Differentiation 92 (2016) 116–131

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Differentiation

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Invited review Fibroblasts and myofibroblasts of the intestinal lamina propria in physiology and disease

Manolis Roulis a, Richard A. Flavell a,b,n a Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA b Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA article info abstract

Article history: In this Review we summarize our current understanding of the biology of mesenchymal cells of the Received 24 February 2016 intestinal lamina propria focusing mainly on fibroblasts and myofibroblasts. The topics covered include Received in revised form 1) the embryonic origin of mesenchymal cells of the intestinal lamina propria and their heterogeneity in 19 April 2016 adults, 2) the role of the mesenchyme in intestinal development, 3) the physiological function of fi- Accepted 3 May 2016 broblasts and myofibroblasts in adults as part of the intestinal stem cell niche and the mucosal immune Available online 7 May 2016 system and 4) the involvement of fibroblasts and myofibroblasts in epithelial homeostasis upon injury Keywords: and in the pathogenesis of diseases such as Inflammatory Bowel Diseases, fibrosis and cancer. We em- Lamina propria mesenchyme phasize studies addressing the function of intestinal mesenchymal cells in vivo, and also discuss major Fibroblast open questions and current challenges in this field. fi Myo broblast & 2016 International Society of Differentiation. Published by Elsevier B.V. All rights reserved. Stromal cells

Contents

1. Introduction...... 117 2. Architecture of the intestinal mesenchyme ...... 117 3. Heterogeneity of mesenchymal cell populations in the lamina propria ...... 118 3.1. Fibroblasts ...... 118 3.2. Myofibroblasts...... 119 4. Developmental origin of intestinal mesenchymal cells ...... 119 5. Mesenchymal-epithelial cell interactions in intestinal development ...... 120 5.1. Hedgehog...... 120 5.2. Notch...... 121 5.3. Fibroblast growth factors ...... 121 5.4. Platelet-derived growth factor alpha ...... 121 5.5. Bone morphogenetic proteins ...... 121 6. The role of mesenchymal cells in the intestinal stem cell niche...... 121 7. Mesenchymal cells and the mucosal immune system ...... 123 7.1. Innate immunity ...... 123 7.2. Antigen presentation and immunoregulation ...... 123 8. The role of intestinal fibroblasts and myofibroblasts in the maintenance of intestinal homeostasis and disease development ...... 123 8.1. Mesenchymal cells, epithelial homeostasis and response to injury ...... 125 8.2. Inflammatory bowel diseases ...... 126 8.3. Intestinal fibrosis...... 126

Abbreviations: α-SMA, α-smooth muscle actin; BMP, bone morphogenetic protein; Cox-2, cyclooxygenase-2; DSS, dextran sodium sulfate; ECM, extracellular matrix; EGF, epidermal growth factor; FGF, fibroblast growth factor; Foxf, forkhead box protein F; HGF, hepatocyte growth factor; IBD, inflammatory bowel diseases; LPS, lipopoly- saccharide; MAPK, mitogen activated protein kinase; MMP, matrix metalloproteinase; NLRP, NACHT, LRR and PYD domains-containing protein; PDGF, platelet-derived growth factor; PGE2, prostaglandin E2; TGF, transforming growth factor; TIMP, tissue inhibitor of metalloproteinases; TNF, tumor necrosis factor; TNBS, trini- trobenzenesulfonic acid; TLR, toll-like receptor n Corresponding author at: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA. E-mail address: richard.fl[email protected] (R.A. Flavell). http://dx.doi.org/10.1016/j.diff.2016.05.002 Join the International Society for Differentiation (www.isdifferentiation.org) 0301-4681/& 2016 International Society of Differentiation. Published by Elsevier B.V. All rights reserved. M. Roulis, R.A. Flavell / Differentiation 92 (2016) 116–131 117

8.4. Cancer...... 127 9. Concluding remarks...... 128 Acknowledgements ...... 128 References...... 128

1. Introduction the mesenchyme in the past is nicely reflected in the origin of this term, from the Greek words mesos (¼intermediate) and énchyma The term “mesenchymal cells” of the intestinal lamina propria (i.e. (¼infusion), used to define a loosely formed tissue filling the gap theconnectivetissuebetweentheepitheliumandthemuscularis between other tissues of known function such as the epithelium mucosae), is used to collectively refer to non-hematopoietic, non- and the smooth muscle. A series of electron microscopy studies epithelial, non-endothelial cell types such as intestinal fibroblasts, performed in the '80s and '90s showed that the lamina propria myofibroblasts, pericytes, lymphatic lacteal smooth muscle cells, mesenchyme has a layered architecture, characterized by the smooth muscle cells of the muscularis mucosae and mesenchymal presence of specialized conformations of the extracellular matrix stromal/stem cells (Powell et al., 2011). The biology of intestinal me- (ECM) and morphologically distinct fibroblast-like cells in each senchymal cells has witnessed significant progress during the last two layer and along the crypt/villus axis (Fig. 1A) (Furuya and Furuya, decades, covered by a series of excellent reviews by Powell and col- 2007). Intestinal epithelial cells lie directly above a layer of ECM, leagues (Mifflin et al., 2011; Pinchuk et al., 2010; Powell et al., 2005; the basal lamina, which is continuous in the crypts but dis- Powell et al., 1999; Powell et al., 2011). Despite this progress, the continuous in the upper part of the villi where 0.5–5 mm in dia- origin, the heterogeneity and the role of intestinal mesenchymal cell meter pores, called fenestrations, are observed (Komuro, 1985). The types in physiology and disease remain poorly understood. Here, we basal lamina rests above a second layer wherein collagen fibrils summarize recent advances in the biology of fibroblasts and myofi- and sub-epithelial fibroblasts form a reticular sheet with 3–7 mm broblasts of the intestinal lamina propria and also discuss emerging in diameter pores juxtaposed to the fenestrations, the foramina questions, open challenges and future directions in this field. (Fig. 1B) (Toyoda et al., 1997). The basal lamina together with the underlying reticular network is known as the basement membrane which lies above an extensive network of fibroblast-like cells. 2. Architecture of the intestinal mesenchyme These fibroblasts form a basket-like network around the crypts that are tightly arranged in the lower part of the villi but their The limited understanding of the structure and the function of morphology changes towards the upper part of the villi where

Fig. 1. Architecture of the intestinal mesenchyme. A. Intestinal epithelial cells are attached to the basement membrane which consists of the basal lamina and a reticular sheet including fibroblasts. The basement membrane lies above an extensive network of fibroblast-like cells located deeper in the lamina propria. B. Scanning electron microscopy observation of the rat jejunum mesenchyme after depletion of the epithelial layer and the basal lamina. Collagen fibrils and sub-epithelial fibroblasts (arrow) form a reticular sheet with 3–7 mm in diameter pores called foramina (Magnification 8800 ). Adapted from Toyoda et al. (1997) with permission from S. Karger, AG, Basel. C. A transmission electron microscopy microphotograph of the sub-epithelial mesenchyme taken from a normal mouse colon specimen. Spindle-shaped fibroblasts (F) are located just under the epithelial layer (Epi), embedded in a dense network of collagen fibrils (arrows). A mesenchymal cell located deeper in the lamina propria is observed at the upper right part of the picture. Download English Version: https://daneshyari.com/en/article/5526101

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