Année : 2024

Scientists have found that partial cellular reprogramming, both full-body and restricted to specific brain regions, rescues neurogenesis in the brains of old mice [1].

Cells going back in time

Partial reprogramming improves various health metrics and increases lifespan in animal models [2]. For instance, Dr. David Sinclair’s group has demonstrated optic nerve regeneration following injury in rodents and non-human primates. Partial reprogramming was also found to improve the functions of several other tissues, including pancreas and muscle [3].

However, the effects of partial reprogramming, specifically on the brain, have not been thoroughly investigated. In this new study published in Nature, scientists report on its impact on neurogenesis, the creation of new neurons.

Increased neuroblast production

Long gone are the days when a common misconception was that adult brains do not produce new neurons. Since then, scientists have found that some brain areas, such as the hippocampus and the subventricular zone (SVZ), contain neurogenic niches that give rise to new neurons even in adulthood. However, this process slows down considerably with age.

In their experiments, the researchers used the classic OSKM Yamanaka cocktail. Many researchers have tinkered with the recipe to boost reprogramming effectiveness and lower the risks of tumorigenesis, which are associated mainly with c-Myc, but this was not the case in this study.

First, the scientists went for whole-body reprogramming by creating genetically modified mice that express OSKM when treated with a molecular trigger: in this case, doxycycline. Using single-cell RNA sequencing, the researchers found that with age, the proportion of neuroblasts, the immediate precursors of neurons, among the progeny of neuronal stem cells (NSCs) decreases, indicating impaired neurogenesis. The treatment reversed this trend, bringing the proportion of neuroblasts back to youthful levels.

Then, the researchers employed an even more sophisticated mouse model in which OSKM expression was spatially restricted to SVZ. Interestingly, this restriction allowed them to increase the time of OSKM expression to what would be lethal in the whole-body model. The effect on the abundance of NSCs and neuroblasts was even more impressive than with the whole-body reprogramming.

More mature neurons

To exclude niche-wide effects, the researchers also experimented with cultured NSCs in vitro. Just like in vivo, NSCs harvested from old mice produced a lower proportion of neuroblasts than those taken from younger mice. Treating old but not young NSCs with OSKM increased the proportion of neuroblasts in their progeny, suggesting a rejuvenation-like effect “rolling things back to normal”.

However, it’s neurons, not the neuroblast precursors, that we are ultimately interested in. Did the treatment result in more neurons being born? Apparently, yes. In mice, neuroblasts originating from SVZ migrate to the olfactory bulb, where they become mature neurons (this shows how important the sense of smell is for these animals). With age, this process slows down dramatically. OSKM treatment increased the number of newborn neurons in the olfactory bulb, although not to youthful levels.

Using single-cell transcriptomics and immunostaining validation, we find that whole-body partial reprogramming in old mice partly reverses the age-associated defect in neuroblast proportion in the SVZ neurogenic niche. This ‘rejuvenation’ effect can be recapitulated by targeting the SVZ itself for partial reprogramming, indicating a niche-intrinsic phenomenon. Furthermore, partial reprogramming in old NSCs in culture cell autonomously improves their differentiation into neuronal precursors. Our study uncovers the impact of partial reprogramming in old brains by systematically probing its effect on multiple different cell types.

Literature

[1] Xu, L., Ramirez-Matias, J., Hauptschein, M., Sun, E. D., Lunger, J. C., Buckley, M. T., & Brunet, A. (2024). Restoration of neuronal progenitors by partial reprogramming in the aged neurogenic niche. Nature aging, 10.1038/s43587-024-00594-3.

[2] Macip, C. C., Hasan, R., Hoznek, V., Kim, J., Lu, Y. R., Metzger IV, L. E., … & Davidsohn, N. (2024). Gene Therapy-Mediated Partial Reprogramming Extends Lifespan and Reverses Age-Related Changes in Aged Mice. Cellular Reprogramming, 26(1), 24-32.

[3] Wang, C., Rabadan Ros, R., Martinez-Redondo, P., Ma, Z., Shi, L., Xue, Y., … & Izpisua Belmonte, J. C. (2021). In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche. Nature Communications, 12(1), 3094.

As the conference season kicks off, VC investors are gearing up for a cautiously optimistic 2024, where the normalization of valuations stands out as a positive trend. However, a growing concern shows over the potential impact of geopolitical conflicts and climate change pressures on this year’s performance. These critical topics are poised to take center stage, shaping discussions during VC panels at the LP/GP ‘0100 Conference Europe,’ scheduled to unfold from April 16th to 18th in Amsterdam.

“I believe we will see a growing stability in the financial markets with relatively predictable interest rates in 2024. However, the dark cloud looming over us is the rising geopolitical tensions in several regions. This tension risks stifling innovation, the exchange of ideas, and cross-border investments. As investors, we need to navigate these challenges with resilience and adaptability”, says John Elvesjö, CEO of The Incredible Machine, a single-family office backing 18 venture GPs.
A similar concern was expressed by France-based VC firm Alven’s Partner, Thomas Cuvelier. “Geopolitics will be the main macro factor impacting the timing of a potential recovery in 2024. This includes the US election results and existing or new conflicts in what is a very volatile global environment”.

“As geopolitical factors increasingly shape the industry landscape, forums like Zero One Hundred Conferences play a pivotal role. Here, decision-makers from investment firms across Europe and the globe convene, fostering fluent relationships and nurturing an environment of continuous innovation,” highlights Pavol Fuchs, CEO of Zero One Hundred Conferences.

Opportunities on the horizon

There are several positive indicators as we enter 2024. “First, the “reckoning” of 2023, with its emphasis on unit economics and sustainable growth, is expected to continue in 2024”, says Courtney Powell Chief Operating Officer, Managing Partner 500 Global. “This shift prioritizes healthy business models over-inflated valuations, creating a more stable environment for long-term investment and exits”. When it comes to opportunities, she highlights some emerging markets. “We’re seeing continued growth in emerging markets, particularly in regions like the Middle East, Africa, and even Southeast Asia. There’s booming potential for alpha generation in these regions with growing populations – especially younger ones – as well as great internet and mobile connectivity. The shift in focus towards these developing startup ecosystems offers new opportunities for investors and entrepreneurs”.

LPs take on VC investing this year

Giuseppe De Filippo, Managing Director at Julius Baer, notes a potential shift in private market dynamics, specifically within VC. “With the period of easy money gone, companies have been forced to pivot from growth to profitability. However, achieving positive cash flow takes patience. GPs had been willing to support their portfolio companies through re-investment during this transition, but the laggards are now being left to perform or perish. I suspect this will translate into broad underperformance among GPs. But more importantly, what we need to think about is whether or not this will have a lasting impact on demand from LPs whose enthusiasm has been integral in driving the industry, and ultimately, innovation forward”.

According to the Investment Principal of family office Dara5, James Heath, 2024 will be the year of the hyper-specialist VC. “Where a conviction is hard to come by, and FOMO isn’t driving investment decisions, specialists who know how to pick in this market will shine”.

Climate change and ESG efforts

“The escalating pace of climate change”, is Carolina de Azevedo, Head of Impact & ESG, Emerald Technology Ventures’ major concern this 2024, this can be overcome by significant technological advancement in renewable energy storage, green hydrogen production, and carbon capture and utilization, expected to happen this year. “These technologies will be key to reducing carbon emissions and building more sustainable infrastructure. Secondly, I see this as a year where we finally get more robust and ambitious policies, due to increased public awareness and the pressure that international cooperation is putting on governments. This should foster a more resilient global response to the challenges posed by climate change”, says.

When it comes to ESG, Silva Deželan, Head of Impact & ESG at Forbion, a robust strategy in the short term, which combines ESG integration in their investment process by strengthening the ESG due diligence process, data collection automation, start using the Life Sciences VC ESG & reporting template which was developed jointly by 13 life sciences focused VC investors in 2023, and implement the new impact and ESG framework in Forbion’s new strategy, which will focus on Bioeconomy. “Our existing venture and growth funds focus on life sciences companies that develop new drugs for rare diseases. The new fund will invest in companies that apply biotechnology to clean and feed the planet”, explains.

The 2nd edition of 0100 Conference Europe will gather over +1000 senior private equity/ venture capital executives, fund investors, fund managers, and industry experts. Hear firsthand from the most influential voices across Europe on April 16th, 17th, and 18th 2024 at Leonardo Royal Hotel Amsterdam, Paul van Vlissingenstraat 24, 1096 BK Amsterdam, Netherlands. For media registration please contact laura@0100conferences.com.

About Zero One Hundred Conferences

Zero One Hundred Conferences is a leading provider of offline and online events for PE & VC players in various regions in Europe with a global outreach. In the last 8 years, we organized 47 events with 1500+ speakers, 6000+ investors, and 11500+ attendees. The locations of these events were Amsterdam, Berlin, Luxembourg, Dublin, Copenhagen, Rome, Vienna, Tallinn, Limassol, Prague and Bratislava.

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Researchers publishing in the Journal of Clinical Investigation have developed a new method of screening for compounds, and they found one that appears to directly attack senescent cells involved in lung fibrosis.

A disease of senescence

Senescent cells are a major part of an age-related lung disease known as idiopathic pulmonary fibrosis (IPF) [1]. Specifically, cells positive for the senescent marker p16INK4a have been implicated, and a previous paper had suggested that targeting them could be effective [2].

As these researchers note, developing a senolytic that works in living animals is not as easy as developing one that works in cellular cultures, as a living organism has a far greater range of environments. Even in cultures, cell types and what drives them into senescence can have significant effects on what they are and how they react [3].

Therefore, these researchers previously developed INKBRITE, a genetic reporter that directly correlates fluorescence with p16INK4a in a mouse model. With this, they showed that the levels of this compound correspond to various senescent cell types in the lungs [4]. For this newest experiment, they wanted to screen for a senolytic compound that targets senescent cells that are directly taken from diseased tissues, then test that compound in living animals.

Making the target glow

Two weels after using bleomycin to induce senescence-causing injury in INKBRITE mice, the researchers extracted cells from the animals and found six subtypes that had been previously documented in fibrotic mouse lungs [5]. The researchers also found specific pathological subtypes that they did not find in their own previous study because that study had used napthalene rather than bleomycin to injure the lungs.

The researchers also conducted an experiment in which they injured the lungs of animals that did not express p16INK4a. Compared to animals that did, these model mice experienced less lung fibrosis after injury. However, before injury, the lungs of the animals were largely the same.

Therefore, they then began their next experiment: testing a library of nearly two thousand small molecules to determine which is the most effective at killing p16INK4a-positive cells while leaving cells without it alive. The fluorescent reporter of the INKBRITE mice was instrumental in determining this. Previous senolytics, most notably dasatinib, quercetin, and fisetin, did not meet the strong threshold of three standard deviations that the researchers used to screen for the best compounds.

Further experimentation with the doses of these compounds revealed three strong candidates that continued to work even at low concentrations. Testing these three against precision-cut lung slices revealed that one of them was likely to be ineffective in living organisms. In total, XSP888, an inhibitor of heat shock protein 90, was found to be the strongest candidate.

Living animals and human cells

The researchers tested XSP888 along with four other promising candidates in the lungs of bleomycin-treated INKBRITE mice. XSP888 was the only one that was found to reduce the percentage of p16INK4a cells in these animals. Fibrosis in total was also reduced, even when the senolytic combination of dasatinib and quercetin did not have any effect in this regard.

Importantly, these findings were replicated in human cells taken from people with IPF. The same senescence markers are found in people as in mice. The researchers found that XSP888 preferentially targets p16INK4a-positive human cells, reducing this marker of pathology.

However, there is no data as to whether or not XSP888 is safe and effective for treating lung fibrosis in people. Further testing, along with a clinical trial, would need to be conducted to determine if this is a drug that might one day make it to the clinic. Hopefully, this and other drugs discovered through these high-throughput screening techniques will eradicate each of the many harmful subsets of senescent cells that drive age-related diseases.

Literature

[1] Barnes, P. J., Baker, J., & Donnelly, L. E. (2019). Cellular senescence as a mechanism and target in chronic lung diseases. American journal of respiratory and critical care medicine, 200(5), 556-564.

[2] Schafer, M. J., White, T. A., Iijima, K., Haak, A. J., Ligresti, G., Atkinson, E. J., … & LeBrasseur, N. K. (2017). Cellular senescence mediates fibrotic pulmonary disease. Nature communications, 8(1), 14532.

[3] Hernandez-Segura, A., de Jong, T. V., Melov, S., Guryev, V., Campisi, J., & Demaria, M. (2017). Unmasking transcriptional heterogeneity in senescent cells. Current Biology, 27(17), 2652-2660.

[4] Reyes, N. S., Krasilnikov, M., Allen, N. C., Lee, J. Y., Hyams, B., Zhou, M., … & Peng, T. (2022). Sentinel p16 INK4a+ cells in the basement membrane form a reparative niche in the lung. Science, 378(6616), 192-201.

[5] Tsukui, T., Sun, K. H., Wetter, J. B., Wilson-Kanamori, J. R., Hazelwood, L. A., Henderson, N. C., … & Sheppard, D. (2020). Collagen-producing lung cell atlas identifies multiple subsets with distinct localization and relevance to fibrosis. Nature communications, 11(1), 1920.