Tissue Of Many Organs Research Articles

Stromal Hücrelerin Tarihçesi: İnterstisyel Cajal Hücrelerinden Telositlere - İnsan Telositlerine ve Olası İşlevlerine Kısa Bir Bakış

In the organ microenvironment stromal cells make up an essential population, however research on them has been very limited. The stroma mainly consists of fibroblasts that reside together with mesenchymal cells, endothelial cells, pericytes, neurons, adipocytes, immune cells etc. The different morphologies and functional properties of stromal cells have led to subclassification of different cell types in connective tissue. Among them are the interstitial cells of Cajal and telocytes. Telocytes are one of the newer cells known for their small cell bodies and long telopods and have been recently identified in the connective tissue of many organs. Telocytes are strategically positioned near nerve endings, around blood capillaries and in close relation with particular cells. The network of telocytes is engaged in integrating information from multiple sources and coordinating the tissue homeostasis in response to the tissues local functional requirements. Extracellular vesicles provide a means of bidirectional communication, and their secretome appears to control the mechanisms of stem cell differentiation. Telocytes have been identified in various organs, specifically in human heart, lungs, brain, eye, thyroid, skeletal muscles, skin, salivary glands, gastrointestinal tract, pancreas, gallbladder, liver, and organs of the male and female urogenital system. Additionally, given the heterogeneity of the organs in which telocytes are found, and their capability to play a role in the etiopathogenesis of various diseases, the concept of "telocytopathies" has emerged. In conclusion, telocytes are increasingly becoming a focal point for the understanding of idiopathic diseases that affect humans as well as the development of new diagnostic and therapeutic approaches, and they have the potential to contribute to regenerative medicine.

Properties of the stem cells of the primitives of third molars

Regenerative medicine becomes an interesting field of research that solves the problem of the treatment of severe illnesses by replacing the affected structures with cell-based therapy or tissue engineering using autogenous stem cells. Due to these researches over the past decade, scientists were able to find new sources of stem cells in the adult body, improve treatment methods of various diseases, regenerate and replace tissues of many organs, and even correct some congenital defects. Systematization of theoretical knowledge and clinical research in the field of regenerative medicine is the basis for further selection of the proper stem cells sources and development of the best methods of regeneration and their successful application in practical medicine.The dental germs of the third permanent molars were used as research objects. To obtain the materials, the germs of the third molars were taken from 20 patients aged from 12 to 25 years old during the surgical stage of orthodontic treatment. Dental manipulations were performed after the signing of the voluntary information consent on conducting clinical trials by patients. It was decided to create three observation groups, taking into account the stage of formation of the third molars germs and the age of patients. The first group consisted of patients with the third molars germs at the stage of unformed root; the second - patients with the third molars germs with formed root and unformed apex; the third onepatients with formed root and formed apex of the third molars germs. Methods of the research: radiological - to assess the stage of development of the third molar germs; histological - for the morphological characteristics of the third molar germs tissues; immunohistochemical - to characterize the degree of maturity of the third molar germs tissues.The unformed root stage contains more reserve of poorly differentiated cells of mesenchymal origin. The light color of the preparation indicates on a low concentration of protein Vimentin in the early stages of development, which indicates on low cell differentiation. At the same time, histological examination of third molars germs of the third observation group showed the presence of highly differentiated cells such as fibroblasts and fibrocytes, as well as a significant content of vimentin protein, which confirms the maturity of these cells.The obtained results allow us to identify the most suitable collection periods of the development for the third molars germs. It gives the opportunity to expand the scientific data on the properties of mesenchymal stem cells of odontogenic origin and to investigate further use of mesenchymal stem cells of odontogenic origin in practical medicine.

Mucilage cells in the flower of Rosales species: reflections on morphological diversity, classification, and functions.

The presence of mucilage cellsin plants, studied mainly in vegetative organs, is a condition shared by several taxonomicgroups and aspects related to their diversity have been discussed with systematic purposes. This study explores the flower distribution and classification of mucilage cells in Rosales species, with inferences about flower functions. Floral buds from fifty-seven species representing seven of nine families recognized in the Rosales were sampled and processed for light and transmission electron microscopy. Mucilage cells were found in about 40% of the studied species of Cannabaceae, Rhamnaceae, Ulmaceae, and Urticaceae families, whereas no floral mucilage cells were found in species of Elaeagnaceae, Moraceae, and Rosaceae. Mucilage cells were found in the epidermis and internal tissues of many organs of different floral morph types. There is a great diversity of forms of presentation of mucilage in cells, from smaller individualized single cells to very bulky cells and to completely filled mucilage reservoirs. In some cases, cells with mucilage apparently in the cell wall and others with mucilage in the vacuole seem to occur side by side. This diversity challenges the existing classifications of mucilage cells and reinforces the importance of ontogenetic and ultrastructural studies following the path of mucilage in cells in order to propose a more natural classification and to elucidate the evolution of mucilage cells in plants.

Transthyretin deposition alters cardiomyocyte sarcomeric architecture, calcium transients, and contractile force.

Age‐related wild‐type transthyretin amyloidosis (wtATTR) is characterized by systemic deposition of amyloidogenic fibrils of misfolded transthyretin (TTR) in the connective tissue of many organs. In the heart, this leads to age‐related heart failure with preserved ejection fraction (HFpEF). The hypothesis tested is that TTR deposited in vitro disrupts cardiac myocyte cell‐to‐cell and cell‐to‐matrix adhesion complexes, resulting in altered calcium handling, force generation, and sarcomeric disorganization. Human iPSC‐derived cardiomyocytes and neonatal rat ventricular myocytes (NRVMs), when grown on TTR‐coated polymeric substrata mimicking the stiffness of the healthy human myocardium (10 kPa), had decreased contraction and relaxation velocities as well as decreased force production measured using traction force microscopy. Both NRVMs and adult mouse atrial cardiomyocytes had altered calcium kinetics with prolonged transients when cultured on TTR fibril‐coated substrates. Furthermore, NRVMs grown on stiff (~GPa), flat or microgrooved substrates coated with TTR fibrils exhibited significantly decreased intercellular electrical coupling as shown by FRAP dynamics of cells loaded with the gap junction‐permeable dye calcein‐AM, along with decreased gap junction content as determined by quantitative connexin 43 staining. Significant sarcomeric disorganization and loss of sarcomere content, with increased ubiquitin localization to the sarcomere, were seen in NRVMs on various TTR fibril‐coated substrata. TTR presence decreased intercellular mechanical junctions as evidenced by quantitative immunofluorescence staining of N‐cadherin and vinculin. Current therapies for wtATTR are cost‐prohibitive and only slow the disease progression; therefore, better understanding of cardiomyocyte maladaptation induced by TTR amyloid may identify novel therapeutic targets.

Spontanious luxation of the lens in Marfan syndrome

We report the case of a 22-year-old-man, who presented to the ophthalmic emergencies for decreased visual acuity since 2 days. The clinical examination found visual acuity reduced to counting fingers in the right eye and 3/10 in the left eye. and an anterior lens dislocation in the right eye, while the examination of the left eye after pupillary dilation, revealed lens dislocation in the superonasal direction and absence of zonules from 2 to 5 o’ clock position. The posterior segment examination was normal in both eyes. Otherwise, on general examination we noticed Marfan syndrome characteristic. In our case of the retained diagnosis was Marfan syndrome. The first clinical description was in 1896 by Antoine-Bernard-Jean Marfan [1], which is a rare genetic disease, that touch the conjunctive tissue of many organs, as well the eye that can present many abnormalities as: Ectopia lentis in 50-80%, which is commonly bilateral and many other manifestations also can be seen [2,3].

Transthyretin amyloid fibrils alter primary fibroblast structure, function, and inflammatory gene expression.

Age-related wild-type transthyretin amyloidosis (wtATTR) is characterized by systemic deposition of amyloidogenic fibrils of misfolded transthyretin (TTR) in the connective tissue of many organs. In the heart, this leads to cardiac dysfunction, which is a significant cause of age-related heart failure. The hypothesis tested is that TTR affects cardiac fibroblasts in ways that may contribute to fibrosis. When primary cardiac fibroblasts were cultured on TTR-deposited substrates, the F-actin cytoskeleton was disorganized, focal adhesion formation was decreased, and nuclear shape was flattened. Fibroblasts had faster collective and single-cell migration velocities on TTR-deposited substrates. In addition, fibroblasts cultured on microposts with TTR deposition had reduced attachment and increased proliferation above untreated. Transcriptomic and proteomic analyses of fibroblasts grown on glass covered with TTR showed significant upregulation of inflammatory genes after 48 h, indicative of progression in TTR-based diseases. Together, results suggest that TTR deposited in tissue extracellular matrix may affect the structure, function, and gene expression of cardiac fibroblasts. As therapies for wtATTR are cost-prohibitive and only slow disease progression, better understanding of cellular maladaptation may elucidate novel therapeutic targets.NEW & NOTEWORTHY Transthyretin (TTR) cardiac amyloidosis involves deposition of fibrils of misfolded TTR in the aging human heart, leading to cardiac dysfunction and heart failure. Our novel in vitro studies show that TTR fibrils alter primary cardiac fibroblast cytoskeletal and nuclear structure and focal adhesion formation. Furthermore, both fibrillar and tetrameric TTR significantly increased cellular migration velocity and caused upregulation of inflammatory genes determined by transcriptomic RNA and protein analysis. These findings may suggest new therapeutic approaches.

Intravenous transplantation of human muse cells improves blood perfusion in a mouse model of limb ischemia

Abstract Introduction Critical limb ischemia (CLI) is the end-stage of peripheral artery disease caused by atherosclerosis and inflammation. Despite advances in treatment of CLI, substantial number of patients with CLI suffer from severe pain, ulceration, and gangrene. Although the advent of stem cell-based therapy has opened a new avenue for the treatment of various diseases, accumulating evidence suggests current cell-based therapies are safe, but their efficacy is modest in CLI patients. Multilineage-differentiating stress enduring (Muse) cells were first reported by one of the authors and colleagues as endogenous pluripotent-like stem cells residing in the bone marrow, peripheral blood and connective tissue of many organs. Previous studies have demonstrated that systemic administration of exogenous Muse cells improves functional recovery after ischemic organ injury such as myocardial infarction. However, their therapeutic potential in CLI remains unclear. Objective The goal of this study is to elucidate the efficacy and safety of exogenous Muse cell transplantation with animal models of CLI. Methods Muse cells were isolated from human bone marrow-derived mesenchymal stem cells (MSCs) by fluorescence-activated cell sorting with anti-SSEA-3 antibody. To establish an animal model of CLI, 12–14-week-old male BALB/c mice were anesthetized and subjected to left femoral artery and vein resection. At 24 hours after establishment of hindlimb ischemia, mice were randomly divided into 5 groups and treated as follows: Group 1, intravenous injection of PBS as control group; group 2, intravenous injection of 3 × 104 SSEA3-negative MSCs (non-Muse MSCs); group 3, intravenous injection of 3 × 104 Muse cells; group 4, intramuscular injection of 3 × 104 Muse cells into ischemic limb; group 5, intramuscular injection of 2 × 105 mouse bone marrow-derived mononuclear cells (BM-MNCs) into ischemic limb (n=5 for each group). Hindlimb blood flow was evaluated by laser Doppler flowmetry for 14 days and expressed as the ratio of ischemic to non-ischemic hindlimb. Results We found that intramuscular injection of xenogeneic Muse cells without immunosuppression significantly improved the blood flow in the ischemic hindlimb compared to control at day 7 and 14 (0.67 vs. 0.52, p=0.0002 and 0.74 vs. 0.53, p<0.0001, respectively) similar to intramuscular injection of allogenic BM-MNCs. In addition, we also found that intravenous injection of xenogeneic Muse cells without immunosuppression significantly improved the blood flow in the ischemic hindlimb compared to control at day 7 and 14 (0.72, p<0.0001 and 0.67, p=0.004, respectively). In contrast, intravenous injection of xenogeneic non-Muse MSCs did not improve blood flow in the ischemic hindlimb. Conclusion Our result suggests that Muse cell-based regenerative therapy could be a novel, less invasive, cost-effective, and subsequently more effective treatment for CLI patients. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Grant-in-Aid for Scientific Research (KAKENHI)

Clinical Importance of Myocardial T2 Mapping and Texture Analysis.

Late gadolinium enhancement (LGE) magnetic resonance imaging (MRI) is valuable for diagnosis and assessment of the severity of various myocardial diseases owing to its potential to visualize myocardial scars. T1 mapping is complementary to LGE because it can quantify the degree of myocardial fibrosis or edema. As such, T1-weighted imaging techniques, including LGE using an inversion recovery sequence, contribute to cardiac MRI. T2-weighted imaging is widely used to characterize the tissue of many organs. T2-weighted imaging is used in cardiac MRI to identify myocardial edema related to chest pain, acute myocardial diseases, or severe myocardial injuries. However, it is difficult to determine the presence and extent of myocardial edema because of the low contrast between normal and diseased myocardium and image artifacts of T2-weighted images and the lack of an established method to quantify the images. T2 mapping quantifies myocardial T2 values and help identify myocardial edema. The T2 values are significantly related to the clinical symptoms or severity of nonischemic cardiomyopathy. Texture analysis is a postprocessing method to quantify tissue alterations that are reflected in the T2-weighted images. Texture analysis provides a variety of parameters, such as skewness, entropy, and grey-scale non-uniformity, without the need for additional sequences. The abnormal signal intensity on T2-weighted images or T2 values may correspond to not only myocardial edema but also other tissue alterations. In this review, the techniques of cardiac T2 mapping and texture analysis and their clinical relevance are described.

Automatic diameter and orientation distribution determination of fibrous materials in micro X-ray CT imaging data.

Fibrous nanomaterials such as electrospun materials have many uses ranging from tissue engineering to biosensors. High-resolution imaging is an important component in the characterization of these materials. Important parameters required to predict and study the properties of fibre rich materials include diameter and orientation distribution as well as fibre spacing. The orientations and the relative dimensions of the fibres can be measured via specially designed imaging software. Difficulties in this measurement process can arise if fibres are distributed in close proximity to each other in relation to the resolution of the imaging modality. For example, if some automation is required in the measurement process and, particularly, if the automated processes are not designed for situations where the fibres are in close proximity to each other. This work is therefore concerned with the development of automated measurement techniques to provide estimates of the diameters of fibres and also the orientation distribution. The software automatically detects special points in the fibrous materials where fibres can be considered to have some delineation from surrounding fibres. These sparse points are considered to be points at which estimates of the fibres' properties can be quantified. Aligned and randomly distributed electrospun poly(caprolactone) nanofibres were prepared. Imaging of these materials was performed with an X-ray Computer Tomography system with an image voxel size of 0.15 × 0.15 × 0.15μm3 . Scanning Electron Microscopy images were also obtained. Fibre diameters estimated using images from both modalities using the developed techniques were found to be in agreement. Orientation distribution was summarized with multiscale entropy and found to be consistent with visual observation across different scales. LAY DESCRIPTION: Fibres are present in many types of materials which can include, for some materials, very small fibres e.g. a few nanometres in diameter. Very small fibres are present in collagen and elastin which are common tissues of many organs in many types of living things. The sizes of these very small fibres and how they are arranged are important information that can help in the understanding of the overall properties of these materials. Materials with very small fibres can also be synthesized using specialised techniques. The properties of these synthesized fibrous materials are also important to help in understanding how the materials will perform in various different applications. Applications are many and can range from tissue engineering to drug delivery. Some properties of these materials can be shown, visually, with the aid of 3D imaging techniques such as X-ray Computer Tomography (XCT) or in 2D, with Scanning Electron Microscopy (SEM) but at a higher magnification. The work described here is centred around the development of computer algorithms to automatically determine material properties from 3D XCT images. Tests are performed with material samples, where the fibres are aligned (in semi-parallel fashion) and another where the fibres are randomly oriented (criss-crossing). The tests show that the developed algorithms are able to successfully and relatively accurately determine the diameters of the fibres. The tests also show that it is possible to quantify the relative randomness of the orientations of the fibres.

An efficient boundary element solver for trans-abdominal high-intensity focused ultrasound treatment planning

High-intensity focused ultrasound (HIFU) is a promising treatment modality for the non-invasive ablation of pathological tissue in many organs, including the liver. Since many patients are not suitable candidates for liver surgery, the possibility to locally deposit thermal energy in a non-invasive way would bear significant clinical impact. Optimal treatment planning strategies based on high-performance computing numerical methods are expected to form a vital component of a successful clinical outcome in which healthy tissue is preserved and optimal focusing achieved, thus compensating for soft tissue heterogeneity and the presence of ribs. The boundary element method (BEM) is an effective approach for this purpose because only the boundaries of the ribs and soft tissue regions require discretization, as opposed to standard approaches which require the entire volume around the ribcage to be meshed. A Galerkin discretized Burton-Miller formulation used in combination with preconditioning and matrix compre...

Directing Cardiomyogenic Differentiation and Transdifferentiation By Ectopic Gene Expression - Direct Transition Or Reprogramming Detour?

Cardiovascular disorders and associated morbidities remain the leading cause of premature death worldwide. Since the regeneration of diseased hearts is very limited and the insufficient supply of donor organs persists, hopes rely on new therapies for heart repair. Reviving the proliferation of endogenous cardiomyocytes (CMs) or the administration of adult stem cells to the heart was of limited curative success to date. Thus, the administration of in vitro generated CMs is under investigation to replenish loss of functional heart muscle tissue. This requires a sustainable source of CMs. Induced pluripotent stem cells (iPSC) have raised hopes for developing autologous cell therapies. To serve for heart repair, efficient and safe iPSC differentiation protocols for CMs production are required. iPSC differentiation into CMs and even functional subtypes was indeed achieved in recent years, either by the ectopic expression of cardiac transcription factors or the supplementation of chemical pathway modulators. An alternative approach aims at the direct transdifferentiation of fibroblasts, which are present in the interstitial tissue of many organs, into functional lineage-specific cell types. As a result the formation of induced cardiomyocyte-like cells (iCMs) by the ectopic expression of specific transcription factors combinations has been demonstrated in vitro and in vivo. This is an important proof-of-concept that the intermediate state of iPSC induction is dispensable. However, most of the early experiments were conducted in mice and translation to more relevant large animal models and subsequently to the clinic are challenging. Progress, drawbacks, and perspectives in this field will be discussed.

MRI-Guided HIFU Methods for the Ablation of Liver and Renal Cancers.

MRI-guided High Intensity Focused Ultrasound (MRI-HIFU) is a promising method for the non-invasive ablation of pathological tissue in many organs, including mobile organs such as liver and kidney. The possibility to locally deposit thermal energy in a non-invasive way opens a path towards new therapeutic strategies with improved reliability and reduced associated trauma, leading to improved efficacy, reduced hospitalization and costs. Liver and kidney tumors represent a major health problem because not all patients are suitable for curative treatment with surgery. Currently, radio-frequency is the most used method for percutaneous ablation. The development of a completely non-invasive method based on MR guided high intensity focused ultrasound (HIFU) treatments is of particular interest due to the associated reduced burden for the patient, treatment related patient morbidity and complication rate. The objective of MR-guidance is hereby to control heat deposition with HIFU within the targeted pathological area, despite the physiological motion of these organs, in order to provide an effective treatment with a reduced duration and an increased level of patient safety. Regarding this, several technological challenges have to be addressed: Firstly, the anatomical location of both organs within the thoracic cage requires inter-costal ablation strategies, which preserve the therapeutic efficiency, but prevent undesired tissue damage to the ribs and the intercostal muscle. Secondly, both therapy guidance and energy deposition have to be rendered compatible with the continuous physiological motion of the abdomen.

Fam83h null mice support a neomorphic mechanism for human ADHCAI.

Truncation mutations in FAM83H (family with sequence similarity 83, member H) cause autosomal dominant hypocalcified amelogenesis imperfecta (ADHCAI), but little is known about FAM83H function and the pathogenesis of ADHCAI. We recruited three ADHCAI families and identified two novel (p.Gln457*; p.Lys639*) and one previously documented (p.Q452*) disease-causing FAM83H mutations. We generated and characterized Fam83h-knockout/lacZ-knockin mice. Surprisingly, enamel thickness, density, Knoop hardness, morphology, and prism patterns were similar in Fam83h (+/+), Fam83h (+/-), and Fam83h (-/-) mice. The histology of ameloblasts in all stages of development, in both molars and incisors, was virtually identical in all three genotypes and showed no signs of pathology, although the Fam83h (-/-) mice usually died after 2 weeks and rarely survived to 7 weeks. LacZ expression in the knockin mice was used to report Fam83h expression in the epithelial tissues of many organs, notably in skin and hair follicles, which manifested a disease phenotype. Pull-down studies determined that FAM83H dimerizes through its N-terminal phospholipase D-like (PLD-like) domain and identified potential FAM83H interacting proteins. Casein kinase 1 (CK1) interacts with the FAM83H PLD-like domain via an F(270)-X-X-X-F(274)-X-X-X-F(278) motif. CK1 can phosphorylate FAM83H invitro, and many phosphorylation sites were identified in the FAM83H C-terminus. Truncation of FAM83H alters its subcellular localization and that of CK1. Our results support the conclusion that FAM83H is not necessary for proper dental enamel formation in mice, but may act as a scaffold protein that localizes CK1. ADHCAI is likely caused by gain-of-function effects mediated by truncated FAM83H, which potentially mislocalizes CK1 as part of its pathological mechanism.

Upper extremity subclinical autonomic and peripheral neuropathy in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune, multiorgan disease that affects connective tissues of many organs or systems, including the nervous system, where it affects the autonomic, the peripheral, and the central nervous system. The aim of this study was to investigate the association of subclinical autonomic and peripheral neuropathy with SLE and to correlate neurophysiological parameters with clinical and laboratory data. Fifty-six SLE patients were included in this study. In addition, thirty age-matched and sex-matched healthy participants served as a control group. Exclusion criteria included patients having symptoms or signs indicating autonomic dysfunction or peripheral neuropathy. Also, endocrinal, toxic, compression, and traumatic neuropathies were excluded. Patients were assessed clinically and by laboratory investigations. Neurophysiological assessment included sympathetic skin response of the median nerve including latency and amplitude. In addition, nerve conduction study of both median and ulnar nerves was performed including motor distal latency, amplitude, nerve conduction velocity, and distal sensory latency. Pure sensory abnormality was detected in one patient, whereas pure motor neuropathy was found in 19 patients. Mixed sensory–motor abnormalities were detected in two patients. Sympathetic skin response was not elicited in 13 patients, whereas latency and amplitude abnormalities were detected in 11/43 and 9/43 patients, respectively. Sympathetic and axonal neuropathy was not correlated with the disease duration or the disease activity. The pattern of neuropathy in SLE is mainly axonal. Also, the sympathetic nervous system is affected in lupus patients with a rate of up to 40% of the cases.

Telocytes express PDGFRα in the human gastrointestinal tract

Telocytes (TC), a cell population located in the connective tissue of many organs of humans and laboratory mammals, are characterized by a small cell body and extremely long and thin processes. Different TC subpopulations share unique ultrastructural features, but express different markers. In the gastrointestinal (GI) tract, cells with features of TC were seen to be CD34-positive/c-kit-negative and several roles have been proposed for them. Other interstitial cell types with regulatory roles described in the gut are the c-kit-positive/CD34-negative/platelet-derived growth factor receptor α (PDGFRα)-negative interstitial cells of Cajal (ICC) and the PDGFRα-positive/c-kit-negative fibroblast-like cells (FLC). As TC display the same features and locations of the PDGFRα-positive cells, we investigated whether TC and PDGFRα-positive cells could be the same cell type. PDGFRα/CD34, PDGFRα/c-kit and CD34/c-kit double immunolabelling was performed in full-thickness specimens from human oesophagus, stomach and small and large intestines. All TC in the mucosa, submucosa and muscle coat were PDGFRα/CD34-positive. TC formed a three-dimensional network in the submucosa and in the interstitium between muscle layers, and an almost continuous layer at the submucosal borders of muscularis mucosae and circular muscle layer. Moreover, TC encircled muscle bundles, nerve structures, blood vessels, funds of gastric glands and intestinal crypts. Some TC were located within the muscle bundles, displaying the same location of ICC and running intermingled with them. ICC were c-kit-positive and CD34/PDGFRα-negative. In conclusion, in the human GI tract the TC are PDGFRα-positive and, therefore, might correspond to the FLC. We also hypothesize that in human gut, there are different TC subpopulations probably playing region-specific roles.

Exploitation of Herpesvirus Immune Evasion Strategies to Modify the Immunogenicity of Human Mesenchymal Stem Cell Transplants

BackgroundMesenchymal stem cells (MSCs) are multipotent cells residing in the connective tissue of many organs and holding great potential for tissue repair. In culture, human MSCs (hMSCs) are capable of extensive proliferation without showing chromosomal aberrations. Large numbers of hMSCs can thus be acquired from small samples of easily obtainable tissues like fat and bone marrow. MSCs can contribute to regeneration indirectly by secretion of cytokines or directly by differentiation into specialized cell types. The latter mechanism requires their long-term acceptance by the recipient. Although MSCs do not elicit immune responses in vitro, animal studies have revealed that allogeneic and xenogeneic MSCs are rejected.Methodology/Principal FindingsWe aim to overcome MSC immune rejection through permanent down-regulation of major histocompatibility complex (MHC) class I proteins on the surface of these MHC class II-negative cells through the use of viral immune evasion proteins. Transduction of hMSCs with a retroviral vector encoding the human cytomegalovirus US11 protein resulted in strong inhibition of MHC class I surface expression. When transplanted into immunocompetent mice, persistence of the US11-expressing and HLA-ABC-negative hMSCs at levels resembling those found in immunodeficient (i.e., NOD/SCID) mice could be attained provided that recipients' natural killer (NK) cells were depleted prior to cell transplantation.Conclusions/SignificanceOur findings demonstrate the potential utility of herpesviral immunoevasins to prevent rejection of xenogeneic MSCs. The observation that down-regulation of MHC class I surface expression renders hMSCs vulnerable to NK cell recognition and cytolysis implies that multiple viral immune evasion proteins are likely required to make hMSCs non-immunogenic and thereby universally transplantable.

Conducta perioperatoria en un paciente con síndrome de San Filippo sometido a exodoncia múltiple

San Filippo syndrome is a hereditary lysosomal disorder resulting in the accumulation of mucopolysaccharides (mucopolysaccharidosis type II). A deficit in the enzyme required to break down heparan sulfate leads to its deposition in the connective tissue of many organs, particularly the brain, liver, heart, and spleen. The first symptoms-including mental deterioration, dimorphism, and behavioral changes such as hyperkinesis and aggressivity-present in childhood. Because this rare disorder has many anesthetic implications, we report the case of a 20-year-old man with San Filippo syndrome who underwent multiple tooth extraction under general combined anesthesia and a block of the second and third branches of the trigeminal nerve. This anesthetic combination provided satisfactory surgical conditions and recovery from anesthesia was rapid. Following surgery the patient developed a respiratory infection that led to severe respiratory failure and death.

SP-A-like molecule may be a marker of the lung-colon connection in IBD

According to Chinese Medicine, lung and colon is a pair of external-internally related organ systems. It means that a lung disease often have colon syndromes whereas a colon disease may have lung syndromes. In clinic, epidemiological and clinical investigation showed that many colon diseases were often accompanied by the pulmonary involvement, and many lung sources of non-specific environmental exposure, smoking stimulation or disorders were also had the colon involvement and vice versa. To date, it remains neither lung nor colon is the primary or secondary injury site. Although there is lots of clinic evidence of lung-colon connection, the laboratory evidence still remains to investigation. Inflammatory bowel disease (IBD), a term that describes two diseases characterized by aberrant immune response of the intestinal mucosa: Crohn's disease (CD) and ulcerative colitis (UC) may be a good example to study lung-colon connection. The reason is that both CD and UC often have pulmonary involvement, and non-specific environmental exposure and smoking contribute the pathogenesis of IBD. The understanding mechanism is that the complicated immunological, environmental and genetic factors should trigger lots of molecular events. Because both lung and colon has a huge vulnerable biological surface and which is continuously exposed to the external environment, frontier host defense molecules play dominant role to balance the open body systemic response. In this study, we investigated one of frontier host defense molecules, surfactant protein A (SP-A) expression in normal, inflammatory and IBD area, In the distal terminal (normal), the SP-A like immunoreactivity was only found at the apical part of epithelia, connective tissue of mucosa and submusoca. In the inflammatory (surround of IBD) area, strong staining was found not only at the apical part of epithelia, connective tissue of mucosa and submusoca, but also in chronic inflammatory cell of lamina propria and submucosa. In CD and UC area, even some epithelia of crypt of Lieberkühn are positive. The staining in IBD area is much stronger than inflammatory area, and the staining in inflammatory area is much stronger than normal area. Physicians believe the body (internal environment) is a society, the Traditional Chinese Medical Scholars even believe the body and external environment is a society. Drs. Whittaker and Hynes analyzed 948 proteins containing 1196 von Willebrand Factor A (vWFA) domain members, they found the majority of members in the family are located in the extracellular matrix with restricted expression in a special kind of tissue in an organ, or a special kind of tissue in many organs, or in circulated blood. The members in the cell membrane or cytoplasm or nucleus are involved in cellular functions such as gene transcription, DNA repair, ribosomal and membrane transport, and proteasome activity. The family members may form a multiprotein complex. We also found IR-SP-A was compatible with the sites, theoretically containing collagenous and lectin domain molecules, also compatible with the primary injury sites of some autoimmune diseases. In this study, we are note the staining signal is SP-A or SP-A like molecules, we do know the positive signal can be blocked by SP-A antigen from recombinant or bronchoalveolar lavage (BAL), it should be containing collagen or lectin domain proteins. Tightly regulated distribution of family members of proteins is related to social property in the open body system. In this opinion, the mechanism of complicated communication of lung-colon may associate with the social property of cell and molecule. Research scientists need to pay more attention on social property of cells and proteins. Our previous study found the distribution of IR-SP-A in colon was compatible with the primary injury sites of some autoimmune diseases including IBD. Clinical observable lung-colon connection as a complex cellular and molecular event remains a long way to establish. It should be a complicated communication. It is most likely to activation the communication between local and system. To our knowledge, however, thus far it remains difficult to answer all questions simply by network of neuroendocrine immune.

Mesenchymal stem cells reside within the connective tissues of many organs

Previous studies have noted the presence of mesenchymal stem cells located within the connective tissue matrices of avian skeletal muscle, dermis, and heart. In these studies, clonal analysis coupled with dexamethasone treatment revealed the presence of multiple populations of stem cells composed of both lineage-committed progenitor mesenchymal stem cells and lineage-uncommitted pluripotent mesenchymal stem cells. The present study was undertaken to assess the distribution of these stem cells in the connective tissues throughout various regions of the body. Day 11 chick embryos were divided into 26 separate regions. Heart, limb skeletal muscle, and limb dermis were included as control tissues. Cells were harvested enzymatically and grown using conditions optimal for the isolation, cryopreservation, and propagation of avian mesenchymal stem cells. Cell aliquots were plated, incubated with various concentrations of dexamethasone, and examined for differentiated phenotypes. Four recurring phenotypes appeared in dexamethasone-treated stem cells: skeletal muscle myotubes, fat cells, cartilage nodules, and bone nodules. These results suggest that progenitor mesenchymal stem cells and putative pluripotent mesenchymal stem cells with the potential to form at least four tissues of mesodermal origin have a widespread distribution throughout the body, being located within the connective tissue compartments of many organs and organ systems.

Characterization of the tissue macrophage and the interstitial dendritic cell as distinct leukocytes normally resident in the connective tissue of rat heart.

Immunohistological studies with a mouse anti-rat macrophage mAb (BMAC-5) demonstrated the presence of numerous positive cells in the interstitial connective tissues of many organs. The pattern resembled that seen with anti-MHC class II antibodies, with the striking exception that BMAC-5+ cells were rare or absent in the portal triad, the islets of Langerhans, and the kidney. Double-labeling fluorescence studies were therefore performed in rat heart using the BMAC-5 mAb in combination with rabbit antisera to pure rat class II MHC antigens and pure rat leukocyte common (CD45) antigens. The tissue macrophages in heart were identified as BMAC-5+, MHC class II-negative, leukocyte common antigen-positive cells. They could be distinguished from the BMAC-5-, MHC class II-positive, leukocyte common antigen-positive interstitial dendritic cells. Moreover, 7 d after lethal irradiation, the class II-positive interstitial dendritic cells had completely disappeared from heart, whereas the BMAC-5+ macrophages were present in undiminished numbers. These studies strongly suggest that the interstitial dendritic cell and the tissue macrophage represent two distinct populations of leukocytes within the connective tissues of antigenically secluded organs such as the heart. They have potentially important implications for the physiology of the immune system, as well as for autoimmunity and transplantation.