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Papers by Julian Nicenboim

Research paper thumbnail of Bacteriophage therapy against pathological Klebsiella pneumoniae that determine the clinical course of primary sclerosing cholangitis

Research paper thumbnail of Bacteriophage therapy against pathological Klebsiella pneumoniae ameliorates the course of primary sclerosing cholangitis

Nature Communications

Primary sclerosing cholangitis (PSC) is characterized by progressive biliary inflammation and fib... more Primary sclerosing cholangitis (PSC) is characterized by progressive biliary inflammation and fibrosis. Although gut commensals are associated with PSC, their causative roles and therapeutic strategies remain elusive. Here we detect abundant Klebsiella pneumoniae (Kp) and Enterococcus gallinarum in fecal samples from 45 PSC patients, regardless of intestinal complications. Carriers of both pathogens exhibit high disease activity and poor clinical outcomes. Colonization of PSC-derived Kp in specific pathogen-free (SPF) hepatobiliary injury-prone mice enhances hepatic Th17 cell responses and exacerbates liver injury through bacterial translocation to mesenteric lymph nodes. We developed a lytic phage cocktail that targets PSC-derived Kp with a sustained suppressive effect in vitro. Oral administration of the phage cocktail lowers Kp levels in Kp-colonized germ-free mice and SPF mice, without off-target dysbiosis. Furthermore, we demonstrate that oral and intravenous phage administrati...

Research paper thumbnail of Development of a topical bacteriophage gel targeting Cutibacterium acnes for acne prone skin and results of a phase 1 cosmetic randomized clinical trial

Skin Health and Disease, 2022

BackgroundTopical antibiotics are frequently used to treat acne vulgaris. Their prolonged use, of... more BackgroundTopical antibiotics are frequently used to treat acne vulgaris. Their prolonged use, often for longer durations than recommended, has led to antibiotic resistance in Cutibacterium acnes (C. acnes), a bacterium implicated in acne pathophysiology. Bacteriophage (phage), which specifically target C. acnes by a different mechanism of action and do not harm potentially beneficial bacteria, may offer an alternative approach for improvement of the appearance of acne prone skin.ObjectivesTo identify and characterize C. acnes targeting phage, carry out a comprehensive preclinical safety evaluation of phages selected for further development and examine their safety, tolerability and ability to target facial C. acnes when applied topically in a cosmetic clinical study including participants with mild‐to‐moderate acne.MethodsPhages were isolated by conventional microbiological methods also used to examine their breadth of host range on different C. acnes strains and specificity to thi...

Research paper thumbnail of 82P Novel analysis of F. nucleatum subspecies in human CRC tissue and engineering of therapeutic F. nucleatum phage

Research paper thumbnail of ePS3.06 Isolation and characterisation of nebulised phage for treatment of chronic Pseudomonas aeruginosa (Pa) pulmonary infections in cystic fibrosis (CF) patients

Journal of Cystic Fibrosis

Research paper thumbnail of Targeted suppression of human IBD-associated gut microbiota commensals by phage consortia for treatment of intestinal inflammation

Research paper thumbnail of Generation of specialized blood vessels via lymphatic transdifferentiation

Research paper thumbnail of Lymphatic vessels arise from specialized angioblasts within a venous niche

Research paper thumbnail of Abstract P064: Novel engineering of therapeutic Fusobacterium nucleatum phage for colorectal cancer treatment

Research paper thumbnail of Cellular and molecular mechanisms underlying the development of late-forming vessels

Research paper thumbnail of Generation of specialized blood vessels through transdifferentiation of lymphatic endothelial cells

The lineage and developmental trajectory of a cell are key determinants of cellular identity. Yet... more The lineage and developmental trajectory of a cell are key determinants of cellular identity. Yet, the functional relevance of deriving a specific cell type from ontologically distinct progenitors, remains an open question. In the case of the vascular system, blood and lymphatic vessels are composed of endothelial cells (ECs) that differentiate and diversify to cater the different physiological demands of each organ. While lymphatic vessels have been shown to originate from multiple cell sources, lymphatic ECs (LECs) themselves seem to have a unipotent cell fate. In this work we uncover a novel mechanism of blood vessel formation through transdifferentiation of LECs. Using advanced long-term reiterative imaging and lineage-tracing of ECs in zebrafish, from embryonic development through adulthood, we reveal a hitherto unknown process of LEC-to-BEC transdifferentiation, underlying vascularization of the anal fin (AF). Moreover, we demonstrate distinct functional implications for deriv...

Research paper thumbnail of BACH family members regulate angiogenesis and lymphangiogenesis by modulating VEGFC expression

Angiogenesis and lymphangiogenesis are key processes during embryogenesis as well as under physio... more Angiogenesis and lymphangiogenesis are key processes during embryogenesis as well as under physiological and pathological conditions. Vascular endothelial growth factor C (VEGFC), the ligand for both VEGFR2 and VEGFR3, is a central lymphangiogenic regulator that also drives angiogenesis. Here we report that members of the highly conserved BACH (BTB and CNC homology) family of transcription factors regulate VEGFC expression, through direct binding to its promoter. Accordingly, downregulation of bach2a hinders blood-vessel formation and impairs lymphatic sprouting in a vegfc-dependent manner during zebrafish embryonic development. In contrast, BACH1-overexpression enhances intratumoral blood-vessel density and peritumoral lymphatic vessel diameter in ovarian and lung mouse tumor models. The effects on the vascular compartment correlate spatially and temporally with BACH1 transcriptional regulation of VEGFC expression. Altogether, our results uncover a novel role for the BACH/VEGFC sig...

Research paper thumbnail of Development of the lymphatic system: new questions and paradigms

Development, 2016

The lymphatic system is a blind-ended network of vessels that plays important roles in mediating ... more The lymphatic system is a blind-ended network of vessels that plays important roles in mediating tissue fluid homeostasis, intestinal lipid absorption and the immune response. A profound understanding of the development of lymphatic vessels, as well as of the molecular cues governing their formation and morphogenesis, might prove essential for our ability to treat lymphatic-related diseases. The embryonic origins of lymphatic vessels have been debated for over a century, with a model claiming a venous origin for the lymphatic endothelium being predominant. However, recent studies have provided new insights into the origins of lymphatic vessels. Here, we review the molecular mechanisms controlling lymphatic specification and sprouting, and we discuss exciting findings that shed new light on previously uncharacterized sources of lymphatic endothelial cells.

Research paper thumbnail of Venous-derived angioblasts generate organ-specific vessels during embryonic development

Development, 2015

Formation and remodeling of vascular beds are complex processes orchestrated by multiple signalin... more Formation and remodeling of vascular beds are complex processes orchestrated by multiple signaling pathways. While it is well accepted that vessels of a particular organ display specific features that enable them to fulfill distinct functions, the embryonic origins of tissue-specific vessels, as well as the molecular mechanisms regulating their formation, are poorly understood. The subintestinal plexus of the zebrafish embryo comprises vessels that vascularize the gut, liver and pancreas, and as such represents an ideal model to investigate the early steps of organ-specific vessel formation. Here we show that both arterial and venous components of the subintestinal plexus originate from a pool of specialized angioblasts residing in the floor of the Posterior Cardinal Vein (PCV). Using live imaging of zebrafish embryos, in combination with photoconvertable transgenic reporters, we demonstrate that these angioblasts undergo two phases of migration and differentiation. Initially, a sub...

Research paper thumbnail of Genetic Ablation of Hypocretin Neurons Alters Behavioral State Transitions in Zebrafish

Journal of Neuroscience, 2012

Research paper thumbnail of Venous-derived angioblasts generate organ-specific vessels during embryonic development

Development, Nov 2, 2015

Formation and remodeling of vascular beds are complex processes orchestrated by multiple signalin... more Formation and remodeling of vascular beds are complex processes orchestrated by multiple signaling pathways. Although it is well accepted that vessels of a particular organ display specific features that enable them to fulfill distinct functions, the embryonic origins of tissue-specific vessels and the molecular mechanisms regulating their formation are poorly understood. The subintestinal plexus of the zebrafish embryo comprises vessels that vascularize the gut, liver and pancreas and, as such, represents an ideal model in which to investigate the early steps of organ-specific vessel formation. Here, we show that both arterial and venous components of the subintestinal plexus originate from a pool of specialized angioblasts residing in the floor of the posterior cardinal vein (PCV). Using live imaging of zebrafish embryos, in combination with photoconvertable transgenic reporters, we demonstrate that these angioblasts undergo two phases of migration and differentiation. Initially, a subintestinal vein forms and expands ventrally through a Bone Morphogenetic Protein-dependent step of collective migration. Concomitantly, a Vascular Endothelial Growth Factor-dependent shift in the directionality of migration, coupled to the upregulation of arterial markers, is observed, which culminates with the generation of the supraintestinal artery. Together, our results establish the zebrafish subintestinal plexus as an advantageous model for the study of organ-specific vessel development and provide new insights into the molecular mechanisms controlling its formation. More broadly, our findings suggest that PCV-specialized angioblasts contribute not only to the formation of the early trunk vasculature, but also to the establishment of late-forming, tissue-specific vascular beds.

Research paper thumbnail of Bacteriophage therapy against pathological Klebsiella pneumoniae that determine the clinical course of primary sclerosing cholangitis

Research paper thumbnail of Bacteriophage therapy against pathological Klebsiella pneumoniae ameliorates the course of primary sclerosing cholangitis

Nature Communications

Primary sclerosing cholangitis (PSC) is characterized by progressive biliary inflammation and fib... more Primary sclerosing cholangitis (PSC) is characterized by progressive biliary inflammation and fibrosis. Although gut commensals are associated with PSC, their causative roles and therapeutic strategies remain elusive. Here we detect abundant Klebsiella pneumoniae (Kp) and Enterococcus gallinarum in fecal samples from 45 PSC patients, regardless of intestinal complications. Carriers of both pathogens exhibit high disease activity and poor clinical outcomes. Colonization of PSC-derived Kp in specific pathogen-free (SPF) hepatobiliary injury-prone mice enhances hepatic Th17 cell responses and exacerbates liver injury through bacterial translocation to mesenteric lymph nodes. We developed a lytic phage cocktail that targets PSC-derived Kp with a sustained suppressive effect in vitro. Oral administration of the phage cocktail lowers Kp levels in Kp-colonized germ-free mice and SPF mice, without off-target dysbiosis. Furthermore, we demonstrate that oral and intravenous phage administrati...

Research paper thumbnail of Development of a topical bacteriophage gel targeting Cutibacterium acnes for acne prone skin and results of a phase 1 cosmetic randomized clinical trial

Skin Health and Disease, 2022

BackgroundTopical antibiotics are frequently used to treat acne vulgaris. Their prolonged use, of... more BackgroundTopical antibiotics are frequently used to treat acne vulgaris. Their prolonged use, often for longer durations than recommended, has led to antibiotic resistance in Cutibacterium acnes (C. acnes), a bacterium implicated in acne pathophysiology. Bacteriophage (phage), which specifically target C. acnes by a different mechanism of action and do not harm potentially beneficial bacteria, may offer an alternative approach for improvement of the appearance of acne prone skin.ObjectivesTo identify and characterize C. acnes targeting phage, carry out a comprehensive preclinical safety evaluation of phages selected for further development and examine their safety, tolerability and ability to target facial C. acnes when applied topically in a cosmetic clinical study including participants with mild‐to‐moderate acne.MethodsPhages were isolated by conventional microbiological methods also used to examine their breadth of host range on different C. acnes strains and specificity to thi...

Research paper thumbnail of 82P Novel analysis of F. nucleatum subspecies in human CRC tissue and engineering of therapeutic F. nucleatum phage

Research paper thumbnail of ePS3.06 Isolation and characterisation of nebulised phage for treatment of chronic Pseudomonas aeruginosa (Pa) pulmonary infections in cystic fibrosis (CF) patients

Journal of Cystic Fibrosis

Research paper thumbnail of Targeted suppression of human IBD-associated gut microbiota commensals by phage consortia for treatment of intestinal inflammation

Research paper thumbnail of Generation of specialized blood vessels via lymphatic transdifferentiation

Research paper thumbnail of Lymphatic vessels arise from specialized angioblasts within a venous niche

Research paper thumbnail of Abstract P064: Novel engineering of therapeutic Fusobacterium nucleatum phage for colorectal cancer treatment

Research paper thumbnail of Cellular and molecular mechanisms underlying the development of late-forming vessels

Research paper thumbnail of Generation of specialized blood vessels through transdifferentiation of lymphatic endothelial cells

The lineage and developmental trajectory of a cell are key determinants of cellular identity. Yet... more The lineage and developmental trajectory of a cell are key determinants of cellular identity. Yet, the functional relevance of deriving a specific cell type from ontologically distinct progenitors, remains an open question. In the case of the vascular system, blood and lymphatic vessels are composed of endothelial cells (ECs) that differentiate and diversify to cater the different physiological demands of each organ. While lymphatic vessels have been shown to originate from multiple cell sources, lymphatic ECs (LECs) themselves seem to have a unipotent cell fate. In this work we uncover a novel mechanism of blood vessel formation through transdifferentiation of LECs. Using advanced long-term reiterative imaging and lineage-tracing of ECs in zebrafish, from embryonic development through adulthood, we reveal a hitherto unknown process of LEC-to-BEC transdifferentiation, underlying vascularization of the anal fin (AF). Moreover, we demonstrate distinct functional implications for deriv...

Research paper thumbnail of BACH family members regulate angiogenesis and lymphangiogenesis by modulating VEGFC expression

Angiogenesis and lymphangiogenesis are key processes during embryogenesis as well as under physio... more Angiogenesis and lymphangiogenesis are key processes during embryogenesis as well as under physiological and pathological conditions. Vascular endothelial growth factor C (VEGFC), the ligand for both VEGFR2 and VEGFR3, is a central lymphangiogenic regulator that also drives angiogenesis. Here we report that members of the highly conserved BACH (BTB and CNC homology) family of transcription factors regulate VEGFC expression, through direct binding to its promoter. Accordingly, downregulation of bach2a hinders blood-vessel formation and impairs lymphatic sprouting in a vegfc-dependent manner during zebrafish embryonic development. In contrast, BACH1-overexpression enhances intratumoral blood-vessel density and peritumoral lymphatic vessel diameter in ovarian and lung mouse tumor models. The effects on the vascular compartment correlate spatially and temporally with BACH1 transcriptional regulation of VEGFC expression. Altogether, our results uncover a novel role for the BACH/VEGFC sig...

Research paper thumbnail of Development of the lymphatic system: new questions and paradigms

Development, 2016

The lymphatic system is a blind-ended network of vessels that plays important roles in mediating ... more The lymphatic system is a blind-ended network of vessels that plays important roles in mediating tissue fluid homeostasis, intestinal lipid absorption and the immune response. A profound understanding of the development of lymphatic vessels, as well as of the molecular cues governing their formation and morphogenesis, might prove essential for our ability to treat lymphatic-related diseases. The embryonic origins of lymphatic vessels have been debated for over a century, with a model claiming a venous origin for the lymphatic endothelium being predominant. However, recent studies have provided new insights into the origins of lymphatic vessels. Here, we review the molecular mechanisms controlling lymphatic specification and sprouting, and we discuss exciting findings that shed new light on previously uncharacterized sources of lymphatic endothelial cells.

Research paper thumbnail of Venous-derived angioblasts generate organ-specific vessels during embryonic development

Development, 2015

Formation and remodeling of vascular beds are complex processes orchestrated by multiple signalin... more Formation and remodeling of vascular beds are complex processes orchestrated by multiple signaling pathways. While it is well accepted that vessels of a particular organ display specific features that enable them to fulfill distinct functions, the embryonic origins of tissue-specific vessels, as well as the molecular mechanisms regulating their formation, are poorly understood. The subintestinal plexus of the zebrafish embryo comprises vessels that vascularize the gut, liver and pancreas, and as such represents an ideal model to investigate the early steps of organ-specific vessel formation. Here we show that both arterial and venous components of the subintestinal plexus originate from a pool of specialized angioblasts residing in the floor of the Posterior Cardinal Vein (PCV). Using live imaging of zebrafish embryos, in combination with photoconvertable transgenic reporters, we demonstrate that these angioblasts undergo two phases of migration and differentiation. Initially, a sub...

Research paper thumbnail of Genetic Ablation of Hypocretin Neurons Alters Behavioral State Transitions in Zebrafish

Journal of Neuroscience, 2012

Research paper thumbnail of Venous-derived angioblasts generate organ-specific vessels during embryonic development

Development, Nov 2, 2015

Formation and remodeling of vascular beds are complex processes orchestrated by multiple signalin... more Formation and remodeling of vascular beds are complex processes orchestrated by multiple signaling pathways. Although it is well accepted that vessels of a particular organ display specific features that enable them to fulfill distinct functions, the embryonic origins of tissue-specific vessels and the molecular mechanisms regulating their formation are poorly understood. The subintestinal plexus of the zebrafish embryo comprises vessels that vascularize the gut, liver and pancreas and, as such, represents an ideal model in which to investigate the early steps of organ-specific vessel formation. Here, we show that both arterial and venous components of the subintestinal plexus originate from a pool of specialized angioblasts residing in the floor of the posterior cardinal vein (PCV). Using live imaging of zebrafish embryos, in combination with photoconvertable transgenic reporters, we demonstrate that these angioblasts undergo two phases of migration and differentiation. Initially, a subintestinal vein forms and expands ventrally through a Bone Morphogenetic Protein-dependent step of collective migration. Concomitantly, a Vascular Endothelial Growth Factor-dependent shift in the directionality of migration, coupled to the upregulation of arterial markers, is observed, which culminates with the generation of the supraintestinal artery. Together, our results establish the zebrafish subintestinal plexus as an advantageous model for the study of organ-specific vessel development and provide new insights into the molecular mechanisms controlling its formation. More broadly, our findings suggest that PCV-specialized angioblasts contribute not only to the formation of the early trunk vasculature, but also to the establishment of late-forming, tissue-specific vascular beds.