Initiation of scutellum-derived callus is regulated by an embryo-like … – Nature.com

Ikeuchi, M., Sugimoto, K. & Iwase, A. Plant callus: mechanisms of induction and repression. Plant Cell 25, 31593173 (2013).

Article CAS PubMed Central PubMed Google Scholar

Ikeuchi, M. et al. Molecular mechanisms of plant regeneration. Annu. Rev. Plant Biol. 70, 377406 (2019).

Article CAS PubMed Google Scholar

Xu, L. & Huang, H. Genetic and epigenetic controls of plant regeneration. Curr. Top. Dev. Biol. 108, 133 (2014).

Article PubMed Google Scholar

Che, P., Lall, S. & Howell, S. H. Developmental steps in acquiring competence for shoot development in Arabidopsis tissue culture. Planta 226, 11831194 (2007).

Article CAS PubMed Google Scholar

Atta, R. et al. Pluripotency of Arabidopsis xylem pericycle underlies shoot regeneration from root and hypocotyl explants grown in vitro. Plant J. 57, 626644 (2009).

Article CAS PubMed Google Scholar

Sugimoto, K., Jiao, Y. & Meyerowitz, E. M. Arabidopsis regeneration from multiple tissues occurs via a root development pathway. Dev. Cell 18, 463471 (2010).

Article CAS PubMed Google Scholar

Hu, B. et al. Divergent regeneration-competent cells adopt a common mechanism for callus initiation in angiosperms. Regeneration 4, 132139 (2017).

Article CAS PubMed Central PubMed Google Scholar

Abe, T. & Futsuhara, Y. Genotypic variability for callus formation and plant regeneration in rice (Oryza sativa L.). Theor. Appl. Genet. 72, 310 (1986).

Article CAS PubMed Google Scholar

Bevitori, R., Popielarska-Konieczna, M., Dos Santos, E. M., Grossi-De-s, M. F. & Petrofeza, S. Morpho-anatomical characterization of mature embryo-derived callus of rice (Oryza sativa L.) suitable for transformation. Protoplasma 251, 545554 (2013).

PubMed Google Scholar

Fan, M., Xu, C., Xu, K. & Hu, Y. LATERAL ORGAN BOUNDARIES DOMAIN transcription factors direct callus formation in Arabidopsis regeneration. Cell Res. 22, 11691180 (2012).

Article CAS PubMed Central PubMed Google Scholar

He, C., Chen, X., Huang, H. & Xu, L. Reprogramming of H3K27me3 is critical for acquisition of pluripotency from cultured Arabidopsis tissues. PLoS Genet. 8, e1002911 (2012).

Article CAS PubMed Central PubMed Google Scholar

Liu, J. et al. The WOX11-LBD16 pathway promotes pluripotency acquisition in callus cells during de novo shoot regeneration in tissue culture. Plant Cell Physiol. 59, 734743 (2018).

Article PubMed Google Scholar

Zhai, N. & Xu, L. Pluripotency acquisition in the middle cell layer of callus is required for organ regeneration. Nat. Plants 7, 14531460 (2021).

Article CAS PubMed Google Scholar

Kareem, A. et al. PLETHORA genes control regeneration by a two-step mechanism. Curr. Biol. 25, 10171030 (2015).

Article CAS PubMed Central PubMed Google Scholar

Sugimoto, K., Gordon, S. P. & Meyerowitz, E. M. Regeneration in plants and animals: dedifferentiation, transdifferentiation, or just differentiation? Trends Cell Biol. 21, 212218 (2011).

Article CAS PubMed Google Scholar

Guo, F. et al. Callus initiation from root explants employs different strategies in rice and Arabidopsis. Plant Cell Physiol. 59, 17821789 (2018).

Article CAS PubMed Google Scholar

Liu, J. et al. WOX11 and 12 are involved in the first-step cell fate transition during de novo root organogenesis in Arabidopsis. Plant Cell 26, 10811093 (2014).

Article CAS PubMed Central PubMed Google Scholar

Kim, J.-Y. et al. Epigenetic reprogramming by histone acetyltransferase HAG1/AtGCN5 is required for pluripotency acquisition in Arabidopsis. EMBO J. 37, e98726 (2018).

Article PubMed Central PubMed Google Scholar

Zhai, N., Pan, X., Zeng, M. & Xu, L. Developmental trajectory of pluripotent stem cell establishment in Arabidopsis callus guided by a quiescent center-related gene network. Development 150, dev200879 (2023).

Shim, S. et al. Transcriptome comparison between pluripotent and non-pluripotent calli derived from mature rice seeds. Sci. Rep. 10, 21257 (2020).

Article CAS PubMed Central PubMed Google Scholar

Zhao, N. et al. Systematic analysis of differential H3K27me3 and H3K4me3 deposition in callus and seedling reveals the epigenetic regulatory mechanisms involved in callus formation in rice. Front. Genet. 11, 116 (2020).

Article Google Scholar

Indoliya, Y. et al. Decoding regulatory landscape of somatic embryogenesis reveals differential regulatory networks between japonica and indica rice subspecies. Sci. Rep. 6, 23050 (2016).

Article CAS PubMed Central PubMed Google Scholar

Zhang, H. et al. OsHDA710-mediated histone deacetylation regulates callus formation of rice mature embryo. Plant Cell Physiol. 61, 16461660 (2020).

Article CAS PubMed Google Scholar

Guo, F. et al. Functional analysis of auxin receptor OsTIR1/OsAFB family members in rice grain yield, tillering, plant height, root system, germination, and auxinic herbicide resistance. N. Phytol. 229, 26762692 (2021).

Article CAS Google Scholar

Xia, K. et al. OsTIR1 and OsAFB2 downregulation via OsmiR393 overexpression leads to more tillers, early flowering and less tolerance to salt and drought in rice. PLoS ONE 7, e30039 (2012).

Article CAS PubMed Central PubMed Google Scholar

Zhu, Z.-X. et al. A gain-of-function mutation in OsIAA11 affects lateral root development in rice. Mol. Plant 5, 154161 (2012).

Article CAS PubMed Google Scholar

Inukai, Y. et al. Crown rootless1, which is essential for crown root formation in rice, is a target of an AUXIN RESPONSE FACTOR in auxin signaling. Plant Cell 17, 13871396 (2005).

Article CAS PubMed Central PubMed Google Scholar

Zeng, M. et al. Stem cell lineage in body layer specialization and vascular patterning of rice root and leaf. Sci. Bull. 61, 847858 (2016).

Article CAS Google Scholar

Sarkar, A. K. et al. Conserved factors regulate signalling in Arabidopsis thaliana shoot and root stem cell organizers. Nature 446, 811814 (2007).

Article CAS PubMed Google Scholar

Langfelder, P. & Horvath, S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinforma. 9, 559 (2008).

Article Google Scholar

Guo, F. et al. Rice LEAFY COTYLEDON1 hinders embryo greening during the seed development. Front Plant Sci. https://doi.org/10.1101/2021.08.18.456739 (2022).

Yang, D. et al. Transcriptome analysis of rice response to blast fungus identified core genes involved in immunity. Plant. Cell Environ. 44, 31033121 (2021).

Article CAS PubMed Google Scholar

Liu, J., Jie, W., Shi, X., Ding, Y. & Ding, C. Transcription elongation factors OsSPT4 and OsSPT5 are essential for rice growth and development and act with APO2. Res. Sq. Prepr. https://doi.org/10.21203/rs.3.rs-2549283/v1 (2023).

Gaj, M. D., Zhang, S., Harada, J. J. & Lemaux, P. G. Leafy cotyledon genes are essential for induction of somatic embryogenesis of Arabidopsis. Planta 222, 977988 (2005).

Article CAS PubMed Google Scholar

Wjcikowska, B. & Gaj, M. D. Expression profiling of AUXIN RESPONSE FACTOR genes during somatic embryogenesis induction in Arabidopsis. Plant Cell Rep. 36, 843858 (2017).

Article PubMed Central PubMed Google Scholar

Shang, B. et al. Very-long-chain fatty acids restrict regeneration capacity by confining pericycle competence for callus formation in Arabidopsis. Proc. Natl Acad. Sci. USA 113, 51015106 (2016).

Article CAS PubMed Central PubMed Google Scholar

Wang, F.-X. et al. Chromatin accessibility dynamics and a hierarchical transcriptional regulatory network structure for plant somatic embryogenesis. Dev. Cell 54, 742757.e8 (2020).

Article CAS PubMed Google Scholar

Salan, C., Lepiniec, L. & Dubreucq, B. Genetic and molecular control of somatic embryogenesis. Plants 10, 1467 (2021).

Article PubMed Central PubMed Google Scholar

Mordhorst, A., Hartog, M., El Tamer, M., Laux, T. & de Vries, S. Somatic embryogenesis from Arabidopsis shoot apical meristem mutants. Planta 214, 829836 (2002).

Article CAS PubMed Google Scholar

Zuo, J., Niu, Q.-W., Frugis, G. & Chua, N.-H. The WUSCHEL gene promotes vegetative-to-embryonic transition in Arabidopsis. Plant J. 30, 349359 (2002).

Article CAS PubMed Google Scholar

Su, Y. H. et al. Auxin-induced WUS expression is essential for embryonic stem cell renewal during somatic embryogenesis in Arabidopsis. Plant J. 59, 448460 (2009).

Article CAS PubMed Central PubMed Google Scholar

Boutilier, K. et al. Ectopic expression of BABY BOOM triggers a conversion from vegetative to embryonic growth. Plant Cell 14, 17371749 (2002).

Article CAS PubMed Central PubMed Google Scholar

Horstman, A. et al. The BABY BOOM transcription factor activates the LEC1-ABI3-FUS3-LEC2 network to induce somatic embryogenesis. Plant Physiol. 175, 848857 (2017).

Article CAS PubMed Central PubMed Google Scholar

Tsuwamoto, R., Yokoi, S. & Takahata, Y. Arabidopsis EMBRYOMAKER encoding an AP2 domain transcription factor plays a key role in developmental change from vegetative to embryonic phase. Plant Mol. Biol. 73, 481492 (2010).

Article CAS PubMed Google Scholar

Lotan, T. et al. Arabidopsis LEAFY COTYLEDON1 is sufficient to induce embryo development in vegetative cells. Cell 93, 11951205 (1998).

Article CAS PubMed Google Scholar

Kwong, R. W. et al. LEAFY COTYLEDON1-LIKE defines a class of regulators essential for embryo development. Plant Cell 15, 518 (2003).

Article CAS PubMed Central PubMed Google Scholar

Kagaya, Y. et al. LEAFY COTYLEDON1 controls seed storage protein genes through its regulation of FUSCA3 and ABSCISIC ACID INSENSITIVE3. Plant Cell Physiol. 46, 399406 (2005).

Article CAS PubMed Google Scholar

Stone, S. L. et al. LEAFY COTYLEDON2 encodes a B3 domain transcription factor that induces embryo development. Proc. Natl Acad. Sci. USA 98, 1180611811 (2001).

Article CAS PubMed Central PubMed Google Scholar

Stone, S. L. et al. Arabidopsis LEAFY COTYLEDON2 induces maturation traits and auxin activity: Implications for somatic embryogenesis. Proc. Natl Acad. Sci. USA 105, 31513156 (2008).

Article CAS PubMed Central PubMed Google Scholar

Braybrook, S. A. et al. Genes directly regulated by LEAFY COTYLEDON2 provide insight into the control of embryo maturation and somatic embryogenesis. Proc. Natl Acad. Sci. USA 103, 34683473 (2006).

Article CAS PubMed Central PubMed Google Scholar

Curaba, J. et al. AtGA3ox2, a key gene responsible for bioactive gibberellin biosynthesis, is regulated during embryogenesis by LEAFY COTYLEDON2 and FUSCA3 in Arabidopsis. Plant Physiol. 136, 36603669 (2004).

Article CAS PubMed Central PubMed Google Scholar

Lueren, H., Kirik, V., Herrmann, P. & Misra, S. FUSCA3 encodes a protein with a conserved VP1/ABI3-like B3 domain which is of functional importance for the regulation of seed maturation in Arabidopsis thaliana. Plant J. 15, 755764 (1998).

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Grnenthal and King’s College London collaborate to develop human induced pluripotent stem cell-based microfluidic cultures for pain research – Yahoo…

Dr Ramin Raouf from King's College London and Grnenthal strive to develop reliable microfluidic culture models relevant for pain research based on human induced pluripotent stem cell-derived neurons

Grnenthal has expertise in developing human induced pluripotent stem cells towards sensory neurones and will support the lab of Dr Raouf with a total consideration of more than 350.000.

AACHEN, Germany and LONDON, April 27, 2023 /PRNewswire/ -- Grnenthal and King's College London announced a 24 months collaboration to develop microfluidic culture (MFC) models based on human induced pluripotent stem cells (iPSCs) and tailored to pain research. The collaboration aims to build on Dr Ramin Raouf's pioneering work on MFCs by establishing models using human iPSC-derived neurons that closely mimic the functionality of human nociceptive neurones. Grnenthal will support the lab of Dr Raouf with its competencies in characterising human iPSCs and a total consideration of more than 350.000.

The collaboration aims to address a significant need for better transational models in pain research. Traditional rodent behavioural models have frequently failed to translate into the clinical setting due to fundamental differences in molecular, cellular and genetic mechanisms of pain across species. As a result, there is a high interest in establishing pre-clinical models that can more accurately represent the conditions in the human body. Chronic pain is a considerable burden that impacts up to one in five people worldwide and is the most common reason for seeking medical help. It stresses healthcare systems and economies, while patients frequently experience limited efficacy from available medicines.

"Compared to traditional cell culture techniques, microfluidic cultures replicate more accurately the anatomy and physiology of the nervous system. Therefore, they can provide significant advantages in pre-clinical pain research", says Dr Ramin Raouf, Lecturer in Molecular Neuroscience at King's College London. "I believe adapting them with human iPSCs will create a transformative platform for generating translatable insights into the mechanisms of pain which will eventually contribute to reducing the attrition rate in clinical development."

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"We are delighted to join forces with Dr Ramin Raouf, a leading expert in microfluidic culture models. Taking this method to the next level may significantly enhance our understanding of how investigational medicines modulate pain", says Jan Adams, M.D., Chief Scientific Officer Grnenthal. "As a leading company in pain research, our ambition is to play a crucial role in developing such pioneering methodologies. We aim to anchor these competencies in our organisation and to include such models in our pre-clinical repertoire."

Grnenthal and Dr Ramin Raouf share a common research interest in neuroscience and the investigation of mechanisms of pathological pain. Dr Ramin Raouf is a world-leading researcher in the field of microfluidic cultures who pioneered the use of microfluidic culture models to study nociceptive neurons and established sophisticated rodent models. Grnenthal is a global leader in pain research and management and has delivered six essential treatment options for pain patients in the last decades. Today, the company is dedicated to creating the next generation of innovative non-opioid pain treatments. For R&D, Grnenthal executes a distinctive therapeutic area strategy focusing on four key pain indications: peripheral neuropathic pain, chronic post-surgical pain, chronic low back pain, and osteoarthritis.

About induced pluripotent stem cells

Induced pluripotent stem cells (iPSCs) are derived from a somatic cell that has been reprogrammed back into a pluripotent state by either introducing specific genes coding for transcription factors or adding small molecules that regulate cell identity. Those iPSCs can be differentiated into different cell types with unique characters, including peripheral sensory neurons.

About microfluidic cultures

Microfluidic devices are compartmentalised chips consisting of different chambers, sometimes called lab on a chip or 'tissue chips', allowing cell-to-cell contact via a series of connecting channels.Microfluidic cultures are used in this present collaboration to investigate the effects of analgesic compounds on different cellular compartments of the pain-sensing neuronal network, as well as the communication between neurons involved in pathological pain signalling.

About Grnenthal

Grnenthal is a global leader in pain management and related diseases. As a science-based, privately-owned pharmaceutical company, we have a long track record of bringing innovative treatments and state-of-the-art technologies to patients worldwide. Our purpose is to change lives for the better, and innovation is our passion. We are focusing all our activities and efforts on working towards our vision of a world free of pain.

Grnenthal is headquartered in Aachen, Germany, and has affiliates in 28 countries across Europe, Latin America, and the U.S. Our products are available in approx. 100 countries. In 2022, Grnenthal employed around 4,400 people and achieved revenues of 1.7 bn.

More information: http://www.grunenthal.com

Follow us on:

LinkedIn: Grunenthal Group

Instagram: grunenthal

About King's College London and the Institute of Psychiatry, Psychology & Neuroscience

King's College London is one of the top 35 universities in the world and one of the top 10 in Europe (QS World University Rankings, 2021/22) and among the oldest in England. King's has more than 33,000 students (including more than 12,800 postgraduates) from over 150 countries worldwide, and 8,500 staff. King's has an outstanding reputation for world-class teaching and cutting-edge research.

The Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King's is a leading centre for mental health and neuroscience research in Europe. It produces more highly cited outputs (top 1% citations) onpsychiatry andmental health than any other centre(SciVal2021),and on this metric has risen from 16th (2014) to 4th (2021) in the world for highly cited neuroscience outputs.In the 2021 Research Excellence Framework (REF),90% of research at the IoPPN was deemed 'world leading' or 'internationally excellent' (3* and 4*). World-leading research from the IoPPN has made, and continues to make, an impact on how we understand, prevent and treat mental illness, neurological conditions, and other conditions that affect the brain.

http://www.kcl.ac.uk/ioppn | Follow @KingsIoPPNon Twitter, Instagram, Facebook and LinkedIn

For further information please contact

Grnenthal

King's College London

Christopher Jansen

Communication Business Partner

Grnenthal GmbH

52099 Aachen

Phone: +49 241 569-1428

E-mail: Christopher.Jansen@grunenthal.com

Patrick O'Brien

Senior Media Officer

Insitute of Psychiatry, Psychology & Neuroscience King's College London

Phone: +44 07813 706 151

Email: Patrick.1.obrien@kcl.ac.uk

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Grnenthal and King's College London collaborate to develop human induced pluripotent stem cell-based microfluidic cultures for pain research - Yahoo...

Researchers reveal an ancient mechanism for wound repair – Science Daily

It's a dangerous world out there. From bacteria and viruses to accidents and injuries, threats surround us all the time. And nothing protects us more steadfastly than our skin. The barrier between inside and out, the body's largest organ is also its most seamless defense.

And yet the skin is not invincible. It suffers daily the slings and arrows of outrageous fortune, and it tries to keep us safe by sensing and responding to these harms. A primary method is the detection of a pathogen, which kicks the immune system into action. But new research from the lab of Rockefeller's Elaine Fuchs, published in Cell, reveals an alternative protective mechanism that responds to injury signals in wounded tissue -- including low oxygen levels from blood vessel disruption and scab formation -- and it doesn't need an infection to get into gear.

The study is the first to identify a damage response pathway that is distinct from but parallel to the classical pathway triggered by pathogens.

At the helm of the response is interleukin-24 (IL24), whose gene is induced in skin epithelial stem cells at the wound edge. Once unleashed, this secreted protein begins to marshal a variety of different cells to begin the complex process of healing.

"IL24 is predominately made by the wound-edge epidermal stem cells, but many cells of the skin -- the epithelial cells, the fibroblasts, and the endothelial cells -- express the IL24 receptor and respond to the signal. IL24 becomes an orchestrator that coordinates tissue repair," says Fuchs, head of the Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development.

Hints from pathogen-induced signaling

Scientists have long understood how the host responses protect our body from pathogen-induced threats: somatic cells recognize invading bacteria or viruses as foreign entities and induce a number of defense mechanisms with the help of signaling proteins such as type 1 interferons.

But how does the body respond to an injury that may or may not involve foreign invader? If we cut a finger while slicing a cucumber, for example, we know it instantly -- there's blood and pain. And yet how the detection of injury leads to healing is poorly understood on a molecular basis.

While type 1 interferons rely on the signaling factors STAT1 and STAT2 to regulate the defense against pathogens, previous research by the Fuchs lab had shown that a similar transcription factor known as STAT3 makes its appearance during wound repair. Siqi Liu, co-first author in both studies, wanted to trace STAT3's pathway back to its origin.

IL24 stood out as a major upstream cytokine that induces STAT3 activation in the wounds.

Microbe-independent action

In collaboration with Daniel Mucida's lab at Rockefeller, the researchers worked with mice under germ-free conditions and found that the wound-induced IL24 signaling cascade is independent of germs.

But what injury signals induced the cascade? Wounds often extend into the skin dermis, where capillaries and blood vessels are located.

"We learned that the epidermal stem cells sense the hypoxic environment of the wound," says Yun Ha Hur, a research fellow in the lab and a co-first author on the paper.

When the blood vessels are severed and a scab forms, epidermal stem cells at the edge of the wound are starved of oxygen. This state of hypoxia is an alarm bell for cell health, and induced a positive feedback loop involving transcription factors HIF1a and STAT3 to amplify IL24 production at the wound edge. The result was a coordinated effort by a variety of cell types expressing the IL24 receptor to repair the wound by replacing damaged epithelial cells, healing broken capillaries, and generating fibroblasts for new skin cells.

Collaborating with Craig Thompson's group at Memorial Sloan Kettering Cancer Center, the researchers showed that they could regulate Il24 gene expression by changing oxygen levels.

Once the researchers pinpointed the origin of the tissue-repair pathway in epidermal stem cells, they studied the wound repair process in mice that had been genetically modified to lack IL24 functionality. Without this key protein, the healing process was sluggish and delayed, taking days longer than in normal mice to completely restore the skin.

They speculate that IL24 might be involved in the injury response in other body organs featuring epithelial layers, which act as a protective sheath. In recent studies, elevated IL24 activity has been spotted in epithelial lung tissue of patients with severe COVID-19 and in colonic tissue in patients with ulcerative colitis, a chronic inflammatory bowel disease.

"IL24 could be working as a cue to signal the need for injury repair in many organs," Hur says.

Linked by function and evolution

"Our findings provide insights into an important tissue damage sensing and repair signaling pathway that is independent of infections," explains Fuchs.

An analysis with evolutionary biologist Qian Cong at UT Southwestern Medical Center revealed that IL24 and its receptors share close sequence and structure homology with the interferon family. Though they may not always be working in coordination at every moment, IL24 and interferons are evolutionarily related and bind to receptors sitting near each other on the surface of cells. The researchers suspect that these signaling molecules derive from a common molecular pathway dating far back in our past.

"We think that hundreds of millions of years ago, this ancestor might have diverged into two pathways -- one being pathogen defense and the other being tissue injury," Liu says.

Perhaps the split occurred to cope with an explosion of pathogens and injuries that caused a sea of troubles for life on Earth.

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Researchers reveal an ancient mechanism for wound repair - Science Daily

The gene-therapy revolution risks stalling if we don’t talk about drug … – Nature.com

A gene-editing therapy to correct deformed red blood cells in sickle-cell disease is in the works but at what cost?Credit: Eric Grave/SPL

We wish to suggest a structure for the salt of deoxyribose nucleic acid (D.N.A.), wrote James Watson and Francis Crick in this journal in 1953 (J. D. Watson and F. H. C. Crick Nature 171, 737738; 1953). This structure has novel features which are of considerable biological interest.

In the 70 years since those famous words were published, researchers have poured huge effort into unravelling those features and harnessing them for medicine. The result is a flourishing understanding of the genetic causes of diseases and a host of therapies designed to treat them.

Seventy years from now, the world might look back on 2023 as a landmark, as well. This year could see the first authorization of a therapy based on CRISPRCas9 gene editing, that involves tweaking the DNA in the bodys non-reproductive (somatic) cells. Gene editing allows scientists and could soon permit clinicians to make changes to targeted regions in the genome, potentially correcting genes that cause disease. Regulators in the United States, the European Union and the United Kingdom are evaluating a therapy that uses this approach to treat sickle-cell disease, and a decision could be made in the next few months.

CRISPR gene therapy shows promise against blood diseases

But even as such advances accrue, researchers are worrying about the future role of gene editing as well as other, more established forms of gene therapy in treating disease. Gene therapies currently carry eye-watering price tags, putting them out of the reach of many who need them. High prices could diminish the willingness of government funders to pay for gene-therapy research. And that, in turn, would make it harder for research institutions to continue to attract top talent to the field. Researchers, especially health economists, must work urgently with industry and governments to find a more affordable funding model.

CRISPRCas9s speedy path to the clinic was paved by years of steady advances in forms of gene therapy that use a virus to shuttle genes into cells. Over the past decade, regulators have approved several such gene therapies, for example CAR-T-cell therapies, which engineer immune cells to treat cancer. Hundreds more are in clinical trials.

These therapies typically cost something like US$1 million for a single treatment, and more once the costs of administering them, such as hospital stays and procedures required to isolate and manipulate cells, are factored in. Last year, the US Food and Drug Administration approved the first gene therapy to treat haemophilia B, a genetic disease that impairs blood clotting. The price is $3.5 million per treatment, making the therapy, called Hemgenix, the most expensive drug in the world.

Gene therapies are more costly to develop and produce than are more well-established treatments based on small-molecule drugs. But gene therapies can also carry the hope of a cure, freeing recipients from both long-term reliance on expensive medicines and the risk of hospitalizations. Some have argued that this justifies the high cost: if a therapy can save millions in downstream treatments, the initial outlay would still save money overall. Over time, after all, the costs of more-conventional treatments add up: one study, for example, found that in the United States, the cost of treating a person with sickle-cell anaemia until the age of 64 is $1.7 million (K. M. Johnson et al. Blood Adv. 7, 365374; 2023).

Researchers welcome $3.5-million haemophilia gene therapy but questions remain

Even in wealthy countries, health-care systems are ill-equipped to shoulder the high initial costs associated with gene therapies. In 2021, therapeutics developer Bluebird Bio in Somerville, Massachusetts, withdrew plans to market a gene therapy for -thalassaemia another blood disorder in Europe, after failing to reach an agreement with European authorities over the price. It said it would focus its sales efforts on the United States, where there has been comparatively little regulation of drug costs.

But even in the United States, costs matter. US health insurance is often subsidized by employers, and some are already saying that they will probably restrict their coverage of gene therapies in the next year, says Steven Pearson, president of the Institute for Clinical and Economic Review, a health-economics think tank in Boston, Massachusetts.

Low- and middle-income countries, meanwhile, are left entirely in the lurch. This is especially painful given that some of the diseases under consideration, such as -thalassaemia and sickle-cell disease, are more common in poorer parts of the world than in wealthy nations. In some sub-Saharan regions, for example, it is estimated that about 2% of children are born with sickle-cell disease. This is likely to be an underestimate, given how little screening is taking place.

It is too soon to know how much the CRISPRCas9 treatment for sickle-cell disease would cost; neither of its developers, Vertex Pharmaceuticals in Boston, Massachusetts, or CRISPR Therapeutics in Cambridge, Massachusetts, have disclosed what they will charge. But researchers are bracing themselves for the price tag to come.

At the Third International Summit on Human Genome Editing, held in London in March, much of the discussion centred on making gene-editing therapies accessible, particularly to low- and middle-income countries. The focus was on technological approaches to streamline the production and testing of such treatments. The sickle-cell treatment, for example, requires clinicians to isolate and edit blood-forming stem cells, destroy those that remain in the body, and then reinfuse the edited cells. Converting this to a genome-editing procedure that could be performed directly in the body rather than in isolated cells could make the treatment cheaper and more accessible.

Expensive treatments for genetic disorders are arriving. But who should foot the bill?

Another appealing approach is to develop gene-therapy platforms that have already been confirmed to be safe and effective. Gene-therapy developers could then just swap in a gene that targets the chosen disease, without the gamut of tests of safety and efficacy that are required when starting from scratch.

But technological solutions such as these will go only so far. US drug pricing has little to do with how much it costs to produce a therapy, says Pearson, because companies can charge as much as the market will bear. How much that price will drop in other countries could be limited by intellectual property rights and hindered by the complexities of making generic copies of biological drugs such as gene therapies. Some academic centres are trying to develop and deploy gene therapies without relying on pharmaceutical companies, but it is unclear how far such efforts can stretch without the financial resources and regulatory expertise found in industry.

In addition to pricing, gene-therapy technologies are mired in debates around regulation and intellectual property. How each of these plays out will determine how far researchers can go in capitalizing on Watson and Cricks initial discovery. Its important that scientists have an active role in these debates, and that they push such discussions to the fore sooner rather than later.

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Research Identifies New Target Which May Prevent Blood Cancer – Cannon Courier

An international coalition of biomedical researchers co-led by Alexander Bick, MD, PhD, at Vanderbilt University Medical Center has determined a new way to measure the growth rate of precancerous clones of blood stem cells that one day could help doctors lower their patients' risk of blood cancer.

The technique, called PACER, led to the identification of a gene that, when activated, drives clonal expansion. The findings, published in the journal Nature, suggest that drugs targeting this gene, TCL1A, may be able to suppress clonal growth and associated cancers.

"We think that TCL1A is a new important drug target for preventing blood cancer," said Bick, the study's co-corresponding author with Stanford University's Siddhartha Jaiswal, MD, PhD.

More than 10% of older adults develop somatic (non-inherited) mutations in blood stem cells that can trigger explosive, clonal expansions of abnormal cells, increasing the risk for blood cancer and cardiovascular disease.

Since arriving at VUMC in 2020, Bick, assistant professor of Medicine in the Division of Genetic Medicine and director of the Vanderbilt Genomics and Therapeutics Clinic, has contributed to more than 30 scientific papers that are revealing the mysteries of clonal growth (hematopoiesis).

With age, dividing cells in the body acquire mutations. Most of these mutations are innocuous "passenger" mutations. But sometimes, a mutation occurs that drives the development of a clone and ultimately causes cancer.

Prior to this study, scientists would measure clonal growth rate by comparing blood samples taken decades apart. Bick and his colleagues figured out a way to determine the growth rate from a single timepoint, by counting the number of passenger mutations.

"You can think of passenger mutations like rings on a tree," Bick said. "The more rings a tree has, the older it is. If we know how old the clone is (how long ago it was born) and how big it is (what percentage of blood it takes up), we can estimate the growth rate."

The PACER technique for determining the "passenger-approximated clonal expansion rate" was applied to more than 5,000 individuals who had acquired specific, cancer-associated driver mutations in their blood stem cells, called "clonal hematopoiesis of indeterminate potential" or CHIP, but who did not have blood cancer.

Using a genome-wide association study, the investigators then looked for genetic variations that were associated with different clonal growth rates. To their surprise, they discovered that TCL1A, a gene which had not previously been implicated in blood stem cell biology, was a major driver of clonal expansion when activated.

The researchers also found that a commonly inherited variant of the TCL1A promoter, the DNA region which normally initiates transcription (and thus activation) of the gene, was associated with a slower clonal expansion rate and a markedly reduced prevalence of several driver mutations in CHIP, the second step in the development of blood cancer.

Experimental studies demonstrated that the variant suppresses gene activation.

"Some people have a mutation that prevents TCL1A from being turned on, which protects them from both faster clone growth and from blood cancer," Bick said. That's what makes the gene so interesting as a potential drug target.

The research is continuing with the hope of identifying additional important pathways relevant to precancerous growth in other tissues as well as blood, he added.

Researchers from more than 50 institutions across the United States, as well as Germany, Sweden, and the Netherlands participated in the study. Other VUMC co-authors were Taralyn Mack, Benjamin Shoemaker, MD, MSCI, and Dan Roden, MD.

The research at VUMC is supported by National Institutes of Health grant OD029586, a Burroughs Wellcome Fund Career Award for Medical Scientists, the E.P. Evans Foundation & RUNX1 Research Program, a Pew-Stewart Scholar for Cancer Research Award, the VUMC Brock Family Endowment, and a Young Ambassador Award from the Vanderbilt-Ingram Cancer Center.

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Research Identifies New Target Which May Prevent Blood Cancer - Cannon Courier

Apoptotic cell death in diseaseCurrent understanding of the … – Nature.com

Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018;25:486541.

Article PubMed Central PubMed Google Scholar

Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol. 2021;22:26682.

Article PubMed Central PubMed Google Scholar

Del Re DP, Amgalan D, Linkermann A, Liu Q, Kitsis RN. Fundamental mechanisms of regulated cell death and implications for heart disease. Physiol Rev. 2019;99:1765817.

Article PubMed Central PubMed Google Scholar

Bock FJ, Tait SWG. Mitochondria as multifaceted regulators of cell death. Nat Rev Mol Cell Biol. 2020;21:85100.

Article CAS PubMed Google Scholar

Broz P, Pelegrn P, Shao F. The gasdermins, a protein family executing cell death and inflammation. Nat Rev Immunol. 2020;20:14357.

Article CAS PubMed Google Scholar

Weinlich R, Oberst A, Beere HM, Green DR. Necroptosis in development, inflammation and disease. Nat Rev Mol Cell Biol. 2017;18:12736.

Article CAS PubMed Google Scholar

Galluzzi L, Buqu A, Kepp O, Zitvogel L, Kroemer G. Immunogenic cell death in cancer and infectious disease. Nat Rev Immunol. 2017;17:97111.

Article CAS PubMed Google Scholar

Tang D, Kang R, Berghe TV, Vandenabeele P, Kroemer G. The molecular machinery of regulated cell death. Cell Res. 2019;29:34764.

Article CAS PubMed Central PubMed Google Scholar

Gudipaty SA, Conner CM, Rosenblatt J, Montell DJ. Unconventional ways to live and die: cell death and survival in development, homeostasis, and disease. Annu Rev Cell Dev Biol. 2018;34:31132.

Article CAS PubMed Central PubMed Google Scholar

Bedoui S, Herold MJ, Strasser A. Emerging connectivity of programmed cell death pathways and its physiological implications. Nat Rev Mol Cell Biol. 2020;21:67895.

Article CAS PubMed Google Scholar

Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MV, et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ. 2012;19:10720.

Article CAS PubMed Google Scholar

Kesavardhana S, Malireddi RKS, Kanneganti TD. Caspases in cell death, inflammation, and pyroptosis. Annu Rev Immunol. 2020;38:56795.

Article CAS PubMed Central PubMed Google Scholar

Kumar S, Dorstyn L, Lim Y. The role of caspases as executioners of apoptosis. Biochem Soc Trans. 2022;50:3345.

Article CAS PubMed Google Scholar

Galluzzi L, Bravo-San Pedro JM, Vitale I, Aaronson SA, Abrams JM, Adam D, et al. Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ. 2015;22:5873.

Article CAS PubMed Google Scholar

Marsden VS, OConnor L, OReilly LA, Silke J, Metcalf D, Ekert PG, et al. Apoptosis initiated by Bcl-2-regulated caspase activation independently of the cytochrome c/Apaf-1/caspase-9 apoptosome. Nature. 2002;419:6347.

Article CAS PubMed Google Scholar

Cheng EH, Wei MC, Weiler S, Flavell RA, Mak TW, Lindsten T, et al. BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell. 2001;8:70511.

Article CAS PubMed Google Scholar

Pandian N, Kanneganti TD. PANoptosis: a unique innate immune inflammatory cell death modality. J Immunol. 2022;209:162533.

Article CAS PubMed Google Scholar

Bonora M, Giorgi C, Pinton P. Molecular mechanisms and consequences of mitochondrial permeability transition. Nat Rev Mol Cell Biol. 2022;23:26685.

Article CAS PubMed Google Scholar

Chen X, Zeh HJ, Kang R, Kroemer G, Tang D. Cell death in pancreatic cancer: from pathogenesis to therapy. Nat Rev Gastroenterol Hepatol. 2021;18:80423.

Article PubMed Google Scholar

Song X, Zhu S, Xie Y, Liu J, Sun L, Zeng D, et al. JTC801 Induces pH-dependent death specifically in cancer cells and slows growth of tumors in mice. Gastroenterology. 2018;154:148093.

Article CAS PubMed Google Scholar

Tsvetkov P, Coy S, Petrova B, Dreishpoon M, Verma A, Abdusamad M, et al. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science. 2022;375:125461.

Article CAS PubMed Central PubMed Google Scholar

Malireddi RKS, Kesavardhana S, Kanneganti TD. ZBP1 and TAK1: master regulators of NLRP3 inflammasome/pyroptosis, apoptosis, and necroptosis (PAN-optosis). Front Cell Infect Microbiol. 2019;9:406.

Article CAS PubMed Central PubMed Google Scholar

Green DR. The coming decade of cell death research: five riddles. Cell. 2019;177:1094107.

Article CAS PubMed Central PubMed Google Scholar

Singh R, Letai A, Sarosiek K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat Rev Mol Cell Biol. 2019;20:17593.

Article CAS PubMed Central PubMed Google Scholar

Ke FFS, Brinkmann K, Voss AK, Strasser A. Some mice lacking intrinsic, as well as death receptor induced apoptosis and necroptosis, can survive to adulthood. Cell Death Dis. 2022;13:317.

Article PubMed Central PubMed Google Scholar

Ke FFS, Vanyai HK, Cowan AD, Delbridge ARD, Whitehead L, Grabow S, et al. Embryogenesis and adult life in the absence of intrinsic apoptosis effectors BAX, BAK, and BOK. Cell. 2018;173:12171230.e1217.

Article CAS PubMed Google Scholar

Spetz J, Galluzzi L. Preface: life through death-key role of cellular suicide for colonial and organismal homeostasis. Int Rev Cell Mol Biol. 2020;352:xixv.

Article PubMed Google Scholar

Carneiro BA, El-Deiry WS. Targeting apoptosis in cancer therapy. Nat Rev Clin Oncol. 2020;17:395417.

Article PubMed Central PubMed Google Scholar

Anderton H, Wicks IP, Silke J. Cell death in chronic inflammation: breaking the cycle to treat rheumatic disease. Nat Rev Rheumatol. 2020;16:496513.

Article PubMed Google Scholar

Li K, van Delft MF, Dewson G. Too much death can kill you: inhibiting intrinsic apoptosis to treat disease. EMBO J. 2021;40:e107341.

Article CAS PubMed Central PubMed Google Scholar

Jain N, Keating M, Thompson P, Ferrajoli A, Burger J, Borthakur G, et al. Ibrutinib and Venetoclax for First-Line Treatment of CLL. N Engl J Med. 2019;380:2095103.

Article CAS PubMed Google Scholar

Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19:2028.

Article CAS PubMed Google Scholar

Diepstraten ST, Anderson MA, Czabotar PE, Lessene G, Strasser A, Kelly GL. The manipulation of apoptosis for cancer therapy using BH3-mimetic drugs. Nat Rev Cancer. 2022;22:4564.

Article CAS PubMed Google Scholar

Merino D, Kelly GL, Lessene G, Wei AH, Roberts AW, Strasser A. BH3-Mimetic drugs: blazing the trail for new cancer medicines. Cancer Cell. 2018;34:87991.

Article CAS PubMed Google Scholar

Fischer K, Al-Sawaf O, Bahlo J, Fink AM, Tandon M, Dixon M, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380:222536.

Article CAS PubMed Google Scholar

Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:31122.

Article CAS PubMed Google Scholar

Seymour JF, Kipps TJ, Eichhorst B, Hillmen P, DRozario J, Assouline S, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378:110720.

Article CAS PubMed Google Scholar

DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, et al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med. 2020;383:61729.

Article CAS PubMed Google Scholar

Frenette CT, Morelli G, Shiffman ML, Frederick RT, Rubin RA, Fallon MB, et al. Emricasan improves liver function in patients with cirrhosis and high model for end-stage liver disease scores compared with placebo. Clin Gastroenterol Hepatol. 2019;17:774783.e774.

Article CAS PubMed Google Scholar

Garcia-Tsao G, Bosch J, Kayali Z, Harrison SA, Abdelmalek MF, Lawitz E, et al. Randomized placebo-controlled trial of emricasan for non-alcoholic steatohepatitis-related cirrhosis with severe portal hypertension. J Hepatol. 2020;72:88595.

Article CAS PubMed Google Scholar

Harrison SA, Goodman Z, Jabbar A, Vemulapalli R, Younes ZH, Freilich B, et al. A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis. J Hepatol. 2020;72:81627.

Article CAS PubMed Google Scholar

Galluzzi L, Aaronson SA, Abrams J, Alnemri ES, Andrews DW, Baehrecke EH, et al. Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes. Cell Death Differ. 2009;16:1093107.

Article CAS PubMed Google Scholar

Boada-Romero E, Martinez J, Heckmann BL, Green DR. The clearance of dead cells by efferocytosis. Nat Rev Mol Cell Biol. 2020;21:398414.

Article CAS PubMed Central PubMed Google Scholar

Rothlin CV, Hille TD, Ghosh S. Determining the effector response to cell death. Nat Rev Immunol. 2021;21:292304.

Article CAS PubMed Google Scholar

Morioka S, Maueroder C, Ravichandran KS. Living on the edge: efferocytosis at the interface of homeostasis and pathology. Immunity. 2019;50:114962.

Article CAS PubMed Central PubMed Google Scholar

Raymond MH, Davidson AJ, Shen Y, Tudor DR, Lucas CD, Morioka S, et al. Live cell tracking of macrophage efferocytosis during Drosophila embryo development in vivo. Science. 2022;375:11827.

Article CAS PubMed Central PubMed Google Scholar

Nonomura K, Yamaguchi Y, Hamachi M, Koike M, Uchiyama Y, Nakazato K, et al. Local apoptosis modulates early mammalian brain development through the elimination of morphogen-producing cells. Dev Cell. 2013;27:62134.

Article CAS PubMed Google Scholar

Li MO, Sarkisian MR, Mehal WZ, Rakic P, Flavell RA. Phosphatidylserine receptor is required for clearance of apoptotic cells. Science. 2003;302:15603.

Article CAS PubMed Google Scholar

Kist M, Vucic D. Cell death pathways: intricate connections and disease implications. EMBO J. 2021;40:e106700.

Article CAS PubMed Central PubMed Google Scholar

Doerflinger M, Deng Y, Whitney P, Salvamoser R, Engel S, Kueh AJ, et al. Flexible usage and interconnectivity of diverse cell death pathways protect against intracellular infection. Immunity. 2020;53:53347.e537.

Article CAS PubMed Central PubMed Google Scholar

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Apoptotic cell death in diseaseCurrent understanding of the ... - Nature.com

Regenerative Medicine Market Present Scenario And The Growth Prospects 2030 – openPR

The World Health Organization (WHO) estimates that non-communicable diseases (NCDs), such as cardiovascular diseases (CVDs), cancer, diabetes, and respiratory diseases, account for around 71% of global deaths, annually. As per the organization, CVDs, cancer, respiratory diseases, and diabetes cause 17.9 million, 9.3 million, 4.1 million, and 1.5 million human deaths, respectively, each year. Furthermore, the United Nations (UN) states that approximately 3,000-5,000 children are born with chromosome disorder, globally. Thus, the surging prevalence of chronic ailments and genetic disorders is creating a huge requirement for regenerative medicines, worldwide.

Moreover, the rising technological advancements in the medical industry will also help the regenerative medicine market progress at a healthy CAGR, of 16.3%, during 2020-2030. According to P&S Intelligence, the market was valued at $8,186.9 million in 2019 and it is expected to generate $39,012.0 million revenue by 2030. Major biotech and pharma companies are making hefty investments in technological developments to provide more effective gene therapies. The advent of 3D bioprinting is one of the prime examples of technological advancements in regenerative medicine.

Browse full report at: https://www.psmarketresearch.com/market-analysis/regenerative-medicine-market

At present, governments across the world are focusing on implementing policy changes to accelerate research activities in the establishment of regenerative medicine as a novel medical discipline. For instance, the Regenerative Medicine Innovation Project (RMIP), established under the 21st Century Cures Act, aims to facilitate clinical research in the field of adult stem cells in the U.S. Under this initiative, the National Institutes of Health (NIH) works in coordination with the U.S. Food and Drug Administration (FDA).

Stem and somatic cell therapies, viral and non-viral gene therapies, and cell-based tissue engineered products are being offered by Smith & Nephew plc, Allergan plc, Integra LifeSciences Holdings Corporation, Organogenesis Holdings Inc., Stryker Corporation, Takeda Pharmaceutical Company Limited, Novartis AG, Vericel Corporation, and Amgen Inc. for patients suffering from chronic ailments and genetic disorders. In the coming years, cell therapy will be adopted at the highest rate due to the soaring number of clinical trials including several cell therapy techniques.

Currently, companies offering regenerative medicines are engaging in product launches and approvals to cater to a greater number of patients. For instance, in October 2020, Novartis AG received the marketing authorization for the Foundation for Biomedical Research and Innovation (FBRI) at Kobe from the Ministry of Health, Labour and Welfare of Japan. With this approval, the company will produce and supply commercial Kymriah (tisagenlecleucel) in the nation. This move makes FBRI the first and only approved commercial production unit for chimeric antigen receptor T (CAR-T) cell therapy in Asia.

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Geographically, North America led the regenerative medicine market in the recent past, and it is also expected to maintain its position in the foreseeable future. This can be owed to the increasing advancements in the field of tissue engineering, rising number of stem cell banks, escalating healthcare spending, and surging reliance on stem cell therapy for chronic disease treatment. Whereas, Asia-Pacific (APAC) will adopt regenerative medicines at the highest rate in the upcoming years, due to the rising prevalence of chronic diseases, flourishing medical tourism industry, and escalating public and private funding in research organizations.

Thus, the surging incidence of chronic diseases and genetic disorders and the increasing technological advancements in the medical sector will fuel the administration of regenerative medicines, worldwide.

Browse more reports:

Gene Therapy Market - https://www.psmarketresearch.com/press-release/gene-therapy-market

Wound Care Market - https://www.psmarketresearch.com/press-release/wound-care-market

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About P&S Intelligence

P&S Intelligence provides market research and consulting services to a vast array of industries across the world. As an enterprising research and consulting company, P&S believes in providing thorough insights on the ever-changing market scenario, to empower companies to make informed decisions and base their business strategies with astuteness. P&S keeps the interest of its clients at heart, which is why the insights we provide are both honest and accurate. Our long list of satisfied clients includes entry-level firms as well as multi-million-dollar businesses and government agencies.

This release was published on openPR.

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Regenerative Medicine Market Present Scenario And The Growth Prospects 2030 - openPR