Differentiation Of Epithelial Progenitor Cells Research Articles

A comparative study of morphological and Immunohistochemical expression of P40 and P63 immunomarkers in squamous cell carcinoma and adenocarcinoma lung

Background: Lung cancer is the leading cause of cancer related death worldwide and accounts for 28% of all cancer mortality and around 1.8 million new cases were diagnosed in 2012. The morphological distinction between pulmonary adenocarcinoma (ADC) and squamous cell carcinomas (SCC) is sometimes difficult, mainly in cases of poorly differentiated tumors or when degenerative changes, necrosis and crushing may obscure the cell characteristics. p63 is a homologue of the p53 tumour suppressor gene that is responsible for proliferation and differentiation of epithelial progenitor cells. p40 is consistently the predominant isoform expressed in squamous cell carcinoma; thus, it offers improved specificity for diagnosing squamous cell carcinoma. Material and Methods: This is a prospective and observational study conducted in the Department of Pathology, Tertiary care Teaching Hospital over a period of 1 year. Primary lung carcinoma cases included with unequivocal morphological diagnosis irrespective of age, gender and nature of biopsy material (endoscopic biopsy/ needle core biopsy / resected specimen). Cases diagnosed as Small cell carcinoma of lung, as metastatic lung cancers, poorly differentiated NSCLC-NOS and with inadequate material for IHC study were excluded from present study. Results: In the present study, a total of 150 patients were included out of which 112 (74.6%) were males and 38 (25.4%) were females. In our study, most of the patients were >61 years i.e., 63 out of 150 (42%), followed by 51-60 years, i.e., 40 out of 150 (26.7%). All 8 cases of well differentiated Adenocarcinoma were positive for P40 and 5 cases showed P63 expression. Out of 13 cases of moderately differentiated Adenocarcinoma, 3 cases were positive for P40 and 10 cases were positive for p63 marker. Out of 30 cases of well differentiated Squamous cell carcinoma 15 cases were P40 positive and 15 cases were P63 positive. All 53 cases of moderately differentiated Squamous cell carcinoma showed positive P40 and P63 expression.

Single-cell RNA sequencing reveals PDFGRα+ stromal cell subpopulations that promote proacinar cell differentiation in embryonic salivary gland organoids.

Stromal cells can direct the differentiation of epithelial progenitor cells during organ development. Fibroblast growth factor (FGF) signaling is essential for submandibular salivary gland development. Through stromal fibroblast cells, FGF2 can indirectly regulate proacinar cell differentiation in organoids, but the mechanisms are not understood. We performed single-cell RNA-sequencing and identified multiple stromal cell subsets, including Pdgfra+ stromal subsets expressing both Fgf2 and Fgf10. When combined with epithelial progenitor cells in organoids, magnetic-activated cell-sorted PDGFRα+ cells promoted proacinar cell differentiation similarly to total stroma. Gene expression analysis revealed that FGF2 increased the expression of multiple stromal genes, including Bmp2 and Bmp7. Both BMP2 and BMP7 synergized with FGF2, stimulating proacinar cell differentiation but not branching. However, stromal cells grown without FGF2 did not support proacinar organoid differentiation and instead differentiated into myofibroblasts. In organoids, TGFβ1 treatment stimulated myofibroblast differentiation and inhibited the proacinar cell differentiation of epithelial progenitor cells. Conversely, FGF2 reversed the effects of TGFβ1. We also demonstrated that adult salivary stromal cells were FGF2 responsive and could promote proacinar cell differentiation. These FGF2 signaling pathways may have applications in future regenerative therapies.

Recapitulating idiopathic pulmonary fibrosis related alveolar epithelial dysfunction in a human iPSC-derived air-liquid interface model.

Idiopathic pulmonary fibrosis (IPF) is a fatal disease of unknown cause that is characterized by progressive fibrotic lung remodeling. An abnormal emergence of airway epithelial-like cells within the alveolar compartments of the lung, herein termed bronchiolization, is often observed in IPF. However, the origin of this dysfunctional distal lung epithelium remains unknown due to a lack of suitable human model systems. In this study, we established a human induced pluripotent stem cell (iPSC)-derived air-liquid interface (ALI) model of alveolar epithelial type II (ATII)-like cell differentiation that allows us to investigate alveolar epithelial progenitor cell differentiation in vitro. We treated this system with an IPF-relevant cocktail (IPF-RC) to mimic the pro-fibrotic cytokine milieu present in IPF lungs. Stimulation with IPF-RC during differentiation increases secretion of IPF biomarkers and RNA sequencing (RNA-seq) of these cultures reveals significant overlap with human IPF patient data. IPF-RC treatment further impairs ATII differentiation by driving a shift toward an airway epithelial-like expression signature, providing evidence that a pro-fibrotic cytokine environment can influence the proximo-distal differentiation pattern of human lung epithelial cells. In conclusion, we show for the first time, the establishment of a human model system that recapitulates aspects of IPF-associated bronchiolization of the lung epithelium in vitro.

Multi-Faceted Notch in Allergic Airway Inflammation.

Notch is an evolutionarily conserved signaling family which iteratively exerts pleiotropic functions in cell fate decisions and various physiological processes, not only during embryonic development but also throughout adult life. In the context of the respiratory system, Notch has been shown to regulate ciliated versus secretory lineage differentiation of epithelial progenitor cells and coordinate morphogenesis of the developing lung. Reminiscent of its role in development, the Notch signaling pathway also plays a role in repair of lung injuries by regulation of stem cell activity, cell differentiation, cell proliferation and apoptosis. In addition to functions in embryonic development, cell and tissue renewal and various physiological processes, including glucose and lipid metabolism, Notch signaling has been demonstrated to regulate differentiation of literally almost all T-cell subsets, and impact on elicitation of inflammatory response and its outcome. We have investigated the role of Notch in allergic airway inflammation in both acute and chronic settings. In this mini-review, we will summarize our own work and recent advances on the role of Notch signaling in allergic airway inflammation, and discuss potential applications of the Notch signaling family in therapy for allergic airway diseases.

Interplay between Follistatin, Activin A, and BMP4 Signaling Regulates Postnatal Thymic Epithelial Progenitor Cell Differentiation during Aging

A key feature of immune functional impairment with age is the progressive involution of thymic tissue responsible for naive Tcell production. In this study, we identify two major phases of thymic epithelial cell (TEC) loss during aging: a block in mature TEC differentiation from the pool of immature precursors, occurring at the onset of puberty, followed by impaired bipotent TEC progenitor differentiation and depletion of Sca-1lo cTEC and mTEC lineage-specific precursors. We reveal that an increase in follistatin production by aging TECs contributes to their own demise. TEC loss occurs primarily through the antagonism of activin A signaling, which we show is required for TEC maturation and acts in dissonance to BMP4, which promotes the maintenance of TEC progenitors. These results support a model in which an imbalance of activin A and BMP4 signaling underpins the degeneration of postnatal TEC maintenance during aging, and its reversal enables the transient replenishment of mature TECs.

Interplay between Follistatin, Activin A and Bmp4 Signaling Regulates Postnatal Thymic Epithelial Progenitor Cell Differentiation During Aging

One of the key features of immune functional impairment with age is the progressive involution of the thymic tissue responsible for naive T cell production. In this study, we identify two major phases of thymic epithelial cell (TEC) loss during aging; a block in mature TEC differentiation from the pool of immature precursors, occurring at the onset of puberty, followed by impaired bipotent TEC progenitor differentiation, with depletion of Sca-1lo cTEC and mTEC lineage-specific precursors. We reveal the increased production of follistatin by aging TECs contributes to their own demise. This TEC loss occurs primarily through antagonism of activin A signaling, which we show is required for TEC maturation and acts in dissonance to Bmp4. Together, these results indicate that an imbalance of activin A and Bmp4 signaling underpins degeneration of postnatal TEC maintenance during aging, and its reversal enables transient replenishment of mature TECs.

EXTL3 mutations cause skeletal dysplasia, immune deficiency, and developmental delay.

We studied three patients with severe skeletal dysplasia, T cell immunodeficiency, and developmental delay. Whole-exome sequencing revealed homozygous missense mutations affecting exostosin-like 3 (EXTL3), a glycosyltransferase involved in heparan sulfate (HS) biosynthesis. Patient-derived fibroblasts showed abnormal HS composition and altered fibroblast growth factor 2 signaling, which was rescued by overexpression of wild-type EXTL3 cDNA. Interleukin-2-mediated STAT5 phosphorylation in patients' lymphocytes was markedly reduced. Interbreeding of the extl3-mutant zebrafish (box) with Tg(rag2:green fluorescent protein) transgenic zebrafish revealed defective thymopoiesis, which was rescued by injection of wild-type human EXTL3 RNA. Targeted differentiation of patient-derived induced pluripotent stem cells showed a reduced expansion of lymphohematopoietic progenitor cells and defects of thymic epithelial progenitor cell differentiation. These data identify EXTL3 mutations as a novel cause of severe immune deficiency with skeletal dysplasia and developmental delay and underline a crucial role of HS in thymopoiesis and skeletal and brain development.

CLMP Expression is Increased in the Intestinal Epithelium Under Inflammatory Conditions and Regulates Intercellular Adhesion, Proliferation and Migration

The intestine is lined by epithelial cells that form a dynamic physical barrier against external substances. Maintenance of this mucosal barrier requires proliferation, migration and differentiation of epithelial progenitor cells along the crypt‐luminal axis while keeping strong cell‐cell cohesion. Epithelial barrier function is created by tight junctions (TJ) and increased intestinal permeability has been linked with the pathogenesis of inflammatory bowel disease. CAR‐Like Membrane Protein (CLMP) is structurally related to the TJ transmembrane protein, Coxsackie and Adenovirus Receptor, but CLMP role in controlling intestinal epithelial barrier function in homeostasis and inflammation is not known. We observed that CLMP is distributed in intercellular junctions of murine and human intestinal epithelial cells (IECs), and its expression is increased after inflammatory cytokine exposure. CLMP overexpression in IECs, unlike its depletion, resulted in strengthened cell‐cell adhesion and increased cell migration after injury indicating a positive role of CLMP in the maintenance of epithelial barrier function and wound repair. Interestingly, CLMP overexpression led to decreased epithelial cell proliferation and inhibited the growth of subcutaneous xenografts in Rag1null mice. Our results support a role of CLMP in controlling intestinal epithelial barrier function and homeostasis. These studies will help to better understand signaling pathways that influence the intestinal epithelial barrier function during chronic inflammation.

The POZ-ZF Transcription Factor Kaiso (ZBTB33) Induces Inflammation and Progenitor Cell Differentiation in the Murine Intestine

Since its discovery, several studies have implicated the POZ-ZF protein Kaiso in both developmental and tumorigenic processes. However, most of the information regarding Kaiso’s function to date has been gleaned from studies in Xenopus laevis embryos and mammalian cultured cells. To examine Kaiso’s role in a relevant, mammalian organ-specific context, we generated and characterized a Kaiso transgenic mouse expressing a murine Kaiso transgene under the control of the intestine-specific villin promoter. Kaiso transgenic mice were viable and fertile but pathological examination of the small intestine revealed distinct morphological changes. Kaiso transgenics (KaisoTg/+) exhibited a crypt expansion phenotype that was accompanied by increased differentiation of epithelial progenitor cells into secretory cell lineages; this was evidenced by increased cell populations expressing Goblet, Paneth and enteroendocrine markers. Paradoxically however, enhanced differentiation in KaisoTg/+ was accompanied by reduced proliferation, a phenotype reminiscent of Notch inhibition. Indeed, expression of the Notch signalling target HES-1 was decreased in KaisoTg/+ animals. Finally, our Kaiso transgenics exhibited several hallmarks of inflammation, including increased neutrophil infiltration and activation, villi fusion and crypt hyperplasia. Interestingly, the Kaiso binding partner and emerging anti-inflammatory mediator p120ctn is recruited to the nucleus in KaisoTg/+ mice intestinal cells suggesting that Kaiso may elicit inflammation by antagonizing p120ctn function.

Pleiotrophin (PTN) Expression and Function and in the Mouse Mammary Gland and Mammary Epithelial Cells

Expression of the heparin-binding growth factor, pleiotrophin (PTN) in the mammary gland has been reported but its function during mammary gland development is not known. We examined the expression of PTN and its receptor ALK (Anaplastic Lymphoma Kinase) at various stages of mouse mammary gland development and found that their expression in epithelial cells is regulated in parallel during pregnancy. A 30-fold downregulation of PTN mRNA expression was observed during mid-pregnancy when the mammary gland undergoes lobular-alveolar differentiation. After weaning of pups, PTN expression was restored although baseline expression of PTN was reduced significantly in mammary glands of mice that had undergone multiple pregnancies. We found PTN expressed in epithelial cells of the mammary gland and thus used a monoclonal anti-PTN blocking antibody to elucidate its function in cultured mammary epithelial cells (MECs) as well as during gland development. Real-time impedance monitoring of MECs growth, migration and invasion during anti-PTN blocking antibody treatment showed that MECs motility and invasion but not proliferation depend on the activity of endogenous PTN. Increased number of mammospheres with laminin deposition after anti-PTN blocking antibody treatment of MECs in 3D culture and expression of progenitor markers suggest that the endogenously expressed PTN inhibits the expansion and differentiation of epithelial progenitor cells by disrupting cell-matrix adhesion. In vivo, PTN activity was found to inhibit ductal outgrowth and branching via the inhibition of phospho ERK1/2 signaling in the mammary epithelial cells. We conclude that PTN delays the maturation of the mammary gland by maintaining mammary epithelial cells in a progenitor phenotype and by inhibiting their differentiation during mammary gland development.

Regulation and role of notch signaling in epithelial progenitor cell differentiation and proliferation in the normal and the fibrotic lung

Introduction: Differenzial regulation of the TGF-ß, Wnt and Notch pathway was recently identified by transcriptome profiling of still normal appearing, microdissected alveolar septae from IPF lungs. The Notch signaling pathway is involved in cell fate decisions, differentiation and proliferation during development, but it may also play a key role in repair processes of the injured lung.

Notch signaling regulates proliferation and differentiation of the intestinal crypt base columnar (CBC) stem cell

This study examined the importance of the Notch signaling pathway for homeostasis of the CBC stem cell in the intestine. The Lgr5‐GFP reporter mouse strain was used to identify and track CBC stem cells after Notch inhibition with DBZ. Global Notch disruption in adult mice induced rapid CBC cell loss, with reduced proliferation and apoptotic cell death. Furthermore, expression of the CBC stem cell‐specific marker Olfactomedin 4 (Olfm4) was observed to be directly dependent on Notch signaling, with transcription activated through RBP‐Jκ binding sites in the promoter. Notch inhibition also led to precocious differentiation of epithelial progenitor cells into secretory cell types, including goblet, enteroendocrine and tuft cells, as well as an unusual secretory cell type that expressed both Paneth and goblet cell markers. Analysis of Notch function in Atoh1‐deficient mouse intestine demonstrated that the generalized secretory cell hyperplasia induced by Notch inhibition was dependent on this transcription factor, whereas Notch regulation of Olfm4 gene expression was Atoh1‐independent. Our findings suggest that Notch targets distinct progenitor cell populations to maintain adult intestinal stem cells and to regulate cell fate choice in order to control epithelial cell proliferation and differentiation.

Caveolin‐1 regulation of mouse lung epithelial progenitor cell differentiation and morphogenesis.

Caveolin‐1 (Cav‐1) is an intracellular scaffolding protein that regulates cell signaling and caveolae formation. We previously observed morphological and patterning defects in Cav‐1−/− mouse lungs and thus hypothesized that Cav‐1 may play an important role in the regulation of lung epithelial cell differentiation and morphogenesis. Distal lung epithelial progenitor cells (LEPCs) isolated from wild‐type (WT) and Cav‐1−/− mouse lungs expressed generic epithelial markers E‐cadherin and pan‐cytokeratin, but were negative for differentiation markers Clara Cell Secretary Protein (CCSP) and Aquaporin‐5 (AQP5). Cav‐1−/− LEPC colonies grown on plastic showed disrupted E‐cadherin and ß‐catenin junctional staining after induction of differentiation by addition of high calcium. qRT‐PCR and Western blot analysis of WT and Cav‐1−/− cells cultured in matrigel showed induction of CCSP and AQP5 in WT cells only. Also, epithelial cell cyst formation was observed in both WT and Cav‐1−/− cells, however cyst diameter was significantly greater for Cav‐1−/− cysts. From these studies, we speculate that defective differentiation and cell‐cell communication in the absence of Cav‐1 leads to dysfunctional distal lung epithelial cell morphogenesis.

A crucial role of WW45 in developing epithelial tissues in the mouse

The role and molecular mechanisms of a new Hippo signalling pathway are not fully understood in mammals. Here, we generated mice that lack WW45 and revealed a crucial role for WW45 in cell-cycle exit and epithelial terminal differentiation. Many organs in the mutant mouse embryos displayed hyperplasia accompanied by defects in terminal differentiation of epithelial progenitor cells owing to impaired proliferation arrest rather than intrinsic acceleration of proliferation during differentiation. Importantly, the MST1 signalling pathway is specifically activated in differentiating epithelial cells. Moreover, WW45 is required for MST1 activation and translocation to the nucleus for subsequent LATS1/2 activation upon differentiation signal. LATS1/2 phosphorylates YAP, which, in turn, translocates from the nucleus into the cytoplasm, resulting in cell-cycle exit and terminal differentiation of epithelial progenitor cells. Collectively, these data provide compelling evidence that WW45 is a key mediator of MST1 signalling in the coordinate coupling of proliferation arrest with terminal differentiation for proper epithelial tissue development in mammals.

Isolation and characterization of epithelial progenitor cells from human fetal liver

Hepatic progenitor cells can serve as an alternative source of hepatocytes for the treatment of liver diseases. We isolated and expanded the epithelial progenitor cells (EPC) from the human fetal liver and investigated the differentiation of EPC into hepatic cells by fluorescence-activated cell sorter (FACS), real-time polymerase chain reaction (PCR), immunofluorescence assay, western blotting, and periodic acid-Schiff staining. Isolated EPC possessed highly proliferative ability and subpassaged for more than 25 passages. Real-time PCR showed that EPC expressed liver epithelial markers (cytokeratin [CK]8 and CK18) and biliary-specific markers (CK7 and CK19). FACS analysis indicated that these cells were positive for CD117, CD147, CD90, CD44, human leucocyte antigen class I and CD71, but negative for CD34 and CD45. The EPCpossessed multipotential indicated by differentiating into osteoblasts and adipocytes; when subjected to the hepatic differentiation condition, EPC could be induced to hepatocyte-like cells, which expressed albumin, alpha-fetoprotein, and CK18 proteins. Two months after EPC transplantation, we observed that the grafted cells differentiated into hepatocyte-like cells and there was no observable tumor mass. We have isolated and characterized the human fetal liver-derived EPC and these cells may serve as an ideal cell source for cell-replacement therapy of diseased livers.

BMP4 Regulates Pancreatic Progenitor Cell Expansion through Id2

Inhibitor of DNA binding (Id) proteins bind to and inhibit the function of basic helix-loop-helix (bHLH) transcription factors including those that regulate pancreatic development. Moreover, bone morphogenetic proteins (BMPs) regulate the expression of Ids. We hypothesized that BMP4 and Id proteins play a role in the expansion and differentiation of epithelial progenitor cells. We demonstrate that BMP4 induces the expression of Id2 along with the expansion of AR42J pancreatic epithelial cells. Furthermore, neutralization of BMP4 significantly reduced duct epithelial cell expansion in a mouse model of islet regeneration. BMP4 stimulation promotes Id2 binding to the bHLH transcription factor NeuroD, which is required for the differentiation of pancreatic islet cells. Therefore, our results indicate that BMP4 stimulation blocks the differentiation of endocrine progenitor cells and instead promotes their expansion thereby revealing a novel paradigm of signaling explaining the balance between expansion and differentiation of pancreatic duct epithelial progenitors. Understanding the mechanisms of BMP and Id function elucidates a key step during pancreas embryogenesis, which is important knowledge for expanding pancreatic progenitors in vitro.

Inhibition of CD95-Mediated Apoptosis through β1 Integrin in the HSG Epithelial Cell Line

The HSG cell line serves as a model for salivary gland epithelial progenitor cell differentiation. In order for a progenitor cell to differentiate, the cell must maintain viability within its niche. Studies were designed to elucidate the mechanism for integrin-mediated HSG cell survival. HSG cells, grown on Matrigel, were resistant to CD95-mediated apoptosis. Western blot analysis showed that Matrigel induced the expression of bcl-2, bcl-xL, p63, and DeltaNp63. This induction occurred by as early as 2 hrs and remained for 24 hrs. CD95-mediated apoptosis resistance was dependent, however, upon the expression of the bcl-2 family. Furthermore, Matrigel induced bcl-2 family expression was dependent on the transactivation of the EGF receptor pathway since PD98059 and AG1478 inhibited Matrigel induced bcl-2 family expression and caused HSG cells to be sensitive to CD95-mediated apoptosis. Activation of the EGF receptor pathway, by itself, however, was not sufficient to inhibit apoptosis. Blocking antibody showed that bcl-2 family expression was mediated through beta1 integrin. These studies show that salivary progenitor epithelial cell survival is integrin dependent and involves the transactivation of the EGF receptor pathway.

Induction of Epithelial Progenitors In Vitro from Mouse Embryonic Stem Cells and Application for Reconstruction of Damaged Cornea in Mice

Severe ocular surface diseases and injuries cause loss of the corneal limbal epithelium, leading to re-epithelialization by bulbar conjunctival cells, resulting in vascularization of the cornea, conjunctival scarring, and loss of visual acuity. In this study, the optimal culture condition for induction of differentiation of epithelial progenitor cells from embryonic stem (ES) cells was determined for use in transplantation to damaged cornea in mice. Mouse ES cells were cultured on Petri dishes coated with several extracellular matrix proteins, and the markers for epithelial cells were analyzed with RT-PCR and Western blot analysis. The optimal condition for induction of epithelial progenitor cells was determined, and the progenitors were transplanted onto mouse eyes with corneal epithelia that had been damaged by exposure to n-heptanol. Epithelial progenitors were successfully induced by culturing mouse ES cells on type IV collagen for 8 days. These progenitors expressed keratin (K)12, which is specific to corneal epithelial cells, and cell surface CD44 and E-cadherin, both of which are essential in corneal epithelial wound healing. Complete re-epithelialization of the corneal surface occurred within 24 hours after transplantation. The resultant corneal epithelial cells expressed markers of the grafted cells, and no teratomata were observed during the follow-up period. Epithelial progenitors were successfully induced in vitro from ES cells and were applicable as grafts for treating corneal epithelial injury. ES cells may become an unlimited donor source of corneal epithelial cells for corneal transplantation and may restore useful vision in patients with a deficiency of limbal epithelial cells. This is an important first trial toward assessing the use of ES cells to reconstruct corneal epithelial cells.

The nude gene encodes a sequence-specific DNA binding protein with homologs in organisms that lack an anticipatory immune system.

In the mouse, the product of the nude locus, Whn, is required for the keratinization of the hair shaft and the differentiation of epithelial progenitor cells in the thymus. A bacterially expressed peptide representing the presumptive DNA binding domain of the mouse whn gene in vitro specifically binds to a 11-bp consensus sequence containing the invariant tetranucleotide 5'-ACGC. In transient transfection assays, such binding sites stimulated reporter gene expression about 30- to 40-fold, when positioned upstream of a minimal promotor. Whn homologs from humans, bony fish (Danio rerio), cartilaginous fish (Scyliorhinus caniculus), agnathans (Lampetra planeri), and cephalochordates (Branchiostoma lanceolatum) share at least 80% of amino acids in the DNA binding domain. In agreement with this remarkable structural conservation, the DNA binding domains from zebrafish, which possesses a thymus but no hair, and amphioxus, which possesses neither thymus nor hair, recognize the same target sequence as the mouse DNA binding domain in vitro and in vivo. The genomes of vertebrates and cephalochordates contain only a single whn-like gene, suggesting that the primordial whn gene was not subject to gene-duplication events. Although the role of whn in cephalochordates and agnathans is unknown, its requirement in the development of the thymus gland and the differentiation of skin appendages in the mouse suggests that changes in the transcriptional control regions of whn genes accompanied their functional reassignments during evolution.

Mesenchyme-dependent differentiation of epithelial progenitor cells in the gut.

The digestive tract and the gut as a paradigm represents an attractive system for the study of mechanisms involved in the differentiation of two types of progenitor cells: the endodermal cells during embryonic life and the undifferentiated crypt cells during epithelial renewal of the adult intestine. The morphological and functional events that accompany the differentiation processes of progenitor cells into the polarized epithelial cell types characteristic of the intestine appear comparable in both situations (1,2). During organogenesis of the gut, histological observations underlined a close relationship between epithelial cells and their underlying mesenchymal cells (3,4). Developmental biologists have emphasized experimentally the importance of interactions between the endoderm and mesenchyme during organogenesis of the digestive tract. In the adult intestine, gastroenterologists have focused their attention on a specialized mesenchymal cell type (the pericryptal fibroblasts) that displays, like epithelial cells, proliferative activities and migrating properties. The aim of this review is to provide current knowledge on epithelial-mesenchymal interactions during ontogenesis of the digestive tract and also to relate some experiments supporting the view of the perpetuation of epithelial-mesenchymal interactions beyond embryonic life.