Talk:Cardiovascular System - Spleen Development
Locating human splenic capillary sheaths in virtual reality
Sci Rep. 2018 Oct 24;8(1):15720. doi: 10.1038/s41598-018-34105-3.
Steiniger BS1, Wilhelmi V2, Berthold M3, Guthe M3, Lobachev O3. Author information Abstract Stromal capillary sheath cells in human spleens strongly express CD271, the low affinity nerve growth factor receptor p75. Serial sections of a representative adult human spleen were double-stained for CD271 versus smooth muscle alpha actin (SMA) plus CD34 to visualise capillary sheaths, the arterial tree and endothelial cells by transmitted light. Preliminary three-dimensional (3D) reconstructions of single regions were inspected in virtual reality (VR). This method showed that a large number of CD271+ sheaths occur in a post-arteriolar position often surrounding capillaries located close to divisions of arterioles. The length and diameter of capillary sheaths are rather heterogeneous. Long sheaths were observed to accompany one or two generations of capillary branches. We hypothesise that human splenic capillary sheaths may attract recirculating B-lymphocytes from the open circulation of the red pulp to start their migration into white pulp follicles along branches of the arterial tree. In addition, they may provide sites of interaction among sheath macrophages and B-lymphocytes. Our innovative approach allows stringent quality control by inserting the original immunostained serial sections into the 3D model for viewing and annotation in VR. Longer series of sections will allow to unequivocally localise most of the capillary sheaths in a given volume. PMID: 30356180 PMCID: PMC6200800 DOI: 10.1038/s41598-018-34105-3
Note this paper has associated VR files available - https://zenodo.org/record/1229434#.XGI-tC1L3OQ
Attrition of T Cell Zone Fibroblastic Reticular Cell Number and Function in Aged Spleens
Immunohorizons. 2018 May;2(5):155-163. doi: 10.4049/immunohorizons.1700062. Epub 2018 Jul 23.
Masters AR1,2, Jellison ER1, Puddington L1, Khanna KM1,3, Haynes L1,2.
Aging has a profound impact on multiple facets of the immune system, culminating in aberrant functionality. The architectural disorganization of splenic white pulp is a hallmark of the aging spleen, yet the factors underlying these structural changes are unclear. Fibroblastic reticular cells comprise one stromal cell subset in the spleen that is important for maintenance of architectural organization, yet it remains to be determined how aging impacts these cells. In this study, we sought to determine how aging impacts splenic T cell zone reticular cell (TRC) numbers, morphology, and function. Using a mouse model of aging, we found that aged naive spleens have fewer TRCs than young spleens. This reduction in TRC number correlated with reduced CCL19 and CCL21 concentrations in aged spleens, which may contribute to impaired homing of T cells. CCL21 in both young and aged spleens localized with TRCs. Aged TRCs extended marginally into B cell follicles and may contribute to the blending of the T cell zone and B cell follicles in aged spleens. The described age-related changes in TRCs number and function may be an underlying factor contributing to impaired immune system function with age. PMID: 30706058 PMCID: PMC6350919 DOI: 10.4049/immunohorizons.1700062
Capillary networks and follicular marginal zones in human spleens. Three-dimensional models based on immunostained serial sections
PLoS One. 2018 Feb 8;13(2):e0191019. doi: 10.1371/journal.pone.0191019. eCollection 2018.
Steiniger BS1, Ulrich C2, Berthold M3, Guthe M3, Lobachev O3.
We have reconstructed small parts of capillary networks in the human splenic white pulp using serial sections immunostained for CD34 alone or for CD34 and CD271. The three-dimensional (3D) models show three types of interconnected networks: a network with very few long capillaries inside the white pulp originating from central arteries, a denser network surrounding follicles plus periarterial T-cell regions and a network in the red pulp. Capillaries of the perifollicular network and the red pulp network have open ends. Perifollicular capillaries form an arrangement similar to a basketball net located in the outer marginal zone. The marginal zone is defined by MAdCAM-1+ marginal reticular stromal cells. Perifollicular capillaries are connected to red pulp capillaries surrounded by CD271+ stromal capillary sheath cells. The scarcity of capillaries inside the splenic white pulp is astonishing, as non-polarised germinal centres with proliferating B-cells occur in adult human spleens. We suggest that specialized stromal marginal reticular cells form a barrier inside the splenic marginal zone, which together with the scarcity of capillaries guarantees the maintenance of gradients necessary for positioning of migratory B- and T-lymphocytes in the human splenic white pulp. PMID: 29420557 PMCID: PMC5805169 DOI: 10.1371/journal.pone.0191019
Determinants of postnatal spleen tissue regeneration and organogenesis
NPJ Regen Med. 2018 Jan 16;3:1. doi: 10.1038/s41536-018-0039-2. eCollection 2018.
Tan JKH1, Watanabe T2,3.
The spleen is an organ that filters the blood and is responsible for generating blood-borne immune responses. It is also an organ with a remarkable capacity to regenerate. Techniques for splenic auto-transplantation have emerged to take advantage of this characteristic and rebuild spleen tissue in individuals undergoing splenectomy. While this procedure has been performed for decades, the underlying mechanisms controlling spleen regeneration have remained elusive. Insights into secondary lymphoid organogenesis and the roles of stromal organiser cells and lymphotoxin signalling in lymph node development have helped reveal similar requirements for spleen regeneration. These factors are now considered in the regulation of embryonic and postnatal spleen formation, and in the establishment of mature white pulp and marginal zone compartments which are essential for spleen-mediated immunity. A greater understanding of the cellular and molecular mechanisms which control spleen development will assist in the design of more precise and efficient tissue grafting methods for spleen regeneration on demand. Regeneration of organs which harbour functional white pulp tissue will also offer novel opportunities for effective immunotherapy against cancer as well as infectious diseases. PMID: 29367882 PMCID: PMC5770394 DOI: 10.1038/s41536-018-0039-2
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Origin and Immunological Functions of Spleen Stromal Cells
Trends Immunol. 2018 Jun;39(6):503-514. doi: 10.1016/j.it.2018.02.007. Epub 2018 Mar 19.
Golub R1, Tan J2, Watanabe T3, Brendolan A4. Author information Abstract The mammalian spleen is a peripheral lymphoid organ that plays a central role in host defense. Consequently, the lack of spleen is often associated with immunodeficiency and increased risk of overwhelming infections. Growing evidence suggests that non-hematopoietic stromal cells are central players in spleen development, organization, and immune functions. In addition to its immunological role, the spleen also provides a site for extramedullary hematopoiesis (EMH) in response to injuries. A deeper understanding of the biology of stromal cells is therefore essential to fully comprehend how these cells modulate the immune system during normal and pathological conditions. Here, we review the specificities of the different mouse spleen stromal cell subsets and complement the murine studies with human data when available. PMID: 29567327 DOI: 10.1016/j.it.2018.02.007
Determinants of postnatal spleen tissue regeneration and organogenesis
NPJ Regen Med. 2018 Jan 16;3:1. doi: 10.1038/s41536-018-0039-2. eCollection 2018.
Tan JKH1, Watanabe T2,3.
The spleen is an organ that filters the blood and is responsible for generating blood-borne immune responses. It is also an organ with a remarkable capacity to regenerate. Techniques for splenic auto-transplantation have emerged to take advantage of this characteristic and rebuild spleen tissue in individuals undergoing splenectomy. While this procedure has been performed for decades, the underlying mechanisms controlling spleen regeneration have remained elusive. Insights into secondary lymphoid organogenesis and the roles of stromal organiser cells and lymphotoxin signalling in lymph node development have helped reveal similar requirements for spleen regeneration. These factors are now considered in the regulation of embryonic and postnatal spleen formation, and in the establishment of mature white pulp and marginal zone compartments which are essential for spleen-mediated immunity. A greater understanding of the cellular and molecular mechanisms which control spleen development will assist in the design of more precise and efficient tissue grafting methods for spleen regeneration on demand. Regeneration of organs which harbour functional white pulp tissue will also offer novel opportunities for effective immunotherapy against cancer as well as infectious diseases. PMID: 29367882 PMCID: PMC5770394 DOI: 10.1038/s41536-018-0039-2 Free PMC Article
Anatomic variations of the spleen: current state of terminology, classification, and embryological background
Surg Radiol Anat. 2018 Jan;40(1):21-29. doi: 10.1007/s00276-017-1893-0. Epub 2017 Jun 19.
Varga I1, Babala J2, Kachlik D3.
A thorough understanding of the anatomy, physiology, and development of the spleen is essential for determining the pathophysiological mechanisms underpinning splenic diseases and congenital variations. The aim of this review is to briefly summarize current knowledge regarding the normal development of the spleen, and to provide an overview of clinically relevant congenital splenic variations. These include such variations as asplenia, polysplenia, hyposplenia, lobulation of spleen, accessory spleens, accessory splenic nodules, wandering spleen, splenogonadal and splenopancreatic fusion, splenic cysts, and cavernous haemangioma of the spleen. All of these congenital variations are also mentioned in internationally accepted embryological nomenclature, known as the Terminologia Embryologica. Interestingly, most patients who have these diseases are asymptomatic, and are often diagnosed only after an injury or during unrelated medical procedures. Using examples from published case reports, we highlight how an understanding of the embryology of the spleen and the etiology of its disease states would improve clinical practice. KEYWORDS: Accessory spleen; Asplenia and polysplenia; Congenital variations; Lobulation of spleen; Spleen; Splenic cyst; Terminologia Embryologica PMID: 28631052
Neural Crest Cells Contribute an Astrocyte-like Glial Population to the Spleen
Sci Rep. 2017 Mar 28;7:45645. doi: 10.1038/srep45645.
Barlow-Anacker AJ1, Fu M2, Erickson CS1, Bertocchini F3, Gosain A2,4.
Neural crest cells (NCC) are multi-potent cells of ectodermal origin that colonize diverse organs, including the gastrointestinal tract to form the enteric nervous system (ENS) and hematopoietic organs (bone marrow, thymus) where they participate in lymphocyte trafficking. Recent studies have implicated the spleen as an anatomic site for integration of inflammatory signals from the intestine with efferent neural inputs. We have previously observed alterations in splenic lymphocyte subsets in animals with defective migration of NCC that model Hirschsprung's disease, leading us to hypothesize that there may be a direct cellular contribution of NCC to the spleen. Here, we demonstrate that NCC colonize the spleen during embryogenesis and persist into adulthood. Splenic NCC display markers indicating a glial lineage and are arranged anatomically adjacent to blood vessels, pericytes and nerves, suggesting an astrocyte-like phenotype. Finally, we identify similar neural-crest derived cells in both the avian and non-human primate spleen, showing evolutionary conservation of these cells. PMID: 28349968 PMCID: PMC5368681 DOI: 10.1038/srep45645
Stromal Cell Subsets Directing Neonatal Spleen Regeneration
Sci Rep. 2017 Jan 9;7:40401. doi: 10.1038/srep40401.
Tan JK1,2, Watanabe T1.
Development of lymphoid tissue is determined by interactions between stromal lymphoid tissue organiser (LTo) and hematopoietic lymphoid tissue inducer (LTi) cells. A failure for LTo to receive appropriate activating signals during embryogenesis through lymphotoxin engagement leads to a complete cessation of lymph node (LN) and Peyer's patch development, identifying LTo as a key stromal population for lymphoid tissue organogenesis. However, little is known about the equivalent stromal cells that induce spleen development. Here, by dissociating neonatal murine spleen stromal tissue for re-aggregation and transplant into adult mouse recipients, we have identified a MAdCAM-1+CD31+CD201+ spleen stromal organizer cell-type critical for new tissue formation. This finding provides an insight into the regulation of post-natal spleen tissue organogenesis, and could be exploited in the development of spleen regenerative therapies.
PMID: 28067323 PMCID: PMC5220291
Human spleen microanatomy: why mice do not suffice
Immunology. 2015 Jul;145(3):334-46. doi: 10.1111/imm.12469.
The microanatomical structure of the spleen has been primarily described in mice and rats. This leads to terminological problems with respect to humans and their species-specific splenic microstructure. In mice, rats and humans the spleen consists of the white pulp embedded in the red pulp. In the white pulp, T and B lymphocytes form accumulations, the periarteriolar lymphatic sheaths and the follicles, located around intermediate-sized arterial vessels, the central arteries. The red pulp is a reticular connective tissue containing all types of blood cells. The spleen of mice and rats exhibits an additional well-delineated B-cell compartment, the marginal zone, between white and red pulp. This area is, however, absent in human spleen. Human splenic secondary follicles comprise three zones: a germinal centre, a mantle zone and a superficial zone. In humans, arterioles and sheathed capillaries in the red pulp are surrounded by lymphocytes, especially by B cells. Human sheathed capillaries are related to the splenic ellipsoids of most other vertebrates. Such vessels are lacking in rats or mice, which form an evolutionary exception. Capillary sheaths are composed of endothelial cells, pericytes, special stromal sheath cells, macrophages and B lymphocytes. Human spleens most probably host a totally open circulation system, as connections from capillaries to sinuses were not found in the red pulp. Three stromal cell types of different phenotype and location occur in the human white pulp. Splenic white and red pulp structure is reviewed in rats, mice and humans to encourage further investigations on lymphocyte recirculation through the spleen. KEYWORDS: human spleen; rat and mouse spleen; sheathed capillaries; splenic follicles; splenic stromal cells PMID: 25827019 PMCID: PMC4479533
The open microcirculation in human spleens: a three-dimensional approach
J Histochem Cytochem. 2011 Jun;59(6):639-48. doi: 10.1369/0022155411408315. Epub 2011 Apr 27.
Steiniger B1, Bette M, Schwarzbach H.
It has long been debated whether the red pulp of human spleens harbors an open or a closed microcirculation or both. To solve this issue, the authors differentially stained the endothelium in red pulp arterial microvessels and in venous sinuses using brightfield and fluorescence immunohistology with reagents against CD34 and CD141. Three-dimensional models of red pulp arterial microvessels and sinuses were derived from serial double-stained paraffin sections with the help of license-free open-access software. In each model, arterial microvascular ends were traced and verified by reference to the original serial sections. In total, 142 ends were analyzed in the specimens of three individuals. None of these ends was connected to a sinus, suggesting that the human splenic red pulp harbors an entirely open circulatory system. Thus, the spleen is the only human organ where blood passes through spaces not lined by endothelia or other barrier-forming cells.
PMID: 21525186 PMCID: PMC3201190 DOI: 10.1369/0022155411408315
Impaired spleen formation perturbs morphogenesis of the gastric lobe of the pancreas
PLoS One. 2011;6(6):e21753. doi: 10.1371/journal.pone.0021753. Epub 2011 Jun 30.
Hörnblad A1, Eriksson AU, Sock E, Hill RE, Ahlgren U. Author information
Despite the extensive use of the mouse as a model for studies of pancreas development and disease, the development of the gastric pancreatic lobe has been largely overlooked. In this study we use optical projection tomography to provide a detailed three-dimensional and quantitative description of pancreatic growth dynamics in the mouse. Hereby, we describe the epithelial and mesenchymal events leading to the formation of the gastric lobe of the pancreas. We show that this structure forms by perpendicular growth from the dorsal pancreatic epithelium into a distinct lateral domain of the dorsal pancreatic mesenchyme. Our data support a role for spleen organogenesis in the establishment of this mesenchymal domain and in mice displaying perturbed spleen development, including Dh +/-, Bapx1-/- and Sox11-/-, gastric lobe development is disturbed. We further show that the expression profile of markers for multipotent progenitors is delayed in the gastric lobe as compared to the splenic and duodenal pancreatic lobes. Altogether, this study provides new information regarding the developmental dynamics underlying the formation of the gastric lobe of the pancreas and recognizes lobular heterogeneities regarding the time course of pancreatic cellular differentiation. Collectively, these data are likely to constitute important elements in future interpretations of the developing and/or diseased pancreas.
Congenital anomalies of the spleen from an embryological point of view
Med Sci Monit. 2009 Dec;15(12):RA269-76.
Varga I, Galfiova P, Adamkov M, Danisovic L, Polak S, Kubikova E, Galbavy S. Department of Histology and Embryology, Faculty of Medicine, Comenius University in Bratislava, Slovak Republic.
Abstract The spleen is the major accumulation of lymphoid tissue in the human body, an organ which prenatally produces and postnatally controls blood cells. Normally, a developed spleen lies in the upper left quadrant in parallel with the long axis of the 10th rib. It is a mesodermal derivate which first appears as a condensation of mesenchymal cells inside the dorsal mesogastrium at the end of the fourth embryonic week. Some congenital anomalies of the spleen are common, such as splenic lobulation and accessory spleen, while other conditions are rare, such as wandering spleen and polysplenia. Splenogonadal fusion is also a rare developmental anomaly, resulting from abnormal fusion of the splenic and gonadal primordia during prenatal development. The purpose of this article is to describe the normal development of the human spleen, supplemented with our own photomicrographs and a review of congenital anomalies of the spleen with their possible embryonic basis.
Development and function of the mammalian spleen
Bioessays. 2007 Feb;29(2):166-77.
Brendolan A, Rosado MM, Carsetti R, Selleri L, Dear TN.
Department of Cell and Developmental Biology, Cornell University, Weill Medical School, New York, NY, USA. Abstract The vertebrate spleen has important functions in immunity and haematopoiesis, many of which have been well studied. In contrast, we know much less about the mechanisms governing its early embryonic development. However, as a result of work over the past decade-mostly using knockout mice--significant progress has been made in unravelling the genetic processes governing the spleen's early development. Key genetic regulators, such as Tlx1 and Pbx1, have been identified, and we know some of the early transcriptional hierarchies that control the early patterning and proliferation of the splenic primordium. In mouse and humans, asplenia can arise as a result of laterality defects, or the spleen can be absent with no other discernible abnormalities. Surprisingly, given the spleen's diverse functions, asplenic individuals suffer no major haematopoietic or immune defects apart from a susceptibility to infection with encapsulated bacteria. Recent evidence has shed light on a previously unknown role of the spleen in the development and maintenance of specific B cell populations that are involved in the initial response to infection caused by encapsulated bacteria. The lack of these populations in asplenic mice and humans may go some way to explaining this susceptibility.
Copyright 2007 Wiley Periodicals, Inc. PMID 17226804
Ontogeny of ovine lymphocytes. II. An immunohistological study on the development of T lymphocytes in the sheep fetal spleen
Immunology. 1987 Sep;62(1):107-12.
Maddox JF, Mackay CR, Brandon MR.
Department of Veterinary Preclinical Sciences, University of Melbourne, Parkville, Victoria, Australia.
The development of T and B lymphocytes in the ovine fetal spleen was studied immunohistologically using a panel of monoclonal antibodies. A specific sequence of appearance of lymphocyte markers on cells was observed. At 43-44 days of gestation, SBU-T1- and SBU-T8-positive lymphocytes were present in low numbers. However, no SBU-T4, 20.96-, 25.69-, 38.38-, or 46.66-positive lymphocytes were seen until 50-55 days of gestation. Surface immunoglobulin (sIg) was first detected on fetal spleen cells at 45-50 days of gestation. SBU-T19 lymphocytes appeared later in gestation, being observed in fetal spleens at 57 days gestational age (g.a.). The distribution of T cells, B cells and MHC antigens in the developing spleen of the ovine fetus is described.