Perithelial Cells Research Articles

On the histological structure of Kaposi’s sarcoma

Objective: to study the histological structure of various types of Kaposi’s sarcoma and the morphogenetic potentials of vascular cells in the tumor growth.Materials and methods: results of the histological examination of Kaposi’s sarcoma from 5 patients have been analyzed: biopsies of the skin and subcutaneous tissue from 3 HIV-infected patients (2 men and 1 woman) and 1 man, a participator of the liquidation (dosimetrist) of the consequences of the Chernobyl accident in 1986. The tumor nodes of the Kaposi’s sarcoma of the stomach, lymphatic mesenteric node and dura mater of a 41-year-old woman who had died aft er allogeneic kidney transplantation due to glomerulonephritis were also examined while the skin was intact. Histological preparations were stained with hematoxylin and eosin, picrofuchsin according to Van Gieson, alcian blue and impregnated with silver according to Bilshovsky.Results: it was confirmed that Kaposi’s sarcoma is the part of a multicentrally occurring viral lesion of the skin, subcutaneous tissue and internal organs caused by herpes infections of the 8th type on the background of immunosuppression. The entire process of tumor formation includes, besides the tumor growth, pre-tumor conditions (viral infection, chronic inflammation), and pre-tumor processes (intravascular neoplasia of low and high degree), which determining the diversity of the histological structure, clinical course, outcomes of neoplasms and complicates the correct diagnosis. The morphogenetic potentialities of endothelial and perithelial cells which make various variants of angiomatous structures, and also form spindle cell, myofibroblastic and fi broblastic components, are also important.Conclusions: the fifth, not yet described in the literature, variant of Kaposi’s sarcoma is highlighted - radiation, due to exposure of radiation energy.

Structural and functional conservation of non-lumenized lymphatic endothelial cells in the mammalian leptomeninges

The vertebrate CNS is surrounded by the meninges, a protective barrier comprised of the outer dura mater and the inner leptomeninges, which includes the arachnoid and pial layers. While the dura mater contains lymphatic vessels, no conventional lymphatics have been found within the brain or leptomeninges. However, non-lumenized cells called Brain/Mural Lymphatic Endothelial Cells or Fluorescent Granule Perithelial cells (muLECs/BLECs/FGPs) that share a developmental program and gene expression with peripheral lymphatic vessels have been described in the meninges of zebrafish. Here we identify a structurally and functionally similar cell type in the mammalian leptomeninges that we name Leptomeningeal Lymphatic Endothelial Cells (LLEC). As in zebrafish, LLECs express multiple lymphatic markers, containing very large, spherical inclusions, and develop independently from the meningeal macrophage lineage. Mouse LLECs also internalize macromolecules from the cerebrospinal fluid, including Amyloid-β, the toxic driver of Alzheimer’s disease progression. Finally, we identify morphologically similar cells co-expressing LLEC markers in human post-mortem leptomeninges. Given that LLECs share molecular, morphological, and functional characteristics with both lymphatics and macrophages, we propose they represent a novel, evolutionary conserved cell type with potential roles in homeostasis and immune organization of the meninges.

Isolation and characterization of minipig perivascular stem cells for bone tissue engineering.

Human subcutaneous adipose tissue has been recognized as a rich source of tissue resident mesenchymal stem/stromal cells (MSC) in recent years. The current study was designed to sort the minipig (mp) perivascular stem cells (PSCs) and investigate the osteogenic potential. Purification of human PSCs was achieved via fluorescence-activated cell sorting (FACS) from human liposuction samples [cluster of differentiation (CD)45−CD34−CD146+ perithelial cells and CD45−CD34+CD146− adventitial cells]. Subsequently, PSCs were isolated from mp adipose tissue samples (n=9), characterized and, using purified mpPSCs (obtained by FACS, which is used in human PSC purification), the mpPSC osteogenic and adipogenic potential was evaluated by Alizarin Red S and Oil Red O staining in vitro, respectively. The cell morphometry was observed following cell isolation and culture, and hematoxylin and eosin staining was performed to identify the fat tissue structure and vascular distribution. Osteogenic and adipogenic differentiation-associated gene expression levels were analyzed by reverse transcription-quantitative polymerase chain reaction. The results demonstrated that the same antigens used for human PSC identification and isolation were working in mp tissue (CD45, CD146 and CD34). The two cell groups: CD45−CD34−CD146+ pericytes and CD45−CD34+CD146− adventitial cells were successfully isolated from the subcutaneous fat in the posterior neck of mps, mpPSCs accounted for 8.6% of the stromal vascular fraction (SVF) with 1.4% pericytes and 7.2% adventitial cells. mpPSCs demonstrated characteristics of MSCs, including cell surface marker expression, colony forming unit-fibroblast inclusion, and the stronger osteogenic and adipogenic differentiation potential than that of the non-selected vascular stromal cells. The mRNA expression levels of osteocalcin, collagen, type I, α1 and peroxisome proliferator-activated receptor-γ in the mpPSCs group were significantly higher than those of the unsorted pSVF group (P<0.05). Thus, the current study successfully isolated and cultured CD146+ and CD34+ cell populations from mp tissues, characterized the cells' PSC-like phenotype and identified their distinctly osteogenic and adipogenic potential.

A novel perivascular cell population in the zebrafish brain.

The blood-brain barrier is essential for the proper homeostasis and function of the CNS, but its mechanism of function is poorly understood. Perivascular cells surrounding brain blood vessels are thought to be important for blood-brain barrier establishment, but their roles are not well defined. Here, we describe a novel perivascular cell population closely associated with blood vessels on the zebrafish brain. Based on similarities in their morphology, location, and scavenger behavior, these cells appear to be the zebrafish equivalent of cells variably characterized as Fluorescent Granular Perithelial cells (FGPs), perivascular macrophages, or 'Mato Cells' in mammals. Despite their macrophage-like morphology and perivascular location, zebrafish FGPs appear molecularly most similar to lymphatic endothelium, and our imaging studies suggest that these cells emerge by differentiation from endothelium of the optic choroidal vascular plexus. Our findings provide the first report of a perivascular cell population in the brain derived from vascular endothelium.

Lipomatous ependymoma: report of a rare differentiation pattern with a comprehensive review of literature

We report the case of a 13-year-old girl presenting with left-sided hemiparesis, altered sensorium and episodic headache with bouts of projectile vomiting. Imaging revealed a large heterodense intraventricular mass lesion displaying focal calcification and hyperintensity on T1- and T2- weighted fluid attenuated inversion recovery (FLAIR) magnetic resonance images suggesting the presence of intratumoral fat. Histologically, the tumour showed sheets of glial cells, focal perithelial rosettes and individual cells showing fat vacuoles. The morphological impression was of an ependymoma with lipomatous differentiation. Glial fibrillary acid protein (GFAP) immunohistochemistry revealed positivity in the cytoplasmic processes of the tumour cells as well as in the cytoplasmic rim of the cells having an adipocytic appearance. S100 and vimentin were also immunoreactive. Ultrastructural studies confirmed the ependymal differentiation of the tumour and the presence of an osmiophilic fat component confirming the diagnosis. After 1 year of follow-up, the patient presented with similar complaints and MRI evidence of recurrence of the tumour. A comprehensive literature review revealed that half of the reported cases of this pattern recurred suggesting a possibly tenacious clinical course.

Selection of two types of rat strains for easily diabetic retinopathy

Background Streptozotocin (STZ)-induced type 1 diabetic model is an acceptable model and is often used to the study of diabetic retinopathy (DR).However,the model is often established using retinal digest preparation in vitro in albino rats,and therefore it is difficult to evaluate the change of retinal vessels by fundus fluorescein angiography (FFA) in vivo.Recently,pigmented rats are being used as the DR model.But the study on the comparison between albino rat model and pigmented rat model is seldom.Objective This study was to observe and compare the manifestations of FFA and retinal digest preparation in early diabetic pigmented diabetic rat and albino diabetic rat,and to select the right model of DR using FFA.Methods Type 1 diabetic models were induced in 15 six-week-old health male BN rats and 15 six-week-old health male SD rats by the injection of STZ (55 mg/kg) via tail vein.The models were thought to be successful in the rats with the blood glucose level ≥ 16.7 mmol/L.The right eyes of the rats were extracted 6 weeks after injection of STZ.Lens were examined by slit lamp microscope.Retinal vascular changes were examined by fundus photography,FFA and periodic acid Schiff staining of retinal digest preparation.The manifestations of FFA and retinal digest preparation were contrasted between BN rats and SD rats.The number of eyes with lens opacification was compared by Chi-square test and the ratio of vascular endothelial cells and perithelial cells (E/P) was compared between BN rats and SD rats.The use and care of experimental animals complied the Statement of Ethic Committee of Tianjin Medicine University.Results Six weeks after injection of STZ,11 BN rats and 10SD rats were included in this study.The blood levels were (24.73±2.98) mmol/L and (22.36±3.65) mmol/L in BN rats and SD rats,respectively,without significant difference between the 2 types of rats (t =7.873,P＞0.05).Lens opacification occurred in 6 BN rats and in 5 SD rats (P=0.717).FFA showed the clear retinal vascular under the brown background.Evident vessel disorder and fluorescence leakage like background stage of DR were seen in 9 eyes.However,in the SD rats,retinal vessel abnormality could not exhibited owing to the interference of choroid fluorescent light from choroidal vessels and vortex vein.Retinal digest preparation exhibited that unevenness of vessel diameter,decrease of perithelial cells and increase of endothelial cells in both types of rats.The E/P values were 11.50±3.68in the BN rats and 12.86±3.94 in the SD rats,without significant difference between them (t=9.785,P＞0.05).Conclusions The abnormality of fundus vascular morphology can be better displayed in pigmented diabetic rats than albino rats by FFA in vivo. Key words: Diabetic retinopathy; Fundus fluorescein angiography; Animal model; Rat strain/ Brown-Norway rat, Sprague-Dawley rat; pigment

PIGMENTARY CHANGES IN CHEDIAK-HIGASHI SYNDROME

Summary.— The skin of 12 patients with the Chediak-Higashi syndrome (C-HS) have been studied by light and electron microscopy. In 6 homozygous patients there was almost complete absence of pigment in some but abundant clumps of enlarged melanin granules in both epidermis and dermis in others. In the dermis melanin was found within histiocytes, endothelial cells, perithelial cells, fibroblasts, Schwann cells, and free in the interstitium. Skin abnormalities were also observed in 6 heterozygotes. Those abnormalities were segmental basal deposition of normal appearing melanin pigment; clumping of slightly enlarged and irregular melanin granules; mild atrophy of the malpighian layer, with scattered cell vacuolization; and abundant melanin pigment within melanophores in the upper dermis where various degrees of mononuclear infiltration with intracytoplasmic inclusions were also observed.

Anderson-Fabry disease*

SUMMARY Electron microscopy of clinically uninvolved skin taken from a 12-month-old male child with biochemically proven angiokeratoma corporis diffusum showed characteristic lamellar lipid deposits within endothclial and perithelial cells of dermal blood vessels. Ultrastructural examination of skin may aid the early identification of males affected with Anderson-Fabry disease long before the development of specific skin lesions.

Maternal Diesel Exhaust Exposure Damages Newborn Murine Brains

To examine pathologically the influence of diesel exhaust (DE) exposure on fetal nervous system development, brain tissue (cerebral cortex and hippocampus) was collected from newborn mice whose mothers were exposed to DE during pregnancy. After DE exposure, these brain tissues showed evidence of numerous caspase 3-positive cells (a common enzymatic biomarker of apoptosis). Some cells were found to contain crescent-shaped spaces, which are suggestive of apoptotic processes. Granular perithelial (GP) cells, scavenger cells surrounding cerebral vessels of the blood-brain barrier, showed signs of apoptosis; furthermore, the GP cytoplasmic granules had degenerated and showed evidence of what appeared to be ultrafine, DE particles. Additionally, the swelling of astrocyte endfoot that surround capillaries showed degenerative changes similar to myelin figures. Furthermore, the apoptosis of endothelial cells and stenosis of some capillaries were observed. These findings varied in severity, depended on DE concentration, and were not observed in the control group. These observations suggest that exposure of pregnant mice to DE might carry a risk of cellular atrophy and might affect fetal brain development. Our findings also reveal that inhalation of DE might be hazardous to the general health of fetuses.

694. Improved Therapeutic Efficacy Following AAV2/8-Mediated Expression of α-Galactosidase A in Fabry Mice

Fabry disease is an inherited disorder that is caused by a deficiency of the lysosomal enzyme α-galactosidase A. This results in the progressive accumulation of the glycosphingolipid, globotriaocylceramide (GL-3) in the lysosomes of endothelial, perithelial and smooth muscle cells. Substrate deposition also occurs in structures of the central, peripheral and autonomic nervous system. Previously, we showed that intravenous administration of 5 × 1011 particles of a recombinant AAV2 vector encoding human α-galactosidase A under the transcriptional control of a liver-restricted enhancer/promoter (DC190) into Fabry mice resulted in expression of therapeutic levels of the enzyme that was sustained for 12 months. Treatment resulted in a reduction of GL-3 in the liver, spleen and heart to basal levels and in the kidney by approximately 40% at 8 weeks. To improve the therapy to the kidney, different AAV serotypes (1, 5, and 8) with reportedly higher hepatic transduction activity were evaluated. A very modest improvement in expression of α-galactosidase A was seen with the AAV pseudotypes 2/1 and 2/5 when compared to 2/2. However, the corresponding AAV2/8 vector generated approximately 100 fold greater levels of the enzyme than the AAV2/2 vector. Moreover, the kinetics of expression from the AAV2/8 vector was more rapid, with α-galactosidase A in the serum detected as early as 1 week post-treatment. Intravenous administration of 5 × 1010 particles of the AAV2/8 virus into Fabry mice resulted in higher levels of expression of the enzyme and more rapid clearance of GL-3 from the affected tissues than with a 10 fold higher dose of the corresponding AAV2/2 vector. Clearance of GL-3 from the AAV2/8-treated tissues including kidney was essentially complete by 4 instead of 8 weeks. Hence a significant improvement in potency was realized with the AAV2/8 pseudotyped vector. In addition to correcting the aberrant GL-3 levels, an improvement in the thermal sensitivity of the treated Fabry mice was also realized. Fabry mice demonstrate a delayed response to placement on a hot plate that is equilibrated to 55°C (as demonstrated by a flick of its hindlimbs) when compared to unaffected normal mice (129/Sv). The response time of untreated Fabry mice became progressively longer over a period of 8 months. In contrast, Fabry mice treated at 5 weeks of age with the AAV2/8 vector demonstrated short response times that were similar to those for age-matched normal 129/Sv mice throughout the study. The hindlimb footpads of the mice, as well as dorsal root ganglia of the spinal cord have been examined histologically to show if the pathology corresponded to the improvement in thermal sensitivity. Finally, we demonstrated that the immune tolerance to α-galactosidase A observed previously using an AAV2/2 vector harboring a liver-restricted promoter also applied to the AAV2/8 vector. Together, these data support the continued development of AAV2/8-mediated gene therapy for Fabry disease.

Neuropatía periférica en la enfermedad de Anderson-Fabry: fisiopatología, evaluación y tratamiento

The purpose of this study was to review the peripheral neurological aspects of Anderson-Fabry disease (AFD). AFD is a disease caused by lysosomal deposits that was first reported in 1898. This entity has begun to attract renewed interest in recent years because of the progress made in diagnostic techniques and the appearance of enzyme replacement therapy. This pathological condition is transmitted by recessive inheritance linked to the X chromosome and results from a deficiency of the enzyme alpha-galactosidase A, which leads to the accumulation of glycosphingolipids in endothelial and perithelial cells, as well as those of the smooth muscles in blood vessels, the dorsal root ganglia and other structures in the central and peripheral nervous systems. Symptoms during childhood include: neuropathic pain that is predominantly distal in the four limbs (and expresses itself as severe attacks that are often linked to changes in temperature and exercise that interfere with daily activities), hypohidrosis and angiokeratomas. The most serious complications appear during adulthood and include: kidney failure, heart failure and strokes. The arrival of enzyme replacement therapy is the first part of a chain in the treatment of AFD, where gene therapy and substrate inhibition therapy are beginning to emerge as real therapeutic alternatives. In spite of all this, at present, the management of painful symptoms is not at all satisfactory for patients and therefore further study and a deeper understanding of the mechanisms involved will allow more specific and effective therapeutic measures to be developed with which to provide patients with greater relief.

A model of mucopolysaccharidosis IIIB (Sanfilippo syndrome type IIIB): N‐acetyl‐α‐D‐glucosaminidase deficiency in Schipperke dogs

Mucopolysaccharidosis III (MPS III) is characterized by lysosomal accumulation of the glycosaminoglycan (GAG) heparan sulphate (HS). In humans, the disease manifests in early childhood, and is characterized by a progressive central neuropathy leading to death in the second decade. This disease has also been described in mice (MPS IIIA and IIIB), dogs (MPS IIIA), emus (MPS IIIB) and goats (MPS IIID). We now report on dogs with naturally occurring MPS IIIB, detailing the clinical signs, diagnosis, histopathology, tissue enzymology and substrate levels. Two 3-year-old Schipperke dogs were evaluated for tremors and episodes of stumbling. Examination of the animals found signs consistent with cerebellar disease including dysmetria, hind limb ataxia and a wide-based stance with truncal swaying. There were mildly dystrophic corneas and small peripheral foci of retinal degeneration. Magnetic resonance imaging of the brain and skeletal radiographs were normal. Intracytoplasmic granules were found in the white cells of peripheral blood and cerebral spinal fluid, and in myeloid lineages in bone marrow. Electrophoresis of urinary GAGs indicated the presence of HS, while assays of cultured fibroblasts found N-acetyl-alpha-D-glucosaminidase (Naglu) activity of between 4.3% and 9.2% of normal. Owing to neurological deterioration, both dogs were euthanized, and post-mortem examinations were performed. Biochemical studies of liver and kidney from both animals demonstrated profound deficiency of Naglu activity and abnormally high GAG levels. Pathology of the brain included severe cerebellar atrophy, Purkinje cell loss, and cytoplasmic vacuolation in neurons and perithelial cells throughout the central nervous system. Pedigree analyses and Naglu levels of family members supported an autosomal recessive mode of inheritance. Using an obligate heterozygote, a breeding colony has been established to aid in understanding the pathogenesis of MPS IIIB and testing of potential therapies.

Inclusions in novel perivascular macrophages (Mato's fluorescent granular perithelial cells) and neurons in the cerebral cortex of Hex A- and Hex B-deficient mice.

Beta-hexosaminidases are important enzymes for lipid and saccharide metabolism in the brain. In mice deficient in these enzymes, indigestible metabolic intermediates deposit in neurons. Inclusions such as membranous cytoplasmic bodies (MCB) and zebra bodies were seen in neurons of Tay-Sachs (TS) model mice, Sandhoff's disease (SD) model mice, and double knockout (DKO) mice. However, the cerebral perivascular macrophages discovered by Mato are active in the uptake of waste products and regarded as scavenger cells under steady-state conditions. We observed that indigestible components derived from neurons were taken up by the perivascular macrophages of TS mice by pinocytosis, but those of SD and DKO mice contained only pale inclusions and had marked vacuolations, and pinocytosis was rarely observed. Histochemically, the inclusions in the perivascular macrophages of TS mice were positive for the PAS stain, but those of SD and DKO mice were negative. In addition, the perivascular cells of TS mice expressed clear positive immunoreactivity against BM-8 and F4/80, but those of DKO mice had very weak BM-8 and F4/80 immunoreactivity. These differences between TS, SD, and DKO mice are based on their metabolism of oligosaccharides and glycosaminoglycans (GAG). Thus, hexosaminidase B is more important for keeping normal morphology and function of perivascular macrophages than hexosaminidase A. The foamy cells that appeared along the cerebral microvessels in lipidosis and saccharidosis were identified as perivascular macrophages (Mato's fluorescent granular perithelial cells: FGP cells).

Central nervous system perivascular cells are immunoregulatory cells that connect the CNS with the peripheral immune system.

Perivascular cells are a heterogeneous population found in the central nervous system (CNS) and the peripheral nervous system (PNS). Several terms are used for these cells, including perivascular cells, perivascular macrophages, perivascular microglia, fluorescent granular perithelial cells (FGP), or Mato cells. Different terminology used may reflect subpopulations of perivascular cells within different anatomic regions and experimental paradigms, neuropathological conditions, and species studied. Different terminology also points to the lack of clear consensus of what cells are perivascular cells in different disease states and models, especially with breakdown of the blood-brain barrier (BBB). Despite this, there is consensus that perivascular cells, although a minor component of the CNS, are important immunoregulatory cells. Perivascular cells are bone marrow derived, continuously turn over in the CNS, and are found adjacent to CNS vessels. Thus, they are potential sensors of CNS and peripheral immune system perturbations; are activated in models of CNS inflammation, autoimmune disease, neuronal injury and death; and are implicated as phagocytic and pinocytotic cells in models of stroke and hypertension. Recent evidence from our laboratory implicate perivascular cells as primary targets of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection in the CNS of humans and macaques. This article reviews current knowledge of perivascular cells, including anatomic location and nomenclature and putative immunoregulatory roles, and discusses new data on the infection of these cells by SIV, their accumulation after SIV infection, and a possible role of the immune system in SIV encephalitis.

A novel monoclonal antibody that recognizes human perivascular cells of the central nervous system under a specific immune reaction.

Perivascular cells or fluorescent granular perithelial cells of the central nervous system are newly recognized members of monocyte/macrophage populations. In this study a monoclonal antibody, GP-3, that labels proteinous lysosomal antigen of human perivascular cells, has been established. It selectively label the cells in foamy-macrophage infiltrating diseased areas, such as Wallerian degeneration and contusion, without significant reaction to the cells in normal areas, infiltrating macrophages or microglia. These findings suggest that the perivascular cell is an independent cell type and the antigen molecule is fairly specific to perivascular cells and plays an unknown role in immune-nervous system interaction.

Removal of terminal α-Galactosyl residues by endo-β-galactosidase C, a potent endoglycosidase which acts under physiological pH conditions

Fabry disease is an X-linked recessive inborn error of glycosphingolipid catabolism caused by the deficient activity of the lysosomal enzyme, α-galactosidase A (α-Gal A). This enzymatic defect results in the progressive accumulation of globotriaosylceramide (GL-3) and related glycosphingolipids with terminal α-galactosyl moieties in the lysosomes of endothelial, epithelial, perithelial, and smooth muscle cells throughout the body. In classically affected males, who have essentially no α-Gal A activity, clinical manifestations result predominantly from the progressive lysosomal deposition of GL-3 in the vascular endothelium. Onset usually occurs in childhood or adolescence with periodic crises of severe pain in the extremities (acroparesthesias), the appearance of vascular cutaneous lesions (angiokeratomas), hypohidrosis, and the characteristic corneal and lenticular opacities. Episodic crises of agonizing, burning pain in the distal extremities most often begin in childhood or early adolescence and signal clinical onset of the disease. These crises typically last from minutes to several days and usually are triggered by exercise, fatigue, emotional stress, or rapid changes in temperature and humidity. The early acroparesthesias that occur in children presumably result from glycosphingolipid deposition in the microvasculature that supplies blood to the peripheral nerve cells. The endothelial glycosphingolipid accumulation narrows the vascular lumen and vessel spasms or frank infarction cause the excruciating pain. Angiokeratomas appear as clusters of individual punctate, dark red to blue-black angiectases in the superficial layers of the skin, and are often one of the earliest manifestations of the disease. Most classically affected males develop cardiovascular and/or cerebrovascular disease in middle age. The progressive vascular involvement is a major cause of morbidity and mortality, particularly after treatment of the renal insufficiency by chronic dialysis or transplantation.

Regional difference of lipid distribution in brain of apolipoprotein E deficient mice

According to recent knowledge, apolipoprotein E (apo E) plays a significant role in the homeostasis of intracellular cholesterol level in various tissues. Apo E deficient mice develop hyperlipidemia, and suffer from atherosclerosis in extracerebral blood vessels and neurodegeneration in the central nervous system. Furthermore, Walker et al. (Am. J. Path., 1997;151:1371–1377) demonstrated cerebral xanthomas of various sizes in the brain of apo E deficient mice. In the present study, it is illustrated that in the homozygous apo E deficient mice of advancing age, a great number of foamy macrophages extravasate from microvessels in thalamus and fimbria hippocampi, and scatter in the perivascular regions and migrate toward the ependyma, fimbria hippocampi, hippocampus, and thalamus. Here, it must be pointed out that under hyperlipidemia, although foamy macrophages made clusters in the perivascular region, the cerebral microvessels did not develop atherosclerosis. On the other hand, in the other cerebral regions such as cerebral cortex, caudoputamen, globus pallidus, and substantia nigra, macrophages did not appear and microvessels retained normal shapes, but the fluorescent granular perithelial (in short, FGP) cells accompanied by these vessels contained a certain amount of lipids. That is, in the cerebral cortex and caudoputamen, lipid components are detected in FGP cells and microglia, while in the globus pallidus and substantia nigra, they are mainly localized in astrocytes. The reason why the astrocytes in such defined regions contain, specifically, a high quantity of lipid components remains unsettled. Axonal degenerations are often represented in thalamus, globus pallidus, and substantia nigra. On the other hand, in the specimens of Wild-type mice, lipid components were observed only in FGP cells, and the vascular architecture took a normal profile. Any lipid laden macrophages and the axonal degenerations could not be detected through the cerebral parenchyma. Furthermore, it is also a noticeable finding that immunohistochemically, the FGP cells express a positive reaction against the antibody of apo E in the Wild-type mice, but those of homozygous apo E deficient mice are immunonegative. FGP cells are not only provided with the scavenger receptor, but also contribute to the lipid metabolism in the brain. Anat Rec 256:165–176, 1999. © 1999 Wiley-Liss, Inc.

Regional difference of lipid distribution in brain of apolipoprotein E deficient mice.

According to recent knowledge, apolipoprotein E (apo E) plays a significant role in the homeostasis of intracellular cholesterol level in various tissues. Apo E deficient mice develop hyperlipidemia, and suffer from atherosclerosis in extracerebral blood vessels and neurodegeneration in the central nervous system. Furthermore, Walker et al. (Am. J. Path., 1997;151:1371-1377) demonstrated cerebral xanthomas of various sizes in the brain of apo E deficient mice. In the present study, it is illustrated that in the homozygous apo E deficient mice of advancing age, a great number of foamy macrophages extravasate from microvessels in thalamus and fimbria hippocampi, and scatter in the perivascular regions and migrate toward the ependyma, fimbria hippocampi, hippocampus, and thalamus. Here, it must be pointed out that under hyperlipidemia, although foamy macrophages made clusters in the perivascular region, the cerebral microvessels did not develop atherosclerosis. On the other hand, in the other cerebral regions such as cerebral cortex, caudoputamen, globus pallidus, and substantia nigra, macrophages did not appear and microvessels retained normal shapes, but the fluorescent granular perithelial (in short, FGP) cells accompanied by these vessels contained a certain amount of lipids. That is, in the cerebral cortex and caudoputamen, lipid components are detected in FGP cells and microglia, while in the globus pallidus and substantia nigra, they are mainly localized in astrocytes. The reason why the astrocytes in such defined regions contain, specifically, a high quantity of lipid components remains unsettled. Axonal degenerations are often represented in thalamus, globus pallidus, and substantia nigra. On the other hand, in the specimens of Wild-type mice, lipid components were observed only in FGP cells, and the vascular architecture took a normal profile. Any lipid laden macrophages and the axonal degenerations could not be detected through the cerebral parenchyma. Furthermore, it is also a noticeable finding that immunohistochemically, the FGP cells express a positive reaction against the antibody of apo E in the Wild-type mice, but those of homozygous apo E deficient mice are immunonegative. FGP cells are not only provided with the scavenger receptor, but also contribute to the lipid metabolism in the brain.

Ultrastructural and immunohistochemical changes of fluorescent granular perithelial cells and the interaction of FGP cells to microglia after lipopolysaccharide administration.

Fluorescent granular perithelial (FGP) cells introduced by Mato et al. (1979, 1980, 1981) are situated in the Virchow-Robin space of cerebral microvessels and exhibit a marked uptake capacity for the endo- and exogenous materials in physiological conditions. That is, the FGP cells are the perivascular macrophage lineage enclosed by a basal lamina and glia limitans and are distributed between blood vessels and cerebral parenchyma. As reported previously, the FGP cells were distinguishable from microglia and pericytes in their morphology, location, and epitopes on their cytoplasmic membrane. On the other hand, it is established that microglia are upregulated by lipopolysaccaride (LPS) administration, but it remains unsettled whether the FGP cells, the perivascular macrophagic cells, are activated by LPS or not and what role the FGP cells play in the upregulation of microglia. Thus far, the morphological relationship between FGP cells and microglia in the process of upregulation has not been clarified. Thirty-six 7-month-old Wistar male rats were employed. The animals were sacrificed at 2, 5, 10, 24, and 72 h after the intravenous administration of 500 microg/kg of LPS. The FGP cells and microglia in their cerebral cortex were studied with immunohistochemical and electron microscopical techniques. The findings of the present study indicated that the majority of FGP cells were upregulated by LPS from the results of immunohistochemical and morphological data, but some of them tended to degenerate. Furthermore, in the time course after LPS administration, microglia were also upregulated and approached the microvessels and occasionally contacted the FGP cells directly. From these findings, it is hypothesized that FGP cells may significantly influence the mobilization and upregulation of microglia caused by LPS administration.

Immunohistochemical Evidence for a Macrophage Scavenger Receptor in Mato Cells and Reactive Microglia of Ischemia and Alzheimer's Disease

Macrophage scavenger receptors (MSR) are implicated in the development of atherosclerosis and amyloid b-protein deposition in Alzheimer's disease. However, histopathological studies of MSR expression in human tissues have been hampered by a lack of specific antibodies. Using MSR-deficient mice, we successfully raised a novel monoclonal antibody against human MSR together with high-titer antisera. These antibodies specifically recognized human tissue macrophages and human MSR protein purified from differentiated THP1 cells. In normal brain, MSR staining was mainly distributed to the perivascular cells, which correspond to Mato's fluorescent granular perithelial cells (Mato cells). In the lesions of ischemia and Alzheimer's disease, a subset of microglia stained positive for MSR. These novel antibodies are useful tools for analysis of MSR expression in human tissues.