Lymphedema on Michael’s Domain

VEGFC-loaded Lignin Nanoparticles

Thu, 24 Apr 2025 00:00:00 +0000

Vascular Endothelial Growth Factor C (abbreviated either VEGFC or VEGF-C) has been used in several preclinical models in regenerative medicine. Its potential applications range from repairing damaged heart tissue to treating neurodegenerative disorders . While repairing damaged hearts and brains is not realistic at this moment, VEGFC does offer a glimmer of hope for patients with lymphedema — a chronic condition that presently can only be treated symptomatically. Yet, despite promising preclinical and even some clinical trial data, one key hurdle remains: effective delivery.The current frontrunner, adenoviral VEGFC (AdVEGFC) gene therapy, had progressed to phase II clinical trials, but the results were inconclusive . One possible explanation is that the amount or the duration of VEGFC production by AdVEGFC is insufficient. Its rapid inactivation by the immune system is a double-edged sword, making it a safe, but perhaps not very potent drug. This shortfall has sparked interest in novel delivery systems that bypass the immune system while providing controlled and sustained release.In our latest preprint , we explore the potential of lignin nanoparticles (LNPs) as carriers for VEGFC, from synthesis to stability. Why lignin? Lignin, a major component of plant cell walls, is the second most abundant biopolymer on planet Earth, and it can be extracted from many different sources and synthesized into nanoparticles.Our stability tests revealed that VEGFC is relatively stable on its own. It easily survives weeks of storage at elevated temperatures, and we have kept it at 4°C for a year without any significant loss of activity. It is also relatively stable against proteolytic attacks. It is not degraded by trypsin or thermolysin, and even withstands limited exposure to proteinase K. However, freezing and thawing cause it to lose activity (one cycle is acceptable, but after 32 cycles, it has lost most of its activity). Therefore, nanoparticle delivery might not be critical for protecting VEGFC from degradation, but sustained and delayed release would be its major advantage.We loaded VEGFC onto the particles and evaluated its release profile. Our findings indicate not only successful encapsulation but also a delayed release pattern, suggesting that LNPs could serve as a slow-release depot for VEGFC. We discovered that VEGFC can hang around for a long time even on its own, as the difference between naked VEGFC and LNP-delivered VEGFC was less than we had expected. In a modified Ba/F3-VEGFR3/EpoR bioassay, naked VEGFC sustained cell survival and proliferation for more than a week, even though at the later time points, not to the same levels as LNP-bound VEGFC. Based on previous studies, we attribute the innate ability of VEGF-C to “hang around for a long time” to its affinity for specific extracellular matrix components and cell surface molecules such as heparan sulfate proteoglycans. Even though most of these interactions are mediated by the silk-homology domain of VEGFC (which was absent in our study, which used mature VEGFC), some of these interaction capabilities also seem to remain in mature VEGFC.With this study, we dipped our toes for the first time into nanoparticle-based delivery of biologics. Our work supports the feasibility of LNPs as an alternative to viral vectors. However, there is room for improvement. One way to improve the delayed release is to modify VEGFC (as was done by Güç et al ). However, instead of modifying a cDNA that codes for mature VEGF-C (as Güç et al. did), it might make sense to try pro-VEGFC. After all, pro-VEGFC is the endogenous, inactive “latent form” of VEGFC. That’s what we’ll try next. Check out the full preprint for detailed methodology and data! Link to the preprint: https://doi.org/10.1101/2025.04.23.649697

What do we really know about lipedema?

Mon, 09 Sep 2024 00:00:00 +0000

Lipedema is an accumulation of subcutaneous fat, mainly in the lower body, which is resistant to weight loss and occurs almost exclusively in women. It is often painful, prone to bruising and is thought to have a genetic component, which is likely triggered by hormonal changes. Although lipoedema was recognised as a condition more than 80 years ago, our understanding of the condition and its aetiology remains incomplete. This is due in no small part to the fact that lipoedema has only recently been included in the official classification of diseases. Virtually all aspects of the condition are controversial, starting with its classification. The symptoms of lipoedema overlap with those of obesity, lipodystrophy, lymphoedema and connective tissue disorders. There are as yet no specific tests, and due to the uncertainty surrounding diagnosis, there is also considerable uncertainty regarding the prevalence of lipoedema, with estimates varying widely from 1 in 75,000 to 39 per cent of all women. Many hypotheses have been put forward regarding the cause of lipoedema, including that it is a lipid metabolism disorder, a connective tissue disorder, or an inflammatory or immune-mediated disease. A definitive cause has not yet been identified, and the search for ‘lipoedema genes’ has so far yielded no conclusive results, with the exception of individual genes that play a role in only a small proportion of all patients.

6. Swiss Lymphsymposium

Sat, 07 Sep 2024 00:00:00 +0000

The 6. Swiss Lymphsymposium has just completed. This symposium seems to gain popularity with every iteration, and I heard that there was a waiting list this year. The Juzo AG had invited experts to discuss topics at the intersection of Edema and Adipositas. The meeting was interesting and did not shy away from controversies. For a bench scientist like me, it is always stimulating to get the healthcare practitioners’ perspective into the diseases whose molecular basis I research. I had been at the 3. Swiss Lymphsymposium in 2021 , and there have been many developments that I have chosen not to pay attention to in my ivory tower of basic biomedical research. Specifically, the new S2k lipedema guidelines which are in effect since the beginning of 2024 received lots of attention.The new lipedema guidelines consider questions and goals related to diagnostic criteria, differential diagnostics, how diagnosis and therapy are influenced by co-morbidities, what therapeutic possibilities exist, and how patients can actively contribute to managing the disease. Given how little we understand about the etiology of lymphedema, these goals are ambitious. Dr. Tobias Bertsch from the Földi Clinic gave a very passionate and persuasive talk about the progress these guidelines represent in his talk “The New Guidelines Concerning the Lipedema Syndrome - More Light Than Shadow”. The presentation loosely followed the position paper he published with many other European experts. The one item where the position paper deviates most from the guidelines is the evaluation of liposuction as a treatment option. The position paper clearly states that liposuction does not produce long-lasting results, whereas the guidelines are surprisingly sparse-worded about this topic, and the reached consensus received the lowest support from the authors among all recommendations.For a bench scientist, making decisions absent high-grade evidence remains unsatisfying. However, guidelines for healthcare professionals cannot speak the same language as scientific articles because that would counteract their usefulness. “Whoever heals is right”, and if the new guidelines result in better medical outcomes, they serve their purpose. Guidelines - as scientific knowledge - are always provisional and subject to adjustment once better evidence becomes available. At the same time, we have to be careful not to block progress by taking them as gospel. After all, the saying “Whoever heals is right” is attributed to Samuel Hahnemann, the German physician who founded homeopathy (which is essentially witchcraft; do I need to mention this?). Nevertheless, when Samuel Hahnemann lived, using homeopathy likely resulted in better medical outcomes than the mainstream treatments of the time, such as bloodletting or patent mercury potions, which were frequently not only useless but dangerous or toxic.How I view lipedemaAfter following the lipedema field for a few years, my hypothesis is that lipedema is one endpoint in the wide spectrum of human fat storage physiology. Fat storage has been such a big asset during 99.999997% of evolution that nature was willing to accept the many risks inherent to complex and difficult systems. The more complex a machine, the more frequently it will fail, and many hereditary lipid-related diseases are failures of this machinery. The essential problem that this complex machinery has evolved to overcome is the insolubility of fat in water. Any transport of fat inside and outside the cell requires rendering fat water-soluble. In the blood, this is achieved by packaging fat molecules into lipoprotein particles.Lipids that are not burned get stored somewhere. They can be stored subcutaneously or viscerally. There are more ways to store fat, but this is the simplified version: Everybody will have a slightly different distribution between visceral and subcutaneous fat storage based on a complex interplay of many genes and the environment. In some people, this interplay results in extreme imbalances between these two compartments with pathological consequences. For example, in coronary heart disease, for most people, the genetic burden results from many genes (polygenic), whereas in a minority of patients, one or a few genes might explain the condition (monogenic or oligogenic). Hunting genes likely won’t result in any actionable findings for most lipedema patients. However, similar to coronary artery disease, it might be possible to identify risk factors. We already know three risk factors for lipedema: being female, undergoing hormonal changes, and having a family history of the disease. It would be helpful to identify additional risk factors that are easier to modify than the three we know of. We need for lipedema something similar to what the blood lipid panel is for coronary heart disease. Here is the link to my presentation (which I will keep updating over time with better information): What do we really know about lipedema? . You can also download the German version Was wissen wir eigentlich sicher über Lipödeme? - Eine Bestandsaufnahme" .

3. Swiss Lymphsymposium

Fri, 17 Sep 2021 00:00:00 +0000

The English translation of the German talk (slides and abstract) is available from here: https://doi.org/10.5281/zenodo.6034307 . The 3. Swiss Lymphsymposium took place on September 4th in Zürich. It is sponsored by Juzo , a producer of garments for complex physical decongestive therapy (CPDT), which is the main therapeutic option for lymphedema therapy. CDT cannot heal but it keeps the symptoms under control. I really liked the talk by Prof. Erich Brenner, since it nicely addressed the issue of blind-ended “lymphatic capillaries”, which, with some exceptions, do probably rarely exist in the steady-state adult human anatomy. I had discussed this previously with others such as Johannes Grünzig ( https://doi.org/10.1016/j.aanat.2018.08.004 ), who specifically looked at the shape of the initial lymphatics in the eye. I was asking Erich where the concept of blind-ended capillaries originates from and it seems to have its origins in early drawings from German physiologists. As a matter of fact, I myself have been perpetuating the blind-ended initial lymphatics in my schematic drawings, e.g. here , without paying much attention to the issue. As a defense, I can argue that the low magnification shows only the larger collectors and the high magnification suffers from the narrow depth of field. In fact, the depth of field can indeed give sometimes the impression of blind endings, while in reality, the vessel might simply make a turn. However, I have also seen convincing images with blind-ended initial lymphatics. From a functional perspective, which geometry would be the better choice? I guess nature is good at optimizing structures…Of course many of us molecular scientists have seen real blind-ended lymphatics. Obviously, during development and other situations of lymphatic expansion (wound healing, VEGF-C application), such lymphatic blind-ended sprouts do exist. We often also look at lymphatics in places where such finger-like structures do de-facto persist throughout adulthood (i.e. in the villi of the digestive tract). However, here the constant high supply of VEGF-C is likely involved in maintaining these unusual structures ( https://doi.org/10.15252/emmm.201505731 ).In my talk, I was addressing the current status of therapeutic lymphangiogenesis. Using VEGF-C, we can induce the growth of new lymphatic structures, but the current gene therapy (Lymfactin) is only able to deliver a short burst of VEGF-C because the delivery vector (an adenovirus) is rapidly inactivated by the immune system. Hence, the clinical studies were well chosen: to jump-start the integration of lymph node transplants into the local lymphatic network. But given this relatively narrow indication, the business decision by Herantis Pharma to focus on its neurodegenerative pipeline and to discontinue the Lymfactin development is even understandable. IMHO, we would need molecular nudging in order to make an impact in most human lymphedema conditions, which are - for the most part - chronic. A low-level, distributed stimulation of lymphatic collector contraction would need to be combined with a higher capacity network. VEGF-C could do the trick, but at this moment, we do not have any technology that could reliably deliver such a molecular nudge for a long time, although there are many ideas on how one could pull this off.The Ketoprofen/Bestatin trials have shown, that there is a big difference between acute and chronic lymphedema. The mouse lymphedema, which was treated surprisingly effectively with ketoprofen, is very different from human chronic lymphedema. One thing we certainly need is better animal models for chronic lymphedema. Interestingly, chronic lymphedema is a common problem in horses.This seems to be an old hat for those familiar with horses, but for me this was new: The same conservative standard treatment is used for horse and human lymphedema: complex physical decongestion therapy. I was just surprised that there are enough equine patients in order for some researchers and practitioners to specialize in the lymphedema treatment for horses: https://www.equicrown.de or https://horsephysio.at/uber-uns.htmlFrom a scientific point of view, this type of edema is likely much more similar to human lymphedema than all the mouse models that we have: it’s a big animal with high hydrostatic pressure in the legs and it’s a chronic condition. I am wondering what are the molecular causes for horse lymphedema, and whether this problem was caused by domestication/breeding, i.e. whether wild horses/zebras have also lymphedema? I would love to talk to somebody who knows something about this!Thanks to Sonja Eham & Dr. Michael Oberlin for the additional info concerning horse lymphedema, and Sonja Eham & Dace Zanker for an impeccable organization. I guess I should immediately start to clone horse VEGF-C…

Searching for a lymphedema drug

Wed, 11 Aug 2021 00:00:00 +0000

More than 20 years ago, I cloned the VEGF-C cDNA into an adenovirus shuttle vector. Even though we had the vectors for the AdEasy system from Bert Vogelstein’s lab to make adenoviruses in-house, we preferred to team up with gene therapy expert Seppo Ylä-Herttuala to make the first adenovirus with VEGF-C cargo (AdVEGF-C). This and other VEGF-C-expressing adenoviruses have been used by Seppo and us in several preclinical studies to show that VEGF-C can be successfully used to treat the underlying cause of certain types of lymphedema.In 2018, Herantis Pharma started Phase 1 clinical trials with AdVEGF-C, which was branded under the name Lymfactin. After Eiger Biopharmaceuticals ’ Phase-2-trials with bestatin failed to show any effect on lymphedema, Lymfactin was the only drug in clinical trials that was aimed at lymphedema. This spring, Herantis announced that it is discontinuing the clinical trials with Lymfactin in order to focus on their neurodegenerative ( CDNF ) drug pipeline. On top of this bummer came the news that the assignment of patients for the phase-2 trial had been non-random and that the Phase-2 results are therefore inconclusive . This is bad news for lymphedema patients just when gene therapy, on the whole, is making a comeback after an almost two-decade-long hiatus.What is the way forward? Even though the small molecule drug bestatin was shown to increase VEGFR-3 expression and activation , it was never a pro-lymphangiogenic therapy. The mouse experiments had shown clearly that it merely supports the endogenous lymphatic repair that is naturally kicking in after acute lymphatic damage. It specifically counteracts too high leukotriene B4 levels, which inhibit lymphangiogenesis, but it does not carry any own lymphangiogenic signal.The strategy to inhibit an inhibitor was also used in mouse studies that were published today in Science Signaling by Kataru et al.: Kataru et al. Kataru et al. used genetic modification of lymphatic endothelial cells to block PTEN, an intracellular inhibitor of VEGFR-3 signalling. The results are convincing: Lymphangiogenesis without any of the drawbacks that are inevitably associated with growth factor therapy, such as having too high growth factor concentrations at the site of delivery, which can lead to vessel leakiness and other unwanted responses. Small molecule PTEN inhibitors do exist, but they are pretty toxic. If a reasonably non-toxic PTEN-inhibitory compound could be found, all that is left is to specifically target it to lymphatic endothelial cells. However, neither finding nor targeting are easy tasks, although there are enough ideas that could be followed if funding was available. Read more about this topic in our opinion piece about searching for a lymphedema drug in Science Signaling: doi-link , e-print link for those who have no access to the full text.

VEGF-C Review in Frontiers in Bioengineering and Biotechnology

Mon, 12 Feb 2018 00:00:00 +0000

The editors of Frontiers in Bioengineering and Biotechnology, section Tissue Engineering and Regenerative Medicine (Andrea Banfi, Wolfgang Holnthoner, Mikaël M. Martino and Seppo Ylä-Herttuala) asked us to contribute to the research topic Vascularization for Regenerative Medicine. We wrote a small review about VEGF-C, which specifically addresses the molecular biology of VEGF-C in relationship to regenerative medicine, i.e., (re)growing lymphatic vessels in vitro or in vivo.You can get it from the publisher directly https://www.frontiersin.org/articles/10.3389/fbioe.2018.00007/full or from here . **UPDATE (April 1, 2023):**The question of whether Frontiers Media is a predatory publisher did not even cross our minds when we were asked to contribute with a review. I know the guest editors of this Research Topic and can vouch for their scientific integrity. However, the journal has recently ended up on the list of predatory journals ( https://predatoryreports.org/news/f/list-of-all-frontiers-media-predatory-journals ), and the issues are discussed here in detail. Our review has meanwhile gathered:

Science good, coffee bad

Thu, 26 Jan 2017 00:00:00 +0000

Last week I took part the Vascular Cell Biology Gordon Research Conference in Ventura (California). My two previous Gordon Conferences (2001 Rhode Island, 2014 Lucca/Italy) were outstanding and also this one did not disappoint.Even though there were many European researchers (19%), the US made up for 69% of the participants (Asia 6%, rest of the Amerikas 5%). This is probably a good representation of where the cutting edge research in vascular biology happens. Makes me wonder why the coffee in the US is as bad as it is (my bias got confirmed again). It cannot be explained by the lack of scientific expertise.Gordon conferences are designed to promote the exchange of unpublished data and hence I am not writing anything about the science. One exception: There are clinical trials to treat lymphedema with leukotriene B4 inhibitors ), but this is already public knowledge and the mouse studies are mostly published ( http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0008380) . So no secrets leaked here… I myself presented a poster about the continued CCBE1 story that is currently under review and some preliminary data about additional VEGF-C activating enzymes.Obviously, the outcome of the presidential elections was a popular topic during lunch and dinner conversations especially as it relates to science funding and science policy. Opinions ranged from “We have no clue what to expect” to “Be afraid. Be very afraid.” I personally enjoyed about 8 hours of Trump presidency since my return flight from Los Angeles to Munich left last Friday at a quarter past five in the afternoon.In the free afternoons, I tried to catch the America-exclusive Taurus Pokémon for my daughter Milena. Sadly, the conference location was almost entirely devoid of poke stops and therfore I was chronically short of poke balls. Insiders told me that Santa Monica beach is the place to go to in order to catch Pokémons. I actually planned to go there Friday morning, but it was raining cats and dogs and so I tried my luck at the airport and about an hour before departure I finally managed to catch a Taurus and another one just before boarding the plane. So all in all a very successful conference journey!

Erkrankungen des Lymphgefäßsystems (Diseases of the Lymphatic System)

Wed, 05 Aug 2015 00:00:00 +0000

The 6th edition of the the book Erkrankungen des Lymphgefäßsystems (Diseases of the Lymphatic System) is out. It’s a German language textbook, for which Kenny Mattonet, Jörg Wilting and myself wrote the fifth chapter (Genetic causes of primary lymphedema). Get it from here , since Amazon still sells the old, 5th edition. If you have a really good excuse why you should get one for free, mail me! I have a few copies.

Best paper award

Fri, 01 May 2015 00:00:00 +0000

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![](/sites/]( http://www.med.helsinki.fi/english/news/2015/20150505_Jeltsch.html)We have won Circulation’s 2014 Best Paper Award in the category of Basic Science. Circulation is the leading cardiology journal and the organ of the American Heart Association . Already when we published the paper (titled [/files/files/Jeltsch%20et%20al.%20-%202014%20-%20CCBE1%20Enhances%20Lymphangiogenesis%20via%20A%20Disintegrin.pdf">“CCBE1 Enhances Lymphangiogenesis via A Disintegrin and Metalloprotease With Thrombospondin Motifs-3–Mediated Vascular Endothelial Growth Factor-C Activation”](/sites/<?php print $_SERVER[)), it was clear that it provided a major overhaul of our understanding of the VEGF-C growth factor and it got featured by Open Heart . The article manages to provide multiple new insights:

New Mechanisms of Lymphangiogenesis and Lymphedema

Fri, 26 Sep 2014 00:00:00 +0000

Here is the presentation that I could not give, because my schedule was too tight to allow for a 1 hour 20 minute delay. If you have questions concerning the talk, please ask via e-mail: michael@jeltsch.org.My Lufthansa flight LH855 from Helsinki to Frankfurt got delayed by 1 hour 20 minutes. Because I had only 1 hour 15 minutes to change my plane in Frankfurt on my way to the 40th Congress of the European Society of Lymphology in Genova/Italy, I did not even board the plane and rather canceled my talk. Because I have another appointment on Saturday in Germany, I had planned the return flight for Friday early morning and hence could not move my talk either. Next time I’ll be smarter.

From the molecular biological foundations to causal treatment options for diseases of the lymphatic system

Tue, 22 Jul 2014 00:00:00 +0000

PD Dr Michael Jeltsch, University of Helsinki, Finland

Research into the molecular basis of lymphangiogenesis in embryonic development and pathological processes has led to a rapid expansion of our knowledge (Krebs and Jeltsch 2013a, 2013b). The molecular biology era of lymphatic research began with the discovery of VEGF growth factors and their receptors 25 years ago. This review therefore focuses on these molecules.