Edited by: Christoph Becker, University of Erlangen-Nuremberg, Germany
Reviewed by: Silvia D’Alessio, Humanitas Università, Italy; Andreas Diefenbach, Charité Universitätsmedizin Berlin, Germany; Claudio Nicoletti, University of Florence, Italy
Specialty section: This article was submitted to Mucosal Immunity, a section of the journal Frontiers in Immunology
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Stromal connective tissue contains mesenchymal cells, including fibroblasts and myofibroblasts, which line the tissue structure. However, it has been identified that the function of mesenchymal cells is not just structural—they also play critical roles in the creation and regulation of intestinal homeostasis. Thus, mucosal mesenchymal cells instruct intestinal immune cell education (or peripheral immune education) and epithelial cell differentiation thereby shaping the local environment of the mucosal immune system. Malfunction of the mesenchymal cell-mediated instruction system (e.g., fibrosis) leads to pathological conditions such as intestinal stricture.
Occurring below the mucosal mucus and membrane layer and at the forefront of host-environmental encounters, interactions between epithelial and immune cells are indispensable for the formation of the chemical, physical, and immunological barriers of the mucosal epithelium. Such interactions lead to immunophysiological functions—secretion of mucus containing anti-microbial peptides and secretory IgA antibodies, and enhancement of tight junctions—ultimately promoting intestinal homeostasis (
Mesenchymal cells are a large heterogenous population that includes fibroblasts, myofibroblasts, interstitial cells of Cajal, pericytes, many of which are within the mucosa (
Characteristics of surface molecules expressed by different mesenchymal cells.
Fibroblasts | Myofibroblasts | Pericytes | Smooth muscle | Interstitial cells of Cajal | |
---|---|---|---|---|---|
Vimentin | + | + | + | − | + |
CD90 | + | + | ± | − | − |
S100A4 | + | + | − | − | − |
Alpha-smooth muscle actin | − | + | + | + | − |
Desmin | − | − | + | + | − |
Smoothelin | − | − | + | + | − |
Platelet-derived growth factor receptor | + | + | + | + | ? |
c-kit | − | − | − | − | + |
Although mesenchymal cells have various origins, they provide mechanical and structural support functions that are integral to intestinal morphogenesis, organogenesis, and homeostasis (
In recent years, it has become apparent that mesenchymal cells act on various immunocompetent cells, such as dendritic cells and mast cells, to modulate differentiation, proliferation, and the function of these cells in peripheral tissues in a process we term “peripheral education” (
Along the gut epithelial layer, which forms the first line of mucosal barrier by producing mucus containing antibacterial substances (
In the villi, mesenchymal cells guide epithelial cell (EC) lineage differentiation in both physiological and pathological conditions (
Mesenchymal cell-instructed intestinal homeostatic and pathological conditions. Under normal conditions, mesenchymal cells promote mucosal homeostasis by maintaining physiological differentiation of absorptive epithelial cells from intestinal stem cells through the production of intestinal stem cell niche factors, including Wnt2b, Gremlin 1, and R-spondin 3. During pathological conditions, including inflammation and infection, mesenchymal cells can promote the essential switch from absorptive to secretory epithelial differentiation which is mediated by interleukin-33.
Homeostatic maintenance of epithelial stem cells is generally understood to be maintained by neighboring Paneth cell production of Wnt3, Wnt5, and EGF (
The intestinal mucosa is frequently threatened by environmental substances (e.g., pathogenic microorganisms, and chemicals such as alcohol) or dysbiosis of commensal microorganisms. The gut is thus equipped with multiple innate and acquired defense mechanisms (e.g., mucus, anti-microbial peptides, IgA antibodies, and Th17 cells) (
Epithelial restitution occurs early on in mucosal epithelial tissue that has suffered tissue damage due to inflammatory diseases (
Alongside epithelial restitution, stimulation of fibroblasts near the inflammation site is an important process. Activation by immune cells (e.g., T cells and macrophages) and EC-produced TGF-β1 induces differentiation of fibroblasts into myofibroblasts expressing smooth muscle α-actin (αSMA) (
In mucosal repair upon inflammatory bowel diseases (e.g., Crohn’s disease), FGF2 and IL-17 produced from regulatory T cells and Th17 cells, respectively, as the result of stimulatory signals caused by dysbiosis of the intestinal flora have been shown to play a critical role (
Transforming growth factor-β1 is an essential cytokine for wound healing and enhancement of ECM production (
The intestinal tract is a special tissue that is constantly in contact with various stimuli such as microflora, foods, and metabolites. Since the intestinal tract acts as a gateway for environmental antigens and pathogenic microorganisms, the mucosal immune system must achieve the appropriate immunological balance between active and quiescent responses. The qualitative and quantitative adjustment of intestinal IgA antibody production is deeply involved in both the protection against pathogenic bacterial infection and the maintenance of the appropriate composition of commensal bacterial flora for a healthy gut environment (
Mesenchymal cell-instructed immune cell education. Mesenchymal cells induce peripheral immune education, thereby refining intestinal-specific immune responses. IgA is involved in the both normal (commensal mutualism) and pathological (the protection against bacterial infection) conditions. Induction of IgA is directly and indirectly regulated by mucosal mesenchymal cells
In addition to RA, cytokines that promote IgA induction such as APRIL (also known as TNFSF13) and BAFF (also known as TNFSF13B) are produced by plasmacytoid dendritic cells, another subgroup of dendritic cells within the intestinal mucosa (
Mast cells undergo maturation after being distributed throughout the whole body, including gut mucosa,
Mast cells are classified into two subsets: “connective tissue type” and “mucosal type” (
In summary, our new and advanced knowledge of the role of mesenchymal cell-instructed functional maturation of immunocompetent cells (e.g., dendritic cells and mast cells) will allow us to create novel strategies for the control of mucosal infection and inflammation in the near future.
The functions of mucosal mesenchymal cells as the peripheral educator of immunological cells are critical in the development and maintenance of the intestinal homeostatic condition. Disruption of mucosal mesenchymal cell-instructed peripheral education system is likely a cause of gut pathological conditions. However, only a portion of the physiological, immunological, and pathological roles of these cells is clear, and detailed molecular and cellular mechanisms of the mucosal mesenchymal cell-instructed peripheral education system have yet to be elucidated.
Since mesenchymal cells are composed of a heterogeneous cell population, including fibroblasts, myofibroblasts, pericytes, interstitial cells of Cajal, adipocytes, and others, there remains a problem regarding the correct classification of subpopulations with specific molecular and morphological identification factors. Further investigations of the molecular role of mesenchymal cells in immune peripheral education, mucosal barrier formation, and fibrosis are required. It is thus important to elucidate the precise molecular interaction(s) between mesenchymal cells and immune cells to understand the bidirectional regulatory mechanisms. To this end, our current and future efforts aim to clarify the novel regulatory function of mesenchymal cells in the prevention of excess inflammatory reactions.
YK, DY, NS, SU, PE, TN, and HK conceived and wrote the manuscript.
The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.
We appreciate our colleagues (S. Matsumura, A. Inami, S. Murasaki, and Y. Kogure), and former and current collaborators, who have shared their expertise of each component of the mucosal immunology. This work was supported by grants from The Ministry of Education, Culture, Sports, Science, and Technology; Translational Research Network Program (at the University of Tokyo) Seeds A (YK), B (HK), and C (HK); Leading Initiative for Excellent Young Researchers (LEADER) (YK) Japan Agency for Medical Research and Development (HK); Japan Society for the Promotion of Science; Grant-in Aid for Scientific Research S (HK; 23229004); Grant-in-Aid for Young Scientists (A) (YK; 16H06243); Challenging Exploratory Research (YK; 17K19550); Senri Life Science Foundation (YK); and Mochida Memorial Foundation for Medical and Pharmaceutical Research (YK) and the Chiba University-UC San Diego Center for Mucosal Immunology, Allergy, and Vaccines (PE and HK).