@article {892, title = {Fetal-like reversion in the regenerating intestine is regulated by mesenchymal asporin}, journal = {Cell Stem Cell}, volume = {32}, year = {2025}, month = {Jan-04-2025}, pages = {613 - 626.e8}, abstract = {Mesenchymal cells and the extracellular matrix (ECM) support epithelium during homeostasis and regeneration. However, the role of the mesenchyme in epithelial conversion into a fetal-like regenerative state after damage is not known. We modeled epithelial regeneration by culturing intestinal epithelium on decellularized small intestinal scaffolds (iECM) and identify asporin (Aspn), an ECM-bound proteoglycan, as a critical mediator of epithelial fetal-like reprogramming. After damage, transient increase in Aspn expression by the pericryptal fibroblasts induces epithelial transforming growth factor b (TGF-b)-signaling via CD44 and promotes timely epithelial reprogramming. Temporal control of Aspn is lost in old mice, and after damage, the persistently high level of Aspn stagnates epithelium in the regenerative state. Increase in Wnt signaling can resolve the stagnated regenerative program of the old epithelium, promoting restoration of tissue function. In summary, we establish a platform for modeling epithelial injury responses ex vivo and show that the mesenchymal Aspn-producing niche modulates tissue repair by regulating epithelial fetal-like reprogramming.}, issn = {19345909}, doi = {10.1016/j.stem.2025.02.009}, url = {https://www.sciencedirect.com/science/article/pii/S1934590925000487}, author = {Iqbal, Sharif and Andersson, Simon and Nesta, Ernesta and Pentinmikko, Nalle and Kumar, Ashish and Jha, Sawan K. and Borshagovski, Daniel and Webb, Anna and Gebert, Nadja and Viitala, Emma W. and Ritchie, Alexandra and Scharaw, Sandra and Kuuluvainen, Emilia and Larsen, Hjalte L. and Saarinen, Tuure and Juuti, Anne and Ristim{\"a}ki, Ari and Jeltsch, Michael and Ori, Alessandro and Varjosalo, Markku and Pietil{\"a}inen, Kirsi H. and Ollila, Saara and Jensen, Kim B. and Oudhoff, Menno J. and Katajisto, Pekka} } @article {588, title = {Factors regulating the substrate specificity of cytosolic phospholipase A2-alpha in vitro}, journal = {Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids}, volume = {1861}, year = {2016}, month = {2016/07/01/}, pages = {1597}, keywords = {Arachidonic acid, Bilayer, Catalytic site, Mass spectrometry, Micelle, Phospholipase A}, author = {Batchu, Krishna C and H{\"a}nninen, Satu and Jha, Sawan K and Jeltsch, Michael and Somerharju, Pentti} } @proceedings {537, title = {From Molecular Genetics and Biology to Effective Treatments of Lymphatic Disorders}, year = {2016}, month = {05/2016}, address = {Mulhouse, France}, abstract = {In 1971, Judah Folkman proposed the concept of anti-angiogenic tumor therapy. 12 years later, Harold Dvorak isolated the responsible growth factor VEGF. Nine years later, Napoleone Ferrara re-ported the generation of neutralizing monoclonal antibodies against VEGF. Another five years later, Phase I trials started with the humanized version of one of the monoclonals: bevacizumab. Since 2004, when it received FDA approval, it has been marketed under the brand name Avastin. The translation of basic biomedical research into tangible benefits for patients appears sometimes ago-nizingly slow. The public has been promised much by hyped scientific breakthroughs [4]. Scien-tific journals and scientists have played along in over-hyping scientific breakthroughs in the hope of impact factors and citations in order to secure and justify funding and fame. Not surprisingly, practitioners ask when the discoveries from basic research will finally improve the standard of care for their patients. Lymphatic research is no exception. Practitioners are largely still limited to symptomatic treatment and there seems to be still an invisible, but perceptible divide between those who do the molecular biol-ogy research and those who treat patients. The Avastin story is a plea for basic research: it might be compli-cated and it might take time, but it eventually does pay off. How is the lymphatic research community doing concerning the translation of research results into treatment options? Examples of lymphatic re-search in or shortly before the clinical trial stage include: - Growth factor enhanced lymph node transplantation to treat secondary lymphedema - Utilizing the Schlemm channel{\textquoteright}s lymphatic character in glaucoma treatment - Anti-angiogenic tumor treatment with anti-lymphangiogenic agents Treatment of primary lymphedema with VEGF-C has been proposed. How-ever, our understand-ing of the physiological process of lymph vessel development is far from com-plete, despite sig-nificant re-cent progress in our understanding of devel-opmental lymphangiogenesis and first attempts at tis-sue-engineering lymphatic vessels. If the results from high throughput cancer profilings are predictive of lymphatic conditions, then many patients will feature very individual, multifactorial disease profiles. Even more challenging than the identification of such causes will be the development of treatment regimens that rapidly can be tailored to such individual needs.}, url = {http://www.eurolymphology.org/JOURNAL/VOL28-N74-2016/$\#$p=14}, author = {Jeltsch, Michael} } @article {536, title = {Functional Importance of a Proteoglycan Co-Receptor in Pathologic Lymphangiogenesis}, journal = {Circulation Research}, volume = {119}, year = {2016}, month = {05/2016}, pages = {210-221}, abstract = {Rationale: Lymphatic vessel growth is mediated by major pro-lymphangiogenic factors such as VEGF-C and -D, among other endothelial effectors. Heparan sulfate is a linear polysaccharide expressed on proteoglycan core proteins on cell-membranes and matrix, playing roles in angiogenesis, although little is known regarding any function(s) in lymphatic remodeling in vivo. Objective: To explore the genetic basis and mechanisms whereby heparan sulfate proteoglycans mediate pathologic lymphatic remodeling. Methods and Results: Lymphatic endothelial deficiency in the major heparan sulfate biosynthetic enzyme N-deacetylase/N-sulfotransferase-1 (Ndst1; involved in glycan-chain sulfation) was associated with reduced lymphangiogenesis in pathologic models, including spontaneous neoplasia. Mouse mutants demonstrated tumor-associated lymphatic vessels with apoptotic nuclei. Mutant lymphatic endothelia demonstrated impaired mitogen (Erk) and survival (Akt) pathway signaling as well as reduced VEGF-C mediated protection from starvation-induced apoptosis. Lymphatic endothelial specific Ndst1 deficiency (in Ndst1f/fProx1+/CreERT2 mice) was sufficient to inhibit VEGF-C dependent lymphangiogenesis. Lymphatic heparan sulfate deficiency reduced phosphorylation of the major lymphatic growth receptor VEGFR-3 in response to multiple VEGF-C species. Syndecan-4 was the dominantly expressed heparan sulfate proteoglycan in mouse lymphatic endothelia, and pathologic lymphangiogenesis was impaired in Sdc4(-/-) mice. On the lymphatic cell surface, VEGF-C induced robust association between syndecan-4 and VEGFR-3 which was sensitive to glycan disruption. Moreover, VEGFR-3 mitogen and survival signaling was reduced in the setting of Ndst1 or Sdc4 deficiency. Conclusions: These findings demonstrate the genetic importance of heparan sulfate and the major lymphatic proteoglycan syndecan-4 in pathologic lymphatic remodeling. This may introduce novel future strategies to alter pathologic lymphatic-vascular remodeling.}, keywords = {endothelial cell growth, glycosaminoglycan, lymphatic capillary, Proteoglycan, vascular endothelial growth factor receptor}, doi = {10.1161/CIRCRESAHA.116.308504}, url = {http://circres.ahajournals.org/content/early/2016/05/25/CIRCRESAHA.116.308504}, author = {Johns, Scott C. and Yin, Xin and Jeltsch, Michael and Bishop, Joseph R. and Schuksz, Manuela and Ghazal, Roland El and Wilcox-Adelman, Sarah A. and Alitalo, Kari and Fuster, Mark M.} } @article {502, title = {Functional Dissection of the CCBE1 Protein: A Crucial Requirement for the Collagen Repeat Domain.}, journal = {Circ Res}, volume = {116}, year = {2015}, month = {2015 May 8}, pages = {1660-1669}, abstract = {

RATIONALE: Collagen- and calcium-binding EGF domain-containing protein 1 (CCBE1) is essential for lymphangiogenesis in vertebrates and has been associated with Hennekam syndrome. Recently, CCBE1 has emerged as a crucial regulator of vascular endothelial growth factor-C (VEGFC) signaling.

OBJECTIVE: CCBE1 is a secreted protein characterized by 2 EGF domains and 2 collagen repeats. The functional role of the different CCBE1 protein domains is completely unknown. Here, we analyzed the functional role of the different CCBE1 domains in vivo and in vitro.

METHODS AND RESULTS: We analyzed the functionality of several CCBE1 deletion mutants by generating knock-in mice expressing these mutants, by analyzing their ability to enhance Vegfc signaling in vivo in zebrafish, and by testing their ability to induce VEGFC processing in vitro. We found that deleting the collagen domains of CCBE1 has a much stronger effect on CCBE1 activity than deleting the EGF domains. First, although CCBE1ΔCollagen mice fully phenocopy CCBE1 knock-out mice, CCBE1ΔEGF knock-in embryos still form rudimentary lymphatics. Second, Ccbe1ΔEGF, but not Ccbe1ΔCollagen, could partially substitute for Ccbe1 to enhance Vegfc signaling in zebrafish. Third, CCBE1ΔEGF, similarly to CCBE1, but not CCBE1ΔCollagen could activate VEGFC processing in vitro. Furthermore, a Hennekam syndrome mutation within the collagen domain has a stronger effect than a Hennekam syndrome mutation within the EGF domain.

CONCLUSIONS: We propose that the collagen domains of CCBE1 are crucial for the activation of VEGFC in vitro and in vivo. The EGF domains of CCBE1 are dispensable for regulation of VEGFC processing in vitro, however, they are necessary for full lymphangiogenic activity of CCBE1 in vivo.

}, keywords = {Animals, Binding Sites, Calcium-Binding Proteins, Collagen, Craniofacial Abnormalities, Endothelial Cells, Epidermal Growth Factor, Gene Expression Regulation, Developmental, Gene Knock-In Techniques, Genital Diseases, Male, Genotype, Gestational Age, HEK293 Cells, Humans, Lymphangiectasis, Intestinal, Lymphatic Vessels, lymphedema, Mice, Mice, Transgenic, Mutation, Phenotype, Protein Binding, Protein Interaction Domains and Motifs, Signal Transduction, Transfection, Tumor Suppressor Proteins, Vascular Endothelial Growth Factor C, Zebrafish, Zebrafish Proteins}, issn = {1524-4571}, doi = {10.1161/CIRCRESAHA.116.304949}, url = {http://circres.ahajournals.org/content/116/10/1660.long}, author = {Roukens, M Guy and Peterson-Maduro, Josi and Padberg, Yvonne and Jeltsch, Michael and Lepp{\"a}nen, Veli-Matti and Bos, Frank L and Alitalo, Kari and Schulte-Merker, Stefan and Schulte, D{\"o}rte} } @proceedings {511, title = {From molecular biology to a causal treatment of lymphatic system disorders}, year = {2014}, month = {10/2014}, publisher = {Deutsche Gesellschaft f{\"u}r Lymphologie}, address = {Halle (Saale), Germany}, abstract = {Original Conference Abstracts (in German)}, keywords = {ADAMTS3, CCBE1, Lymphangiogenesis, lymphedema, VEGF-C, VEGFR-3}, url = {https://jeltsch.org/abstract-Halle2014}, author = {Jeltsch, M} } @article {31, title = {Functional interaction of VEGF-C and VEGF-D with neuropilin receptors}, journal = {FASEB J}, volume = {20}, year = {2006}, month = {2006/Jul/}, pages = {1462 - 72}, abstract = {Lymphatic vascular development is regulated by vascular endothelial growth factor receptor-3 (VEGFR-3), which is activated by its ligands VEGF-C and VEGF-D. Neuropilin-2 (NP2), known to be involved in neuronal development, has also been implicated to play a role in lymphangiogenesis. We aimed to elucidate the mechanism by which NP2 is involved in lymphatic endothelial cell signaling. By in vitro binding studies we found that both VEGF-C and VEGF-D interact with NP2, VEGF-C in a heparin-independent and VEGF-D in a heparin-dependent manner. We also mapped the domains of VEGF-C and NP2 required for their binding. The functional importance of the interaction of NP2 with the lymphangiogenic growth factors was demonstrated by cointernalization of NP2 along with VEGFR-3 in endocytic vesicles of lymphatic endothelial cells upon stimulation with VEGF-C or VEGF-D. NP2 also interacted with VEGFR-3 in coprecipitation studies. Our results show that NP2 is directly involved in an active signaling complex with the key regulators of lymphangiogenesis and thus suggest a mechanism by which NP2 functions in the development of the lymphatic vasculature.}, url = {http://view.ncbi.nlm.nih.gov/pubmed/16816121}, author = {K{\"a}rp{\"a}nen, Terhi and Heckman, Caroline A and Keskitalo, Salla and Jeltsch, Michael and Ollila, Hanna and Neufeld, Gera and Tamagnone, Luca and Alitalo, Kari} } @mastersthesis {71, title = {Functional Analysis of VEGF-B and VEGF-C}, volume = {Master{\textquoteright}s Thesis}, year = {1997}, school = {Univeristy of Helsinki}, type = {M.Sc.}, address = {Helsinki}, abstract = {Vascular endothelial growth factor (VEGF) is an important regulator of endothelial cell proliferation and migration dur- ing embryonic vasculogenesis and angiogenesis as well as in pathological angiogenesis. The recently cloned new factors structurally homologous to VEGF were designated as VEGF-B/VRF and VEGF-C/VRP. The receptor for VEGF-B is unknown. VEGF-C is the ligand for FLT4, a receptor tyrosine kinase whose expression becomes restricted largely to lymphatic endothelia during development and that is related to VEGF receptors FLT1 and KDR. In this study keratin 14-promoter-directed VEGF-C overexpression in the basal epidermis of transgenic mice was capa- ble of promoting an abundant growth of extensive lymphatic-like vessel structures in the dermis, including large vessel lacunae resembling in their histopathology the human condition known as lymphangioma. Thus, VEGF-C appears to induce selective angiogenesis of the lymphatic vessels in vivo. In contrast, preliminary data on mice, which overexpress VEGF-B under the same promoter, does not yet allow us draw any conclusions about its possible biological function. Recombinant biologically active human VEGF-C was produced using the baculovirus system. Unpurified and purified VEGF-C were used to confirm the interaction of VEGF-C with KDR, a fact recently missed by others. The recombinant protein is going to be used in a large number of future experiments. The production of VEGF-B seems to be intrinsically difficult in non-mammalian cells. Although quantitatively satisfying results could not be obtained yet, the purified growth factor will be used in experiments to identify its receptor.}, keywords = {VEGF-B, VEGF-C}, url = {http://urn.fi/URN:NBN:fi-fe977347}, author = {Jeltsch, Michael} }