Cranial Blood Vessels Research Articles

Is selective 5-HT1F receptor agonism an entity apart from that of the triptans in antimigraine therapy?

Migraine is a neurovascular disorder that involves activation of the trigeminovascular system and cranial vasodilation mediated by release of calcitonin gene-related peptide (CGRP). The gold standard for acute migraine treatment are the triptans, 5-HT1B/1D/(1F) receptor agonists. Their actions are thought to be mediated through activation of: (i) 5-HT1B receptors in cranial blood vessels with subsequent cranial vasoconstriction; (ii) prejunctional 5-HT1D receptors on trigeminal fibers that inhibit trigeminal CGRP release; and (iii) 5-HT1B/1D/1F receptors in central nervous system involved in (anti)nociceptive modulation. Unfortunately, coronary arteries also express 5-HT1B receptors whose activation would produce coronary vasoconstriction; hence, triptans are contraindicated in patients with cardiovascular disease. In addition, since migraineurs have an increased cardiovascular risk, it is important to develop antimigraine drugs devoid of vascular (side) effects. Ditans, here defined as selective 5-HT1F receptor agonists, were developed on the basis that most of the triptans activate trigeminal 5-HT1F receptors, which may explain part of the triptans' antimigraine action. Amongst the ditans, lasmiditan: (i) fails to constrict human coronary arteries; and (ii) is effective for the acute treatment of migraine in preliminary Phase III clinical trials. Admittedly, the exact site of action is still unknown, but lasmiditan possess a high lipophilicity, which suggests a direct action on the central descending antinociceptive pathways. Furthermore, since 5-HT1F receptors are located on trigeminal fibers, they could modulate CGRP release. This review will be particularly focussed on the similarities and differences between the triptans and the ditans, their proposed sites of action, side effects and their cardiovascular risk profile.

Stroke, Migraine and Triptans: From Bedside to Bench

Stroke, Migraine and Triptans: From Bedside to Bench

Planar Visualization of Treelike Structures.

We present a novel method to create planar visualizations of treelike structures (e.g., blood vessels and airway trees) where the shape of the object is well preserved, allowing for easy recognition by users familiar with the structures. Based on the extracted skeleton within the treelike object, a radial planar embedding is first obtained such that there are no self-intersections of the skeleton which would have resulted in occlusions in the final view. An optimization procedure which adjusts the angular positions of the skeleton nodes is then used to reconstruct the shape as closely as possible to the original, according to a specified view plane, which thus preserves the global geometric context of the object. Using this shape recovered embedded skeleton, the object surface is then flattened to the plane without occlusions using harmonic mapping. The boundary of the mesh is adjusted during the flattening step to account for regions where the mesh is stretched over concavities. This parameterized surface can then be used either as a map for guidance during endoluminal navigation or directly for interrogation and decision making. Depth cues are provided with a grayscale border to aid in shape understanding. Examples are presented using bronchial trees, cranial and lower limb blood vessels, and upper aorta datasets, and the results are evaluated quantitatively and with a user study.

Pre-operative image-based segmentation of the cranial nerves and blood vessels in microvascular decompression: Can we prevent unnecessary explorations?

ObjectivesThis study was conducted to validate the accuracy of image-based pre-operative segmentation using the gold standard endoscopic and microscopic findings for localization and pre-operative diagnosis of the offensive vessel. Patients and methodsFourteen TN and 6 HS cases were randomly selected. All patients had 3T MRI, which included thin-sectioned 3D space T2, 3D Time of Flight and MPRAGE Sequences. Imaging sequences were loaded in BrainLab iPlanNet and fused. Individual segmentation of the affected cranial nerves and the compressing vascular structure was performed by a neurosurgeon, and the results were compared with the microscopic and endoscopic findings by two blinded neurosurgeons. For each case, at least three neurovascular landmarks were targeted. Each segmented neurovascular element was validated by manual placement of the navigation probe over each target, and errors of localization were measured in mm. ResultsAll patients underwent retro-sigmoid craniotomy and MVD using both microscope and endoscope. Based on image segmentation, the compressing vessel was identified in all cases except one, which was also negative intraoperatively. Perfect correspondence was found between image-based segmentation and endoscopic and microscopic images and videos (Dice coefficient of 1). Measurement accuracy was 0.45±0.21mm (mean±SD). ConclusionImage-based segmentation is a promising method for pre-operative identification and localization of offending blood vessels causing HFS and TN. Using this method may prevent some unnecessary explorations on especially atypical cases with no vascular contacts. However, negative pre-operative image segmentation may not preclude one from exploration in classic cases of TN or HFS. A multicenter study with larger number of cases is recommended.

3D Light-Sheet Fluorescence Microscopy of Cranial Neurons and Vasculature during Zebrafish Embryogenesis.

Precise 3D spatial mapping of cells and their connections within living tissues is required to fully understand developmental processes and neural activities. Zebrafish embryos are relatively small and optically transparent, making them the vertebrate model of choice for live in vivo imaging. However, embryonic brains cannot be imaged in their entirety by confocal or two-photon microscopy due to limitations in optical range and scanning speed. Here, we use light-sheet fluorescence microscopy to overcome these limitations and image the entire head of live transgenic zebrafish embryos. We simultaneously imaged cranial neurons and blood vessels during embryogenesis, generating comprehensive 3D maps that provide insight into the coordinated morphogenesis of the nervous system and vasculature during early development. In addition, blood cells circulating through the entire head, vagal and cardiac vasculature were also visualized at high resolution in a 3D movie. These data provide the foundation for the construction of a complete 4D atlas of zebrafish embryogenesis and neural activity.

Live Imaging of Host-Parasite Interactions in a Zebrafish Infection Model Reveals Cryptococcal Determinants of Virulence and Central Nervous System Invasion.

ABSTRACTThe human fungal pathogen Cryptococcus neoformans is capable of infecting a broad range of hosts, from invertebrates like amoebas and nematodes to standard vertebrate models such as mice and rabbits. Here we have taken advantage of a zebrafish model to investigate host-pathogen interactions of Cryptococcus with the zebrafish innate immune system, which shares a highly conserved framework with that of mammals. Through live-imaging observations and genetic knockdown, we establish that macrophages are the primary immune cells responsible for responding to and containing acute cryptococcal infections. By interrogating survival and cryptococcal burden following infection with a panel of Cryptococcus mutants, we find that virulence factors initially identified as important in causing disease in mice are also necessary for pathogenesis in zebrafish larvae. Live imaging of the cranial blood vessels of infected larvae reveals that C. neoformans is able to penetrate the zebrafish brain following intravenous infection. By studying a C. neoformans FNX1 gene mutant, we find that blood-brain barrier invasion is dependent on a known cryptococcal invasion-promoting pathway previously identified in a murine model of central nervous system invasion. The zebrafish-C. neoformans platform provides a visually and genetically accessible vertebrate model system for cryptococcal pathogenesis with many of the advantages of small invertebrates. This model is well suited for higher-throughput screening of mutants, mechanistic dissection of cryptococcal pathogenesis in live animals, and use in the evaluation of therapeutic agents.

Dural administration of inflammatory soup or Complete Freund's Adjuvant induces activation and inflammatory response in the rat trigeminal ganglion.

BackgroundMigraine is a painful disorder with a huge impact on individual and public health. We hypothesize that migraine pain originates from a central mechanism that results secondarily in hypersensitivity in peripheral afferents associated with the cerebral and cranial blood vessels. It has previously been shown that application of inflammatory or algesic substances onto the dura mater or chemical stimulation of the dural receptive fields causes hypersensitivity to mechanical and thermal stimulation together with direct activation of the TG. We asked whether local inflammation of dura mater induces inflammatory activation in the trigeminal ganglion.MethodsWe performed topical administration of inflammatory soup (IS) or Complete Freund’s Adjuvant (CFA) onto an exposed area of the rat dura mater in vivo for 20 min. The window was closed and the rats were sacrificed after 4 h and up to 7 days. Myography was performed on middle meningeal arteries. The trigeminal ganglia were removed and processed for immunohistochemistry or Western blot.ResultsBoth CFA and IS induced enhanced expression of pERK1/2, IL-1β and CGRP in the trigeminal ganglia. The pERK1/2 immunoreactivity was mainly seen in the satellite glial cells, while IL-1β reactivity was observed in the neuronal cytoplasm, close to the cell membrane, seemingly as sign of neuro-glial interaction. The CGRP expression in the neurons and nerve fibres was enhanced after the application of either inflammatory agent. Myography resulted in a strong vasoconstrictor response to IS, but not to CFA.ConclusionsThese results suggest that the application of IS or CFA onto the dura mater causes long-term activation of the TG and demonstrate the importance of the neuro-glial interaction in the activation of the trigeminovascular system.Electronic supplementary materialThe online version of this article (doi:10.1186/s10194-015-0564-y) contains supplementary material, which is available to authorized users.

Clinical evaluation of an Ayurvedic therapy– Sutashekhara Rasa and Brihat Jeevakadya Taila Nasya in the management of Ardhavabhedaka (Migraine)

Ardhavabhedaka-hemicranial headache is a psychosomatic disorder: later replaced by migraine a Greek word "half of the head" because the pain of migraine often occurs on one side(classical Migraine) may affect the entire head. The term "migraine" refers to a syndrome of vascular pathology of the cranial blood vessels and is one of the commonest headache encountered in clinical practise. The survey results suggested that both patients and physicians believe migraine treatment is elusive and that patients are becoming increasingly frustrated and dissatisfied with treatment outcomes. Clinically, it is a Rakta/Pitta dominant disease;andAcharya Charaka opined that the vitiated Doshas after reaching Shirah vitiates Rakta (Rasavaha and Raktavaha Srotas) there to produce Shiro Roga (headache). Its diagnosis is based on mainly clinical history. For the present study, it was planned to compare the result between Brihat Jeevakadhya Taila Nasyaand Sutashekhara Rasa orally (Pitashamaka, Raktashodhaka, Deepana etc.) in Treatment Trial group and Flunarizine in Control group. The overall effect of therapy showed that in Trial group 80. 00% patients had marked improvement, followed by moderate improvement in 13. 33% and complete improvement in 6. 67%. In control group marked and moderate improvement was seen in 60. 00% and 33. 33% respectively; and 6. 67% had mild improvement. No any adverse drug reaction was found during whole study. Total 30 patients were registered and from the results and observation which were received from this study it can be concluded that Trial group is showing better results in Ardhavabhedaka

Interpretation of ultrasound findings in otorhinolaryngology. Salivary glands, paraganglioma, angioma, esophagus, hypopharynx, extra cranial vessels and temporomandibular joint

The second part of this continuing medical education article focuses on sonographic assessment of the salivary glands, cervical paraganglioma, angioma, esophagus, extra cranial blood vessels and the temporomandibular joint. The currently available minimally invasive therapeutic options (e. g. sialendoscopy, lithotripsy, therapeutic duct lavage and extracapsular dissection) for salivary gland disease presuppose a precise imaging modality. Modern ultrasound is able to meet this challenge, making additional imaging a rare necessity. Regions of the neck with a difficult topography (esophagus and hypopharynx) can often be successfully portrayed sonographically. Furthermore, ultrasound enables functional evaluation of swallowing in the cervical parts of the esophagus in dysphagia patients. In addition to the branchial cleft anomalies and lymph nodes discussed in part 1, paraganglioma, angiomatosis and neurogenic tumors are important differential diagnoses of solid lesions of the neck. Finally, venous and arterial alterations of the extracranial vessels of the neck relevant to clinical routine are depicted, as are pathological conditions of the temporomandibular joint relevant to the otorhinolaryngologist.

Occipital foramina development involves localised regulation of mesenchyme proliferation and is independent of apoptosis.

Cranial foramina are holes within the skull, formed during development, allowing entry and exit of blood vessels and nerves. Once formed they must remain open, due to the vital structures they contain, i.e. optic nerves, jugular vein, carotid artery, and other cranial nerves and blood vessels. Understanding cranial foramina development is essential as cranial malformations lead to the stenosis or complete closure of these structures, resulting in blindness, deafness, facial paralysis, raised intracranial pressure and lethality. Here we focus on describing early events in the formation of the jugular, carotid and hypoglossal cranial foramina that form in the mesoderm-derived, endochondral occipital bones at the base of the embryonic chick skull. Whole-mount skeletal staining of skulls indicates the appearance of these foramina from HH32/D7.5 onwards. Haematoxylin & eosin staining of sections shows that the intimately associated mesenchyme, neighbouring the contents of these cranial foramina, is initially very dense and gradually becomes sparser as development proceeds. Histological examination also revealed that these foramina initially contain relatively large-diameter nerves, which later become refined, and are closely associated with the blood vessel, which they also innervate within the confines of the foramina. Interestingly cranial foramina in the base of the skull contain blood vessels lacking smooth muscle actin, which suggests these blood vessels belong to glomus body structures within the foramina. The blood vessel shape also appears to dictate the overall shape of the resulting foramina. We initially hypothesised that cranial foramina development could involve targeted proliferation and local apoptosis to cause 'mesenchymal clearing' and the creation of cavities in a mechanism similar to joint cavitation. We find that this is not the case, and propose that a mechanism reliant upon local nerve/blood vessel-derived restriction of ossification may contribute to foramina formation during cranial development.

Endoscopic Endonasal Anatomical Study of the Cavernous Sinus Segment of the Ophthalmic Nerve

Background: The emergence of endonasal skull base surgery has led neurosurgeons to rediscover the surgical anatomy of this region from a ventral perspective. This cadaveric study analyzes the endoscopic endonasal anatomy of ophthalmic nerve (V1), the ophthalmic division of the trigeminal nerve, from its origin in the middle fossa to its orbital entry via the superior orbital fissure. The authors evaluated its relations with the surrounding cranial nerves and blood vessels, with emphasis on the clinical role of these anatomical correlations during surgery in this region.

Endoscopic endonasal anatomical study of the cavernous sinus segment of the ophthalmic nerve.

This cadaveric study analyzes the endoscopic endonasal anatomy of the ophthalmic division of the trigeminal nerve (V1 ), from the middle fossa to its orbital entry via the superior orbital fissure. Anatomical relationships with the surrounding cranial nerves and blood vessels are described, with emphasis on their clinical correlation during surgery in this region. Our objective was to describe the anatomical relationships of the ophthalmic division of the trigeminal nerve. Cadaveric study. Thirty middle cranial fossae, in adult human cadaveric specimens, were dissected endonasally under direct endoscopic visualization. During the dissection, we noted the relationships of the V1 nerve with the other trigeminal branches, as well as with the oculomotor and trochlear nerves, the paraclival and cavernous portions of the internal carotid artery, and the superior orbital fissure (SOF). The V1 nerve is the most superior trigeminal branch and runs upward and obliquely, along the middle portion of the lateral wall of the cavernous sinus. The V1 nerve joins the oculomotor and trochlear nerves to exit the cavernous sinus and enter the orbit through the SOF. Ten percent of the specimens displayed the trochlear nerve running along as a mate of the V1 nerve. The V1 nerve borders two key triangles in the lateral wall of the cavernous sinus, and the Parkinson's and anteromedial triangles. In this study, the V1 nerve was a constant and reliable landmark, thus allowing the identification of the anteromedial triangle. This potential space can serve as an adequate window to access the temporal lobe. Knowledge of this anatomy is essential when planning and executing endonasal surgery in this region. NA.

CGRP as a new target in prevention and treatment of migraine

CGRP as a new target in prevention and treatment of migraine

Endocranial anatomy of a new fossil porpoise (Odontoceti, Phocoenidae) from the Pliocene San Diego Formation of California

The Pliocene fossil porpoise SDSNH 65276 has extremely elongate mandibular morphology, unlike that of any marine amniote, and is superficially most similar to the living bird species known as skimmers (Rynchops sp.). Endocasts of the pterygoid sinuses and endocranial cavity were digitally segmented from high-resolution X-ray CT scans of the specimen to explore internal anatomy of functionally and phylogenetically important anatomical features of this specimen and odontocetes in general. The sinuses are similar in volume and shape to extant porpoise species, but the dorsal extension of the preorbital lobes are particularly elongate as in the harbor porpoise (Phocoena phocoena). The cranial endocast also shows similarities with extant porpoises, but has much deeper interhemispheric fissures, which are filled by ossified meninges, particularly a deep falx cerebri and shallower tentorium cerebelli. Ossifications of these parts of the meninges may reflect faster angular accelerations of the head, deeper diving ability, or both. Penetrations of the endocranial cavity for cranial nerves and blood vessels are like those of extant porpoises. The internal skull morphology of this unique delphinoid sheds additional light both on its phylogenetic affinities and novel odontocete adaptations.

The braincase of the North American therizinosaurian Nothronychus mckinleyi (Dinosauria, Theropoda)

ABSTRACTThe description and comparison of the posterior braincase of Nothronychus mckinleyi (MSM P-2117) from the Upper Cretaceous (Turonian) Moreno Hills Formation of east-central New Mexico is updated. As a result of the enlarged basicranial pneumatic system, this region of the skeleton has undergone extensive rearrangement of the cranial nerves and blood vessels from the plesiomorphic theropod condition. Nothronychus and Falcarius possessed a number of avian-associated characters or avian-trending characters in the braincase and endocranium characteristic of highly derived coelurosaurs. These traits, in some cases hypothesized, include the posterior endocranium nearly filled with nervous tissue, a laterally directed enlarged optic tectum, an enlarged flocculus, an intracranial trigeminal ganglion, and the abducens canal entering the endocranium separate from the infundibulum with no associated cavernous sinus. The angle of the occipital plate with the basal plate of the basicranium appears to be perpendicular and, therefore, intermediate between more basal theropods and extant birds. However, the posterior endocranial cavity does not appear flexed, which would result in a posteroventral rotation of the endocranial cavity in Nothronychus, a character also seen in the Cretaceous hesperornithiform bird Enaliornis and in contrast to extant birds. Therefore, the evolution of the coelurosaurian brain and braincase was trending in an avian direction before the rest of the skeleton. The results presented here support the model that therizinosaurs possessed weak bite forces as compared to obligatory carnivorous theropods.

Clinical and psychological characteristics and quality of life in teenagers with а long-lasting low-grade fever both associated and not associated with hypothalamic syndrome

Aim. To describe clinical and psychological characteristics and quality of life in teenagers with a long-lasting low-grade fever associated with hypothalamic syndrome. Methods. Life history, objective status were assessed, clinical, laboratory and instrumental examinations were performed, quality of life and psychological status were estimated throughout the study. Clinical and laboratory investigations included complete blood count, urinalysis, stool examination; blood immunochemistry for mycoplasma, chlamydia, herpes virus, cytomegalovirus; blood biochemistry; bacteriology of nose and the pharynx swabs. Instrumental investigations included skull and cervical spine X-Ray, neurophysiological examinations (electroencephalography, echoencephalography, rheoencephalography), cranial and cervical blood vessels ultrasonography. The quality of life was estimated using special pediatric questionnaires (proposed by Molchanova L.F., Izhevsk State Medical Academy). Psychological status was assessed by questionnaires of H. Eysenck (temperament assessment) and C.D. Spielberg (research of personal and situation anxiety). Results. All teenagers underwent a complex treatment according to diagnosis, including antimicrobial treatment in case of chronic infections, antimicrobial treatment and immunostimulators in case of upper and lower airway infections caused by chlamydia and mycoplasma, correction of functional conditions of central nervous system (nootropics, vasoactive drugs, diuretics, anxiolytics, metabolic medications, hypotensives), massages, exercise therapy, physiotherapy, herbal treatment. After the course of treatment relapse of low-grade fever was 4-fold more often in teenagers with hypothalamic syndrome compared to those without. Teenagers with low-grade fever associated with hypothalamic syndrome had higher rates of melancholy, higher anxiety levels, leading to significant alterations of physical and mental health. Those changes may lead to mental and social adaptation problems, borderline social and family behavior, and increased rate of psychosomatic diseases. Conclusion. As it was revealed that relapsing low-grade fever might lead to reduced quality of life, further exacerbations of borderline mental problems, aggravate mental adaptation and social and family behavior problems, these teenagers require family and individual mental therapy, repeated treatment with nootropics, vasoactive drugs, diuretics, anxiolytics.

Partial labyrinthectomy presigmoid transpetrosal resection of petroclival meningioma

A petroclival meningioma represents a challenging tumor to resect in the cerebellopontine angle and ventral to the brain stem. Multiple cranial nerves and blood vessels may be intimately involved with the tumor. A partial labyrinthectomy presigmoid transpetrosal approach can facilitate resection while preserving hearing. This approach allows for a direct line of sight along the petrous bone while sealing the canals can preserve hearing. In this video operative manuscript, we demonstrate a step-by-step illustration of a partial labyrinthectomy presigmoid transpetrosal resection of a petroclival meningioma. This approach affords the best chance of hearing preservation and an opportunity for maximum tumor resection. The video can be found here: http://youtu.be/29I4KEXz1vY .

Nonthermal ablation with microbubble-enhanced focused ultrasound close to the optic tract without affecting nerve function

Tumors at the skull base are challenging for both resection and radiosurgery given the presence of critical adjacent structures, such as cranial nerves, blood vessels, and brainstem. Magnetic resonance imaging-guided thermal ablation via laser or other methods has been evaluated as a minimally invasive alternative to these techniques in the brain. Focused ultrasound (FUS) offers a noninvasive method of thermal ablation; however, skull heating limits currently available technology to ablation at regions distant from the skull bone. Here, the authors evaluated a method that circumvents this problem by combining the FUS exposures with injected microbubble-based ultrasound contrast agent. These microbubbles concentrate the ultrasound-induced effects on the vasculature, enabling an ablation method that does not cause significant heating of the brain or skull. In 29 rats, a 525-kHz FUS transducer was used to ablate tissue structures at the skull base that were centered on or adjacent to the optic tract or chiasm. Low-intensity, low-duty-cycle ultrasound exposures (sonications) were applied for 5 minutes after intravenous injection of an ultrasound contrast agent (Definity, Lantheus Medical Imaging Inc.). Using histological analysis and visual evoked potential (VEP) measurements, the authors determined whether structural or functional damage was induced in the optic tract or chiasm. Overall, while the sonications produced a well-defined lesion in the gray matter targets, the adjacent tract and chiasm had comparatively little or no damage. No significant changes (p > 0.05) were found in the magnitude or latency of the VEP recordings, either immediately after sonication or at later times up to 4 weeks after sonication, and no delayed effects were evident in the histological features of the optic nerve and retina. This technique, which selectively targets the intravascular microbubbles, appears to be a promising method of noninvasively producing sharply demarcated lesions in deep brain structures while preserving function in adjacent nerves. Because of low vascularity--and thus a low microbubble concentration--some large white matter tracts appear to have some natural resistance to this type of ablation compared with gray matter. While future work is needed to develop methods of monitoring the procedure and establishing its safety at deep brain targets, the technique does appear to be a potential solution that allows FUS ablation of deep brain targets while sparing adjacent nerve structures.

Pearls and pitfalls in human pharmacological models of migraine: 30 years' experience

Invitro studies have contributed to the characterization of receptors in cranial blood vessels and the identification of new possible anti-migraine agents. Invivo animal models enable the study of vascular responses, neurogenic inflammation, peptide release and genetic predisposition and thus have provided leads in the search for migraine mechanisms. All animal-based results must, however, be validated in human studies because so far no animal models can predict the efficacy of new therapies for migraine. Given the nature of migraine attacks, fully reversible and treatable, the headache- or migraine-provoking property of naturally occurring signaling molecules can be tested in a human model. If such an endogenous substance can provoke migraine in human patients, then it is likely, although not certain, that blocking its effect will be effective in the treatment of acute migraine attacks. To this end, a human invivo model of experimental headache and migraine in humans has been developed. Human models of migraine offer unique possibilities to study mechanisms responsible for migraine and to explore the mechanisms of action of existing and future anti-migraine drugs. The human model has played an important role in translational migraine research leading to the identification of three new principally different targets in the treatment of acute migraine attacks and has been used to examine other endogenous signaling molecules as well as genetic susceptibility factors. New additions to the model, such as advanced neuroimaging, may lead to a better understanding of the complex events that constitute a migraine attack, and better and more targeted ways of intervention.

Human Fetal Keratocytes Have Multipotent Characteristics in the Developing Avian Embryo

The human cornea contains stem cells that can be induced to express markers consistent with multipotency in cell culture; however, there have been no studies demonstrating that human corneal keratocytes are multipotent. The objective of this study is to examine the potential of human fetal keratocytes (HFKs) to differentiate into neural crest-derived tissues when challenged in an embryonic environment. HFKs were injected bilaterally into the cranial mesenchyme adjacent to the neural tube and the periocular mesenchyme in chick embryos at embryonic days 1.5 and 3, respectively. The injected keratocytes were detected by immunofluorescence using the human cell-specific marker, HuNu. HuNu-positive keratocytes injected along the neural crest pathway were localized adjacent to HNK-1-positive migratory host neural crest cells and in the cardiac cushion mesenchyme. The HuNu-positive cells transformed into neural crest derivatives such as smooth muscle in cranial blood vessels, stromal keratocytes, and corneal endothelium. However, they failed to form neurons despite their presence in the condensing trigeminal ganglion. These results show that HFKs retain the ability to differentiate into some neural crest-derived tissues. Their ability to respond to embryonic cues and generate corneal endothelium and stromal keratocytes provides a basis for understanding the feasibility of creating specialized cells for possible use in regenerative medicine.