Tumor lymphangiogenesis is typically associated with cancer progression and metastasis. However, ... more Tumor lymphangiogenesis is typically associated with cancer progression and metastasis. However, recent studies from our group have demonstrated that tumor lymphangiogenesis promotes intratumor T cell infiltration and potentiates the efficacy of a wide range of immunotherapies in melanoma-bearing mice as well as patients undergoing checkpoint blockade. Radiotherapy (RT) can also induce immunogenic tumor cell death, so we investigated whether lymphangiogenic tumors would yield more immunogenic responses to RT than non-lymphangiogenic tumors. Here, we compared effects of RT in mice bearing B16-F10 melanomas expressing either a control vector (B16-Ctrl) or overexpression the lymphangiogenic factor VEGF-C (B16-VC), where lymphatic vessels were significantly increased in number and size compared to B16-Ctrl tumors. First, we find that B16-VC regress faster than B16-CT after RT (either a single 20 Gy dose or two 15 Gy doses), and that this regression was correlated with enhanced CD8+ T cell activity. On the other hand, lymphatic endothelial cells (LECs) can be more sensitive to damage from RT if they are undergoing lymphangiogenesis. We found that irradiated B16-VC tumors showed higher levels of intra-lymphatic fibrin. Consistent with this, LECs in the irradiated B16-VC tumors expressed higher levels of tissue factor and caspase-3, which correlated with the degree of lymphatic clotting. Fibrin clotting was also observed in the subcapsular sinus of the draining lymph nodes of irradiated B16-VC tumors. These findings highlight the complex role of tumor lymphangiogenesis in radiotherapy responses, where they may potentiate acute anti-tumor immune responses but may also cause localized damage of the vasculature, potentially leading to increased metastasis. Further studies are needed to investigate therapeutic targets to inhibit lymphatic coagulation and look at its effects on cancer immunotherapy and metastasis. Citation Format: Anish Mukherjee, Nikolaos Mitrousis, Mari Stella Sasso, Margo MacDonald, Ainhoa Arina, Phillip Ang, Ariana Baginski, J. Emiliano G. Medellin, Ralph R. Weichselbaum, Melody A. Swartz. Tumor lymphangiogenesis sensitizes melanomas to the immunological effects of radiotherapy but also disrupts the local lymphatic vasculature. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4585.
Skull malformations are associated with vascular anomalies that can impair fluid balance in the c... more Skull malformations are associated with vascular anomalies that can impair fluid balance in the central nervous system. We previously reported that humans with craniosynostosis and mutations in TWIST1 have dural venous sinus malformations. It is still unknown whether meningeal lymphatic networks, which are patterned alongside the venous sinuses, are also affected. We now show that the growth and expansion of meningeal lymphatics are perturbed in Twist1 craniosynostosis models. Changes to the local meningeal environment, including hypoplastic dura and venous malformations, affect the ability of lymphatic networks to sprout and remodel. Dorsal networks along the transverse sinus are hypoplastic with reduced branching. By contrast, basal networks closer to the skull base are more variably affected, showing exuberant growth in some animals, suggesting they are compensating for vessel loss in dorsal networks. Injecting a molecular tracer into cerebrospinal fluid reveals significantly less drainage to the deep cervical lymph nodes, which is indicative of impaired lymphatic function. Collectively, our results show that meningeal lymphatic networks are affected in craniosynostosis, suggesting that the clearance of β-amyloid and waste from the central nervous system may be impeded.
bioRxiv (Cold Spring Harbor Laboratory), Apr 29, 2023
Butyrate, a metabolite produced by commensal bacteria, has been intensively studied for its immun... more Butyrate, a metabolite produced by commensal bacteria, has been intensively studied for its immunomodulatory effects on various immune cells, including T regulatory cells, macrophages, and dendritic cells. Butyrate's development as a drug has been limited by its poor oral bioavailability due to its rapid metabolism in the gut, its low potency and thus high dosing, and its foul smell and taste. By simply esterifying butyrate to serine (SerBut), a design based on the concept of utilizing amino acid transporters to escape the gut and enhance systemic uptake thus increasing bioavailability, we developed an odorless and tasteless compound for oral administration. In the collagen antibody-induced arthritis (CAIA) and experimental autoimmune encephalomyelitis (EAE) murine models of rheumatoid arthritis and multiple sclerosis, we demonstrated that SerBut significantly ameliorated disease severity, modulated key immune cell populations both systemically and in disease-associated tissues, and reduced inflammatory responses without compromising global immune response to vaccination. Our findings highlight SerBut as a promising next-generation therapeutic agent for autoimmune and inflammatory diseases.
ABSTRACT Craniofacial development requires precise spatiotemporal regulation of multiple signalin... more ABSTRACT Craniofacial development requires precise spatiotemporal regulation of multiple signaling pathways that crosstalk to coordinate the growth and patterning of the skull with surrounding tissues. Recent insights into these signaling pathways and previously uncharacterized progenitor cell populations have refined our understanding of skull patterning, bone mineralization and tissue homeostasis. Here, we touch upon classical studies and recent advances with an emphasis on developmental and signaling mechanisms that regulate the osteoblast lineage for the calvaria, which forms the roof of the skull. We highlight studies that illustrate the roles of osteoprogenitor cells and cranial suture-derived stem cells for proper calvarial growth and homeostasis. We also discuss genes and signaling pathways that control suture patency and highlight how perturbing the molecular regulation of these pathways leads to craniosynostosis. Finally, we discuss the recently discovered tissue and signaling interactions that integrate skull and cerebrovascular development, and the potential implications for both cerebrospinal fluid hydrodynamics and brain waste clearance in craniosynostosis.
Skull development coincides with the onset of cerebrospinal fluid (CSF) circulation, brain-CSF pe... more Skull development coincides with the onset of cerebrospinal fluid (CSF) circulation, brain-CSF perfusion, and meningeal lymphangiogenesis, processes essential for brain waste clearance. How these processes are affected by craniofacial disorders such as craniosynostosis are poorly understood. We report that raised intracranial pressure and diminished CSF flow in craniosynostosis mouse models associates with pathological changes to meningeal lymphatic vessels that affect their sprouting, expansion, and long-term maintenance. We also show that craniosynostosis affects CSF circulatory pathways and perfusion into the brain. Further, craniosynostosis exacerbates amyloid pathology and plaque buildup inTwist1+/−:5xFADtransgenic Alzheimer’s disease models. Treating craniosynostosis mice with Yoda1, a small molecule agonist for Piezo1, reduces intracranial pressure and improves CSF flow, in addition to restoring meningeal lymphangiogenesis, drainage to the deep cervical lymph nodes, and brain...
Sickle cell disease (SCD) is the most common monogenetic condition in the United States (US) and ... more Sickle cell disease (SCD) is the most common monogenetic condition in the United States (US) and one that has been subjected to a history of negative bias. Since SCD was first described approximately 120 years ago, the medical establishment has, directly and indirectly, harmed patients by reinforcing biases and assumptions about the disease. Furthermore, negative biases and stigmas have been levied upon patients with SCD by healthcare providers and society, researchers, and legislators. This article will explore the historical context of SCD in the US; discuss specific issues in care that lead to biases, social and self-stigma, inequities in access to care, and research funding; and highlight interventions over recent years that address racial biases and stigma.
Secondary lissencephaly evolved in mice due to effects on neurogenesis and the tangential distrib... more Secondary lissencephaly evolved in mice due to effects on neurogenesis and the tangential distribution of neurons. Signaling pathways that help maintain lissencephaly are still poorly understood. We show that inactivating Twist1 in the primitive meninges causes cortical folding in mice. Cell proliferation in the meninges is reduced, causing loss of arachnoid fibroblasts that express Raldh2, an enzyme required for retinoic acid synthesis. Regionalized loss of Raldh2 in the dorsolateral meninges is first detected when folding begins. The ventricular zone expands and the forebrain lengthens at this time due to expansion of apical radial glia. As the cortex expands, regionalized differences in the levels of neurogenesis are coupled with changes to the tangential distribution of neurons. Consequentially, cortical growth at and adjacent to the midline accelerates in respect to more dorsolateral regions, resulting in cortical buckling and folding. Maternal retinoic acid supplementation sup...
Tumor lymphangiogenesis is typically associated with cancer progression and metastasis. However, ... more Tumor lymphangiogenesis is typically associated with cancer progression and metastasis. However, recent studies from our group have demonstrated that tumor lymphangiogenesis promotes intratumor T cell infiltration and potentiates the efficacy of a wide range of immunotherapies in melanoma-bearing mice as well as patients undergoing checkpoint blockade. Radiotherapy (RT) can also induce immunogenic tumor cell death, so we investigated whether lymphangiogenic tumors would yield more immunogenic responses to RT than non-lymphangiogenic tumors. Here, we compared effects of RT in mice bearing B16-F10 melanomas expressing either a control vector (B16-Ctrl) or overexpression the lymphangiogenic factor VEGF-C (B16-VC), where lymphatic vessels were significantly increased in number and size compared to B16-Ctrl tumors. First, we find that B16-VC regress faster than B16-CT after RT (either a single 20 Gy dose or two 15 Gy doses), and that this regression was correlated with enhanced CD8+ T ce...
Butyrate, a metabolite produced by commensal bacteria, has been intensively studied for its immun... more Butyrate, a metabolite produced by commensal bacteria, has been intensively studied for its immunomodulatory effects on various immune cells, including T regulatory cells, macrophages, and dendritic cells. Butyrate's development as a drug has been limited by its poor oral bioavailability due to its rapid metabolism in the gut, its low potency and thus high dosing, and its foul smell and taste. By simply esterifying butyrate to serine (SerBut), a design based on the concept of utilizing amino acid transporters to escape the gut and enhance systemic uptake thus increasing bioavailability, we developed an odorless and tasteless compound for oral administration. In the collagen antibody-induced arthritis (CAIA) and experimental autoimmune encephalomyelitis (EAE) murine models of rheumatoid arthritis and multiple sclerosis, we demonstrated that SerBut significantly ameliorated disease severity, modulated key immune cell populations both systemically and in disease-associated tissues,...
Craniofacial development requires precise spatiotemporal regulation of multiple signaling pathway... more Craniofacial development requires precise spatiotemporal regulation of multiple signaling pathways that crosstalk to coordinate the growth and patterning of the skull with surrounding tissues. Recent insights into these signaling pathways and previously uncharacterized progenitor cell populations have refined our understanding of skull patterning, bone mineralization and tissue homeostasis. Here, we touch upon classical studies and recent advances with an emphasis on developmental and signaling mechanisms that regulate the osteoblast lineage for the calvaria, which forms the roof of the skull. We highlight studies that illustrate the roles of osteoprogenitor cells and cranial suture-derived stem cells for proper calvarial growth and homeostasis. We also discuss genes and signaling pathways that control suture patency and highlight how perturbing the molecular regulation of these pathways leads to craniosynostosis. Finally, we discuss the recently discovered tissue and signaling inte...
Evolution of cortical folding in gyrencephalic animals enabled higher cognitive functions and com... more Evolution of cortical folding in gyrencephalic animals enabled higher cognitive functions and complex behaviors. Gene expression patterns and signaling molecules that control cortical folding have only recently been described and thus are still not well understood. In transgenic mouse models with induced cortical folding, amplification of neuroprogenitor cells or loss of their adhesion from the apical ventricular surface leads to gyri formation, whereas decreased cell adhesion in migrating projection neurons causes abnormal neuronal clustering and development of cortical fissures that resemble sulci. We now report that loss of Twist1 expression in the primitive meninx results in cortical folding and sulci formation in the dorsolateral telencephalon. In developing sulcal regions, generation of apical and basal neuroprogenitor cells is normal. Instead, cell proliferation in the developing meninges is reduced, leading to loss of arachnoid fibroblasts that express Raldh2, an enzyme requ...
Congenital skull malformations are associated with vascular anomalies that can impair fluid balan... more Congenital skull malformations are associated with vascular anomalies that can impair fluid balance in the central nervous system. We previously reported that humans with craniosynostosis and mutations in TWIST1 have dural venous sinus malformations. It is still unknown whether meningeal lymphatic networks, which are patterned alongside the venous sinuses, are also affected. Using a novel skull flat mounting technique, we show that the growth and expansion of meningeal lymphatics are perturbed in Twist1 craniosynostosis models. Changes to the local meningeal environment, including hypoplastic dura and venous malformations, affect the ability of lymphatic networks to sprout and remodel. Dorsal networks along the transverse sinus are hypoplastic with reduced branching. By contrast, basal networks closer to the skull base are more variably affected, showing exuberant growth in some animals suggesting they are compensating for vessel loss in dorsal networks. Injecting molecular tracers ...
Tumor lymphangiogenesis is typically associated with cancer progression and metastasis. However, ... more Tumor lymphangiogenesis is typically associated with cancer progression and metastasis. However, recent studies from our group have demonstrated that tumor lymphangiogenesis promotes intratumor T cell infiltration and potentiates the efficacy of a wide range of immunotherapies in melanoma-bearing mice as well as patients undergoing checkpoint blockade. Radiotherapy (RT) can also induce immunogenic tumor cell death, so we investigated whether lymphangiogenic tumors would yield more immunogenic responses to RT than non-lymphangiogenic tumors. Here, we compared effects of RT in mice bearing B16-F10 melanomas expressing either a control vector (B16-Ctrl) or overexpression the lymphangiogenic factor VEGF-C (B16-VC), where lymphatic vessels were significantly increased in number and size compared to B16-Ctrl tumors. First, we find that B16-VC regress faster than B16-CT after RT (either a single 20 Gy dose or two 15 Gy doses), and that this regression was correlated with enhanced CD8+ T cell activity. On the other hand, lymphatic endothelial cells (LECs) can be more sensitive to damage from RT if they are undergoing lymphangiogenesis. We found that irradiated B16-VC tumors showed higher levels of intra-lymphatic fibrin. Consistent with this, LECs in the irradiated B16-VC tumors expressed higher levels of tissue factor and caspase-3, which correlated with the degree of lymphatic clotting. Fibrin clotting was also observed in the subcapsular sinus of the draining lymph nodes of irradiated B16-VC tumors. These findings highlight the complex role of tumor lymphangiogenesis in radiotherapy responses, where they may potentiate acute anti-tumor immune responses but may also cause localized damage of the vasculature, potentially leading to increased metastasis. Further studies are needed to investigate therapeutic targets to inhibit lymphatic coagulation and look at its effects on cancer immunotherapy and metastasis. Citation Format: Anish Mukherjee, Nikolaos Mitrousis, Mari Stella Sasso, Margo MacDonald, Ainhoa Arina, Phillip Ang, Ariana Baginski, J. Emiliano G. Medellin, Ralph R. Weichselbaum, Melody A. Swartz. Tumor lymphangiogenesis sensitizes melanomas to the immunological effects of radiotherapy but also disrupts the local lymphatic vasculature. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4585.
Skull malformations are associated with vascular anomalies that can impair fluid balance in the c... more Skull malformations are associated with vascular anomalies that can impair fluid balance in the central nervous system. We previously reported that humans with craniosynostosis and mutations in TWIST1 have dural venous sinus malformations. It is still unknown whether meningeal lymphatic networks, which are patterned alongside the venous sinuses, are also affected. We now show that the growth and expansion of meningeal lymphatics are perturbed in Twist1 craniosynostosis models. Changes to the local meningeal environment, including hypoplastic dura and venous malformations, affect the ability of lymphatic networks to sprout and remodel. Dorsal networks along the transverse sinus are hypoplastic with reduced branching. By contrast, basal networks closer to the skull base are more variably affected, showing exuberant growth in some animals, suggesting they are compensating for vessel loss in dorsal networks. Injecting a molecular tracer into cerebrospinal fluid reveals significantly less drainage to the deep cervical lymph nodes, which is indicative of impaired lymphatic function. Collectively, our results show that meningeal lymphatic networks are affected in craniosynostosis, suggesting that the clearance of β-amyloid and waste from the central nervous system may be impeded.
bioRxiv (Cold Spring Harbor Laboratory), Apr 29, 2023
Butyrate, a metabolite produced by commensal bacteria, has been intensively studied for its immun... more Butyrate, a metabolite produced by commensal bacteria, has been intensively studied for its immunomodulatory effects on various immune cells, including T regulatory cells, macrophages, and dendritic cells. Butyrate's development as a drug has been limited by its poor oral bioavailability due to its rapid metabolism in the gut, its low potency and thus high dosing, and its foul smell and taste. By simply esterifying butyrate to serine (SerBut), a design based on the concept of utilizing amino acid transporters to escape the gut and enhance systemic uptake thus increasing bioavailability, we developed an odorless and tasteless compound for oral administration. In the collagen antibody-induced arthritis (CAIA) and experimental autoimmune encephalomyelitis (EAE) murine models of rheumatoid arthritis and multiple sclerosis, we demonstrated that SerBut significantly ameliorated disease severity, modulated key immune cell populations both systemically and in disease-associated tissues, and reduced inflammatory responses without compromising global immune response to vaccination. Our findings highlight SerBut as a promising next-generation therapeutic agent for autoimmune and inflammatory diseases.
ABSTRACT Craniofacial development requires precise spatiotemporal regulation of multiple signalin... more ABSTRACT Craniofacial development requires precise spatiotemporal regulation of multiple signaling pathways that crosstalk to coordinate the growth and patterning of the skull with surrounding tissues. Recent insights into these signaling pathways and previously uncharacterized progenitor cell populations have refined our understanding of skull patterning, bone mineralization and tissue homeostasis. Here, we touch upon classical studies and recent advances with an emphasis on developmental and signaling mechanisms that regulate the osteoblast lineage for the calvaria, which forms the roof of the skull. We highlight studies that illustrate the roles of osteoprogenitor cells and cranial suture-derived stem cells for proper calvarial growth and homeostasis. We also discuss genes and signaling pathways that control suture patency and highlight how perturbing the molecular regulation of these pathways leads to craniosynostosis. Finally, we discuss the recently discovered tissue and signaling interactions that integrate skull and cerebrovascular development, and the potential implications for both cerebrospinal fluid hydrodynamics and brain waste clearance in craniosynostosis.
Skull development coincides with the onset of cerebrospinal fluid (CSF) circulation, brain-CSF pe... more Skull development coincides with the onset of cerebrospinal fluid (CSF) circulation, brain-CSF perfusion, and meningeal lymphangiogenesis, processes essential for brain waste clearance. How these processes are affected by craniofacial disorders such as craniosynostosis are poorly understood. We report that raised intracranial pressure and diminished CSF flow in craniosynostosis mouse models associates with pathological changes to meningeal lymphatic vessels that affect their sprouting, expansion, and long-term maintenance. We also show that craniosynostosis affects CSF circulatory pathways and perfusion into the brain. Further, craniosynostosis exacerbates amyloid pathology and plaque buildup inTwist1+/−:5xFADtransgenic Alzheimer’s disease models. Treating craniosynostosis mice with Yoda1, a small molecule agonist for Piezo1, reduces intracranial pressure and improves CSF flow, in addition to restoring meningeal lymphangiogenesis, drainage to the deep cervical lymph nodes, and brain...
Sickle cell disease (SCD) is the most common monogenetic condition in the United States (US) and ... more Sickle cell disease (SCD) is the most common monogenetic condition in the United States (US) and one that has been subjected to a history of negative bias. Since SCD was first described approximately 120 years ago, the medical establishment has, directly and indirectly, harmed patients by reinforcing biases and assumptions about the disease. Furthermore, negative biases and stigmas have been levied upon patients with SCD by healthcare providers and society, researchers, and legislators. This article will explore the historical context of SCD in the US; discuss specific issues in care that lead to biases, social and self-stigma, inequities in access to care, and research funding; and highlight interventions over recent years that address racial biases and stigma.
Secondary lissencephaly evolved in mice due to effects on neurogenesis and the tangential distrib... more Secondary lissencephaly evolved in mice due to effects on neurogenesis and the tangential distribution of neurons. Signaling pathways that help maintain lissencephaly are still poorly understood. We show that inactivating Twist1 in the primitive meninges causes cortical folding in mice. Cell proliferation in the meninges is reduced, causing loss of arachnoid fibroblasts that express Raldh2, an enzyme required for retinoic acid synthesis. Regionalized loss of Raldh2 in the dorsolateral meninges is first detected when folding begins. The ventricular zone expands and the forebrain lengthens at this time due to expansion of apical radial glia. As the cortex expands, regionalized differences in the levels of neurogenesis are coupled with changes to the tangential distribution of neurons. Consequentially, cortical growth at and adjacent to the midline accelerates in respect to more dorsolateral regions, resulting in cortical buckling and folding. Maternal retinoic acid supplementation sup...
Tumor lymphangiogenesis is typically associated with cancer progression and metastasis. However, ... more Tumor lymphangiogenesis is typically associated with cancer progression and metastasis. However, recent studies from our group have demonstrated that tumor lymphangiogenesis promotes intratumor T cell infiltration and potentiates the efficacy of a wide range of immunotherapies in melanoma-bearing mice as well as patients undergoing checkpoint blockade. Radiotherapy (RT) can also induce immunogenic tumor cell death, so we investigated whether lymphangiogenic tumors would yield more immunogenic responses to RT than non-lymphangiogenic tumors. Here, we compared effects of RT in mice bearing B16-F10 melanomas expressing either a control vector (B16-Ctrl) or overexpression the lymphangiogenic factor VEGF-C (B16-VC), where lymphatic vessels were significantly increased in number and size compared to B16-Ctrl tumors. First, we find that B16-VC regress faster than B16-CT after RT (either a single 20 Gy dose or two 15 Gy doses), and that this regression was correlated with enhanced CD8+ T ce...
Butyrate, a metabolite produced by commensal bacteria, has been intensively studied for its immun... more Butyrate, a metabolite produced by commensal bacteria, has been intensively studied for its immunomodulatory effects on various immune cells, including T regulatory cells, macrophages, and dendritic cells. Butyrate's development as a drug has been limited by its poor oral bioavailability due to its rapid metabolism in the gut, its low potency and thus high dosing, and its foul smell and taste. By simply esterifying butyrate to serine (SerBut), a design based on the concept of utilizing amino acid transporters to escape the gut and enhance systemic uptake thus increasing bioavailability, we developed an odorless and tasteless compound for oral administration. In the collagen antibody-induced arthritis (CAIA) and experimental autoimmune encephalomyelitis (EAE) murine models of rheumatoid arthritis and multiple sclerosis, we demonstrated that SerBut significantly ameliorated disease severity, modulated key immune cell populations both systemically and in disease-associated tissues,...
Craniofacial development requires precise spatiotemporal regulation of multiple signaling pathway... more Craniofacial development requires precise spatiotemporal regulation of multiple signaling pathways that crosstalk to coordinate the growth and patterning of the skull with surrounding tissues. Recent insights into these signaling pathways and previously uncharacterized progenitor cell populations have refined our understanding of skull patterning, bone mineralization and tissue homeostasis. Here, we touch upon classical studies and recent advances with an emphasis on developmental and signaling mechanisms that regulate the osteoblast lineage for the calvaria, which forms the roof of the skull. We highlight studies that illustrate the roles of osteoprogenitor cells and cranial suture-derived stem cells for proper calvarial growth and homeostasis. We also discuss genes and signaling pathways that control suture patency and highlight how perturbing the molecular regulation of these pathways leads to craniosynostosis. Finally, we discuss the recently discovered tissue and signaling inte...
Evolution of cortical folding in gyrencephalic animals enabled higher cognitive functions and com... more Evolution of cortical folding in gyrencephalic animals enabled higher cognitive functions and complex behaviors. Gene expression patterns and signaling molecules that control cortical folding have only recently been described and thus are still not well understood. In transgenic mouse models with induced cortical folding, amplification of neuroprogenitor cells or loss of their adhesion from the apical ventricular surface leads to gyri formation, whereas decreased cell adhesion in migrating projection neurons causes abnormal neuronal clustering and development of cortical fissures that resemble sulci. We now report that loss of Twist1 expression in the primitive meninx results in cortical folding and sulci formation in the dorsolateral telencephalon. In developing sulcal regions, generation of apical and basal neuroprogenitor cells is normal. Instead, cell proliferation in the developing meninges is reduced, leading to loss of arachnoid fibroblasts that express Raldh2, an enzyme requ...
Congenital skull malformations are associated with vascular anomalies that can impair fluid balan... more Congenital skull malformations are associated with vascular anomalies that can impair fluid balance in the central nervous system. We previously reported that humans with craniosynostosis and mutations in TWIST1 have dural venous sinus malformations. It is still unknown whether meningeal lymphatic networks, which are patterned alongside the venous sinuses, are also affected. Using a novel skull flat mounting technique, we show that the growth and expansion of meningeal lymphatics are perturbed in Twist1 craniosynostosis models. Changes to the local meningeal environment, including hypoplastic dura and venous malformations, affect the ability of lymphatic networks to sprout and remodel. Dorsal networks along the transverse sinus are hypoplastic with reduced branching. By contrast, basal networks closer to the skull base are more variably affected, showing exuberant growth in some animals suggesting they are compensating for vessel loss in dorsal networks. Injecting molecular tracers ...
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