Associate editor: J.S. Fedan
Role of intestinal subepithelial myofibroblasts in inflammation and regenerative response in the gut

https://doi.org/10.1016/j.pharmthera.2006.12.004Get rights and content

Abstract

Inflammatory bowel disease (IBD) is characterized by an ongoing mucosal inflammation caused by a dysfunctional host immune response to commensal microbiota and dietary factors. In the pathophysiology of IBD, mesenchymal cells such as intestinal subepithelial myofibroblasts (ISEMF) affect the recruitment, retention and activation of immune cells. Mesenchymal cells also promote resolution of inflammatory activity accompanied with balanced repair processes. The transient appearance of mesenchymal cells is a feature of normal wound healing, but the persistence of these cells is associated with tissue fibrosis. Recent studies suggest that mesenchymal cells derived from bone marrow (BM) stem cells play a crucial role in intestinal repair and fibrosis. This article focuses on recent knowledge about ISEMF in the field of immune response inflammation and repair. Two major topics were documented: interaction between interleukin (IL)-17-secreting CD4+ cells (Th-17 cells) and about role of BM-derived stem cells in mucosal regenerative response via differentiation to ISEMF. Recent therapeutic strategies targeting BM stem cells for IBD patients were also documented.

Introduction

Ulcerative colitis (UC) and Crohn's disease (CD) comprise the 2 most common forms of inflammatory bowel disease (IBD) and are characterized by an ongoing mucosal inflammation caused by a dysfunctional host immune response to commensal microbiota and dietary factors (Riddle, 1995, Stenson, 1995, Podolsky, 2002, Hibi and Ogata, 2006). Intestinal inflammation has traditionally been considered a process, in which effector immune cells cause the destruction of other mucosal cells that behave as passive bystander targets (Fiocchi, 1997). The chronic inflammatory process leads to destruction of the epithelial barrier and subsequent epithelial ulceration, which permits easy access of luminal microbiota and dietary antigens to the cell resident in the lamina propria. In this response, mesenchymal cells such as stromal fibroblasts and myofibroblasts affect the recruitment, retention and activation of immune cells, through their synthesis of cytokines, chemokines, eicosanoids and extracellular matrix (ECM) components (Powell et al., 1999a, Powell et al., 1999b, Andoh et al., 2005a, Andoh et al., 2005b). The importance of mesenchymal cells to the perpetuation of chronic inflammation has been previously appreciated in the literature (Fiocchi, 1997, Andoh et al., 2002b).

Resolution of inflammatory activity is associated with balanced repair processes that facilitate tissue remodeling and, in turn, restore normal intestinal architecture and mucosal structure. The transient appearance of mesenchymal cells is a feature of normal wound healing, but the persistence of these cells is associated with excessive collagen deposition and fibrosis, which is frequently observed in CD patients and involves mesenchymal cell hyperplasia, tissue disorganization and fibrillar collagen deposition (Riddle, 1995, Stenson, 1995). Recent studies suggest that mesenchymal cells derived from bone marrow (BM) stem cells play a crucial role in intestinal repair and fibrosis (Pucilowska et al., 2000, Brittan and Wright, 2002, Brittan and Wright, 2004). This article focuses on recent knowledge about intestinal subepithelial myofibroblasts (ISEMF) in the field of immune response, inflammation and repair.

Section snippets

Characterization of intestinal subepithelial myofibroblasts

The subepithelial mesenchymal cells and their secreted basement membrane factors comprise the lamina propria, which provides a supporting network for the epithelial cells and regulates epithelial cell function (Powell et al., 1999a, Powell et al., 1999b, Andoh et al., 2005a, Andoh et al., 2005b). The lamina propria contains 2 intestinal myofibroblast populations: the interstitial cells of Cajal (ICC) and ISEMF. ICC are pacemaker cells located in an intramuscular space between the submucosa and

Extracellular matrix turnover and matrix metalloproteinases secretion

The ECM consists of collagens, other glycoproteins, and proteoglycans (Scott-Burden et al., 1989, Simon-Assmann et al., 1995). ISEMF constitutively secrete large amounts of ECM factors modulated by proinflammatory cytokines and growth factors. In isolated ISEMF, the secretion of types I, IV collagens and fibronectin into the culture medium was stimulated by IL-1β, TNF-α and TGF-β (Okuno et al., 2002, Simmons et al., 2002).

Matrix metalloproteinases (MMP) belong to the major enzyme group capable

Interleukin-17-producing T cells are distinct lineage from Th1 and Th2 cells

IL-17 was originally identified as cytotoxic T lymphocyte-associated antigen-8 and viral IL-17, the open reading frame 13 of T-lymphotropic Herpesvirus saimir (Kolls & Linden, 2004). Human IL-17 is a ∼ 20-kDa glycoprotein of 155 amino acids, with close sequence homology to both murine and viral IL-17 (Kolls & Linden, 2004). IL-17 secretion is limited to T lymphocytes, predominantly in memory CD45RO+ cells. In contrast, the IL-17 receptor is widely distributed in various cell types. Expression of

Stem cell factor

Stem cell factor (SCF) and its receptor c-kit have been extensively studied (Broudy et al., 1995, Liesveld et al., 1995). SCF has been shown to act synergistically with a number of cytokines to augument cellular proliferation, differentiation and/or function. SCF increases detection of myeloid, erythroid and megakaryocytic progenitors in short-term and long-term marrow colony assays (Liesveld et al., 1995). SCF acts synergistically with erythropoietin, thrombopoietin (c-mpl ligand) and IL-11 to

The gastrointestinal stem cells and the stem cell “niche”

Stem cells are undifferentiated primitive cells that exist within a tissue throughout the lifetime of an organism due to their ability to divide asymmetrically and undergo self-replication and also to produce committed daughter cells that can differentiate to form all adult lineages within a tissue. The gastrointestinal epithelial stem cells are located and maintained within a mesenchymal niche, a specialized microenvironment that provides an optimal milieu for stem cell survival and function,

The Wnt/β-catenin signaling pathway and intestinal subepithelial myofibroblasts

The signaling protein Wnt, of which there are 19 family members identified in humans, activates the cytoplasmic phosphoprotein “dishevelled” through its receptor “frizzled,” causing inhibition of GSK3β and a resultant accumulation of cytosolic β-catenin (Kinzler & Vogelstein, 1996). β-catenin then translocates to the nucleus and interacts with members of the Tcf/LEF (T-cell factor/lymphocyte enhancer factor) family of DNA binding proteins, converting them from transcriptional repressors to

Plasticity of adult bone marrow cells

Adult stem cells from several tissues, in addition to their fundamental role of formation of all adult lineages within their native tissue, can extricate their niche and engraft within foreign tissues and transform to contribute to adult lineages within these tissues. This phenomenon is commonly termed “plasticity,” or “transdifferentiation.” Adult BM cells contribute to adult lineages within several nonhaematopoietic tissues, including the gastrointestinal tract (Brittan et al., 2002, Okamoto

Therapeutic approaches targeting induction of bone marrow-derived stem cells in inflammatory bowel disease

IBD patients are mainly treated with immunosuppressive drugs such as corticosteroid and immunosuppressant. However, based on the notion that BM-derived stem cells transdifferentiate into mucosal compartments, several therapeutic approaches that target induction of circulating BM-derived stem cells have been recently tried in IBD patients. Such approaches may contribute to mucosal repair through stimulation of regenerative reponses via differentiation of BM-derived stem cells.

Significant amounts

Conclusion

In this review, we summarized recent findings of the role of ISEMF in mucosal inflammatory and repair. There are increasing reports concerning Th-17 cells, a new subclass of helper T cells, in the pathophysiology of intestinal inflammation. IL-17 and Th-17 cells may be a potential target for the treatment of patients with IBD. Furthermore, recent studies suggest that BM-derived cells colonize the intestinal mucosa and differentiate into ISEMF, thereby, controlling mucosal inflammatory and

References (119)

  • J.K. Kolls et al.

    Interleukin-17 family members and inflammation

    Immunity

    (2004)
  • D.S. Krause et al.

    Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell

    Cell

    (2001)
  • S.O. Lopez-Cubero et al.

    Course of Crohn's disease after allogeneic marrow transplantation

    Gastroenterology

    (1998)
  • M.N. Marsh et al.

    Morphology and cell proliferation of subepithelial fibroblasts in adult mouse jejunum: II. Radioautographic studies

    Gastroenterology

    (1974)
  • B.C. McKaig et al.

    Expression and regulation of tissue inhibitor of metalloproteinase-1 and matrix metalloproteinases by intestinal myofibroblasts in inflammatory bowel disease

    Am J Pathol

    (2003)
  • H. Nagase et al.

    Matrix metalloproteinases

    J Biol Chem

    (1999)
  • B. Oppmann et al.

    Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12

    Immunity

    (2000)
  • H. Oshima et al.

    Morphogenesis and renewal of hair follicles from adult multipotent stem cells

    Cell

    (2001)
  • J.M. Otte et al.

    Intestinal myofibroblasts in innate immune responses of the intestine

    Gastroenterology

    (2003)
  • R.R. Pascal et al.

    Colonic pericryptal fibroblast sheath: replication, migration, and cytodifferentiation of a mesenchymal cell system in adult tissue. I. Autoradiographic studies of normal rabbit colon

    Gastroenterology

    (1968)
  • R.L. Reinhardt et al.

    T helper cell effector fates- who, how and where?

    Curr Opin Immunol

    (2006)
  • M.R. Alison et al.

    Hepatocytes from non-hepatic adult stem cells

    Nature

    (2000)
  • A. Andoh et al.

    IL-17 selectively down-regulates TNF-alpha-induced RANTES gene expression in human colonic subepithelial myofibroblasts

    J Immunol

    (2002)
  • A. Andoh et al.

    Intestinal subepithelial myofibroblasts in inflammatory bowel diseases

    J Gastroenterol

    (2002)
  • A. Andoh et al.

    Interleukin (IL)-4 and IL-17 synergistically stimulate IL-6 secretion in human colonic myofibroblasts

    Int J Mol Med

    (2002)
  • A. Andoh et al.

    Suppression of interleukin-1beta- and tumor necrosis factor-alpha-induced inflammatory responses by leukocytapheresis therapy in patients with ulcerative colitis

    J Gastroenterol

    (2004)
  • A. Andoh et al.

    Colonic subepithelial myofibroblasts in mucosal inflammation and repair: contribution of bone marrow-derived stem cells to the gut regenerative response

    J Gastroenterol

    (2005)
  • A. Andoh et al.

    Interleukin-17 augments tumor necrosis factor-alpha-induced granulocyte and granulocyte/macrophage colony-stimulating factor release from human colonic myofibroblasts

    J Gastroenterol

    (2005)
  • A. Andoh et al.

    Interleukin (IL)-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts via NF-kappaB, AP-1 and MAP-kinase dependent pathways

    Gastroenterology

    (2005)
  • S. Bamba et al.

    Matrix metalloproteinase-3 secretion from human colonic subepithelial myofibroblasts: role of interleukin-17

    J Gastroenterol

    (2003)
  • S. Bamba et al.

    Regulation of IL-11 expression in intestinal myofibroblasts: role of c-Jun AP-1- and MAPK-dependent pathways

    Am J Physiol Gastrointest Liver Physiol

    (2003)
  • S. Bamba et al.

    Bone marrow transplantation ameliorates pathology in interleukin-10 knockout colitic mice

    J Pathol

    (2006)
  • M.L. Belladonna et al.

    IL-23 and IL-12 have overlapping but distinct, effects on murine dendritic cells

    J Immunol

    (2002)
  • C. Booth et al.

    Effects of IL-11 on the growth of intestinal epithelial cells in vitro

    Cell Prolif

    (1995)
  • T.R. Brazelton et al.

    From marrow to brain: expression of neuronal phenotypes in adult mice

    Science

    (2000)
  • R.L. Brinster et al.

    Spermatogenesis following male germ-cell transplantation

    Proc Natl Acad Sci U S A

    (1994)
  • M. Brittan et al.

    Gastrointestinal stem cells

    J Pathol

    (2002)
  • M. Brittan et al.

    The gastrointestinal stem cell

    Cell Prolif

    (2004)
  • M. Brittan et al.

    Bone marrow derivation of pericryptal myofibroblasts in the mouse and human small intestine and colon

    Gut

    (2002)
  • A.B. Cairnie

    Homeostasis in the Small Intestine

    (1976)
  • H. Cheng et al.

    Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine: V. Unitarian theory of the origin of the four epithelial cell types

    Am J Anat

    (1974)
  • P.S. Crosier et al.

    Basic biology of the hematopoietic growth factors

    Semin Oncol

    (1992)
  • D.J. Cua et al.

    Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain

    Nature

    (2003)
  • N.J. Davidson et al.

    Chronic colitis in IL-10−/− mice: insufficient counter regulation of a Th1 response

    Int Rev Immunol

    (2000)
  • L. Eckmann

    Innate immunity and mucosal bacterial interactions in the intestine

    Curr Opin Gastroenterol

    (2004)
  • M.A. Eglitis et al.

    Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice

    Proc Natl Acad Sci U S A

    (1997)
  • R.A. Fava et al.

    Vascular permeability factor/endothelial growth factor (VPF/VEGF): accumulation and expression in human synovial fluids and rheumatoid synovial tissue

    J Exp Med

    (1994)
  • G. Ferrari et al.

    Muscle regeneration by bone marrow-derived myogenic progenitors

    Science

    (1998)
  • C. Fiocchi

    Intestinal inflammation: a complex interplay of immune and nonimmune cell interactions

    Am J Physiol

    (1997)
  • S. Fujino et al.

    Increased expression of interleukin 17 in inflammatory bowel disease

    Gut

    (2003)

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