Mois : janvier 2025

German scientists have created lab-grown “patches” of heart muscle tissue derived from pluripotent stem cells. Following a success with rhesus monkeys, they have obtained approval for a human trial [1].

Wear and tear

As one of the most hard-working tissues in the body, the heart muscle is subject to incessant wear and tear due to aging and various health conditions. Unsurprisingly, heart failure is one of the most common age-related causes of death.

Scientists have tried to repair damaged heart tissue by injecting healthy heart muscle cells (cardiomyocytes), but retention and rejection issues are abundant. In a new study published in Nature, a group of German researchers has reported on an exciting new technique: growing entire patches of brand-new heart tissue from scratch.

Let it grow

The process starts with induced pluripotent stem cells (iPSCs), which are cells that were de-differentiated using cellular reprogramming methods into a stem-like pluripotent state. Such cells can then be re-differentiated into many cell types. Reprogramming also makes them epigenetically younger, so they are ready to do heavy lifting.

These newly differentiated cardiomyocytes are then mixed with stromal cells that provide structural support, and a patch of something closely resembling heart muscle tissue is grown in culture. The researchers call these structures engineered heart muscle (EHM).

After a series of previous experiments in rodent models, the group decided to take a major step up and move to non-human primates. While it is possible to produce iPSCs from the patient’s own cells, the researchers decided to use existing lines of iPSC-derived cardiomyocytes. The trade-off was the need for immunosuppression.

A group of rhesus macaques was subjected to a procedure imitating heart failure, and then their injured hearts were reinforced with EHMs in two different doses: either two or five patches. The higher dose uses about 200 million cardiomyocytes.

High retention, improved function

With both doses, but more so with the higher one, the researchers achieved a sustained and significant increase in heart wall thickness. Two of the three monkeys in the high dose group also showed increased heart wall contractility, indicating improved heart function.

The engrafted tissue, which initially lacked its own blood vessels, underwent vascularization upon implantation, even though blood perfusion was not as good as in the surrounding tissue. EHM cardiomyocytes were less developed, “younger,” than their resident counterparts, which is to be expected. It remains to be seen to what degree they can eventually develop.

Importantly, graft retention was confirmed for up to six months after the procedure, when the study ended. The researchers claim that this is the best result achieved by anyone so far.

Now, to humans!

In another experiment, the group previously implanted EHMs in a human patient who was awaiting a transplant for his severely damaged heart. After the new heart was transplanted, the researchers were able to study how their EHM patches performed on the old one.

Just like in monkeys, cardiomyocyte retention was good, and a high degree of vascularization was achieved. The patient demonstrated a stable disease course. “Collectively, the obtained clinical data confirmed the translatability of heart remuscularization by EHM allograft implantation from rhesus macaques to human patients with advanced heart failure,” the paper says.

“We have shown in rhesus macaques that cardiac patch implantation can be applied to re-muscularize the failing heart. The challenge was to generate and implant enough heart muscle cells from rhesus macaque induced pluripotent stem cells to achieve sustainable heart repair without dangerous side effects such as cardiac arrhythmia or tumor growth,” said Professor Wolfram-Hubertus Zimmermann, director of the Department of Pharmacology and Toxicology at the University Medical Center Göttingen, the study’s lead author.

Based on these results, the researchers have secured approval for a first-of-its-kind trial in human patients: “Safety and Efficacy of Induced Pluripotent Stem Cell-derived Engineered Human Myocardium as Biological Ventricular Assist Tissue in Terminal Heart Failure.”

Literature

[1] Jebran, AF., Seidler, T., Tiburcy, M. et al. (2025). Engineered heart muscle allografts for heart repair in primates and humans. Nature.

Researchers have devised a method of reducing brain inflammation by creating a long-lasting inhibitor of the inflammatory factor NF-κB.

Targeting inflammaging at its roots

This study, published in the Nature journal Experimental & Molecular Medicine, begins with a discussion of age-related chronic inflammation (inflammaging) and its contributions to aging. Specifically, the researchers focus on neuroinflammation, which occurs when age-affected brain microglia begin sending out pro-inflammatory signals, particularly the cytokine NF-κB [1]. While considerable research has elucidated many of the fundamental reasons why this signaling occurs [2], treatments have remained elusive.

NF-κB, in particular, has been well documented; many papers on age-related diseases have pinpointed it as a problem and potential target [3]. However, while these researchers have noted that despite the existence of more than 700 NF-κB inhibitors in the laboratory, there is not a single one that has gone through the clinical trial process.

These researchers’ candidate is a variant of a known natural inhibitor, IκB. Replacing two of its amino acids prevents this protein from being degraded by cells as the natural version would be; this engineered super-repressor is termed srIκB, and it is intended to linger in the cellular cytoplasm and inhibit NF-κB in a long-lasting way.

As their delivery vector, the researchers have chosen exosomes, cellular messengers that do not stimulate the immune system [4], and the exosomes loaded with the super-repressor are called Exo-srIκB. In previous work, this research team has used Exo-srIκB to treat inflammatory diseases in animal models [5]; this, however, is their first foray into tackling brain inflammation.

Directly affecting aspects of inflammation

In the researchers’ first experiment, they examined the brains of 2- to 3-month-old mice and compared them with the brains of 21- to 22-month-old mice. As expected, the cytokines and inflammatory factors were significantly greater in the old mice, and the amount of natural IκB was lower. Leukocytes had infiltrated the brains of the old mice, and a gene expression analysis revealed a broad increase in inflammatory factor production.

The researchers then injected pairs of 2- to 3-month-old and 18- to 22-month-old mice with Exo-srIκB for three days, along with control groups receiving empty exosomes. The older mice given Exo-srIκB had considerably lower levels of key inflammatory factors, including interleukins such as IL-1α. They also had significantly lower levels of immune B cells and macrophages compared to their control group, meaning that the immune systems had reduced responses to inflammation. Genes relating to leukocyte migration and activation were downregulated as well.

Oligodendrocytes, play supportive roles in the functioning of the brain, such as myelination, and become more oriented towards inflammation with age. However, this age-related shift was largely reduced in the older mice given Exo-srIκB. Interestingly, however, the number of oligodendrocytes engaged in initial myelination was also reduced with the treatment; the researchers hypothesize that this is due to less need for it, as inflammation decreases myelination.

Astrocytes, which also play a supporting role in the brain, did not appear to change how they behaved. Concerningly, the numbers of some cells were changed in the same direction with Exo-srIκB as with aging. However, the endothelial cells appeared to move towards a more youthful phenotype, with brain permeability being decreased.

Intercellular communication was also significantly affected. Pathways involved in chemokine activation, which encourage B cells to infiltrate the brain, were significantly reduced in the old mice given Exo-srIκB. However, other pathways relating to T cells seemed to be even stronger than before, which, as these researchers discuss, may explain why the T cells continued to be prevalent even after Exo-srIκB treatment.

While it is clearly not a complete solution by itself, these researchers believe that “Exo-srIκB may serve as a potent therapeutic agent against pathological age-related inflammatory processes, especially those that target macrophages and microglia.” They note that while they used high concentrations of this protein, it did not appear to have any significant side effects. However, the populations used were low, and this was only a mouse study conducted over a limited time period. Further work will need to be done to determine if this approach could work in human beings.

Literature

[1] Rawji, K. S., Mishra, M. K., Michaels, N. J., Rivest, S., Stys, P. K., & Yong, V. W. (2016). Immunosenescence of microglia and macrophages: impact on the ageing central nervous system. Brain, 139(3), 653-661.

[2] Hammond, T. R., Dufort, C., Dissing-Olesen, L., Giera, S., Young, A., Wysoker, A., … & Stevens, B. (2019). Single-cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes. Immunity, 50(1), 253-271.

[3] Barnes, P. J., & Karin, M. (1997). Nuclear factor-κB—a pivotal transcription factor in chronic inflammatory diseases. New England journal of medicine, 336(15), 1066-1071.

[4] Shiue, S. J., Rau, R. H., Shiue, H. S., Hung, Y. W., Li, Z. X., Yang, K. D., & Cheng, J. K. (2019). Mesenchymal stem cell exosomes as a cell-free therapy for nerve injury–induced pain in rats. Pain, 160(1), 210-223.

[5] Chae, J. S., Park, H., Ahn, S. H., Han, E. C., Lee, Y., Kim, Y. J., … & Kim, W. J. (2023). The effect of super-repressor IkB-Loaded Exosomes (Exo-srIκBs) in chronic post-ischemia pain (CPIP) models. Pharmaceutics, 15(2), 553.

On February 4-5, 2025, Hevolution Foundation will hold its second Global Healthspan Summit (GHS) in Riyadh, Saudi Arabia. The two-day event at the Four Seasons Hotel brings together international attendees, including world leaders, policymakers, researchers & scientists, and experts from the biotechnology, pharmaceutical, healthcare, and private sectors, to explore innovative solutions in the rapidly advancing fields of geroscience and healthspan. The event will address one of humanity’s greatest challenges: the rapidly growing aging population. Attendees will gain exclusive insights into pioneering research and emerging technologies that are shaping the future of healthspan science, presented by biotechnology founders, leaders, and researchers.

There is a significant gap between global life expectancy and healthspan—the number of years lived in good health — currently about 10 years (73.4 vs. 63.7 years, respectively). The global population aged 60 and older is expected to double by 2050, with individuals aged 65 and above projected to represent 1 in 6 people, up from 1 in 10 in 2021.

“A key part of our commitment to bringing everyone to the table is the Global Healthspan Summit. As a convener of stakeholders across sectors, GHS – the world’s largest event of its kind – provides a unique platform to kick off discussions among researchers, industry leaders, entrepreneurs, investors, and policymakers,” says Dr. Mehmood Khan, CEO, Hevolution Foundation. “Under the theme ‘Architecting the Future’, this summit not only serves as a forum for sharing insights and showcasing advancements but also as a catalyst for future collaborations.”

GHS 2025 features a diverse pool of speakers who will foster out-of-the-box thinking among all attendees. Some of the areas these sessions will focus on include:

The current healthspan investment landscape and perspectives on the latest market trends
How philanthropy can be a catalyst for advancing equity and driving policy change to lead to a sustainable, systematic transformation of our global healthcare system
Implementing healthspan-focused approaches within complex healthcare systems, addressing challenges such as interdisciplinary collaboration, data integration, and policy alignment.

In 2023, Hevolution hosted the first edition of the Global Healthspan Summit, bringing together leading experts for discussions on aging, healthcare innovation, and the healthspan ecosystem. The event attracted over 2,000 delegates and 120 speakers from top organizations such as Eli Lilly, GSK, Harvard, Mayo Clinic, Milken Institute, Saudi Arabia’s Ministry of Health, the World Bank, and the World Health Organization.

At the inaugural summit, Hevolution announced over $100 million in funding to accelerate healthspan research, including $40 million as the lead funder for the Hevolution XPRIZE healthspan partnership, $21 million for a multi-year partnership with the Buck Institute, $16 million for early-career researchers through the American Federation for Aging Research, and $5 million for postdoctoral fellowships.

This demographic shift makes aging a critical global issue, which will be addressed by international stakeholders at GHS 2025. The Hevolution Foundation leads efforts to tackle these changes, using its unique model to increase the number of geroscientists, expand the number of companies in the healthspan field, and attract funding. Through collaborative partnerships, the foundation is driving the shift from lifespan to healthspan, working toward solutions to the global challenge of aging.

About Hevolution Foundation

Hevolution Foundation is a global catalyst, partner, and convener dedicated to extending healthy human lifespans and advancing our understanding of aging. By treating aging as a process that can be addressed, the Foundation works to increase the availability of aging-related treatments, accelerate drug development timelines, and improve access to therapeutics that enhance healthspan — the number of years we live in good health. Headquartered in Riyadh, Saudi Arabia with a North American hub and an annual budget of up to $1 billion, Hevolution is the world’s largest philanthropic funder in healthspan and aging research. Over the past three years, the Foundation has committed $400 million to advancing research and innovation in this field. With plans to establish offices in additional locations worldwide, the Foundation is on a mission to propel and deliver breakthroughs that empower humanity to live healthier, longer lives.

Summit Website: Home – GHS – Hevolution Website

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