Normal wound binding material does work well,” said Wu, noting that fibres are the most reliable material currently available, which, like surgical glue, is less biocompatible. “Biocompatibility is a significant advantage of our system,” he explained, “It is superior compared to current existing materials.”
