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Gastroenterology Jun 2022Epithelial wound healing is compromised and represents an unleveraged therapeutic target in inflammatory bowel disease (IBD). Intestinal epithelial cells exhibit...
BACKGROUND & AIMS
Epithelial wound healing is compromised and represents an unleveraged therapeutic target in inflammatory bowel disease (IBD). Intestinal epithelial cells exhibit plasticity that facilitates dedifferentiation and repair during the response to injury. However, it is not known whether epithelial cells of a neighboring organ can be activated to mediate re-epithelialization in acute colitis. Histological findings of a permanent squamous tissue structure in the distal colon in human IBD could suggest diverse cellular origins of repair-associated epithelium. Here, we tested whether skin-like cells from the anus mediate colonic re-epithelialization in murine colitis.
METHODS
We studied dextran sulfate sodium-induced colitis and interleukin 10-deficient colitis in transgenic mice. We performed lineage tracing, 3-dimensional (3D) imaging, single-cell transcriptomics, and biophysical modeling to map squamous cell fates and to identify squamous cell types involved in colonic repair.
RESULTS
In acute and chronic colitis, we found a large squamous epithelium, called squamous neo-epithelium of the colon (SNEC), near the anorectal junction. Neighboring squamous cells of the anus rapidly migrate into the ulcerated colon and establish this permanent epithelium of crypt-like morphology. These squamous cells derive from a small unique transition zone, distal to the border of colonic and anal epithelium, that resists colitic injury. The cells of this zone have a pre-loaded program of colonic differentiation and further upregulate key aspects of colonic epithelium during repair.
CONCLUSION
Transitional anal cells represent unique reserve cells capable of rebuilding epithelial structures in the colon after colitis. Further study of these cells could reveal novel approaches to direct mucosal healing in inflammation and disease.
Topics: Anal Canal; Animals; Carcinoma, Squamous Cell; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Epithelial Cells; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Mice; Mice, Inbred C57BL; Re-Epithelialization
PubMed: 35227778
DOI: 10.1053/j.gastro.2022.02.031 -
Renal Failure Dec 2023Our research explores the role of M1 macrophage polarization in endothelium-to-myofibroblast transition (EndMT) and chronic allograft dysfunction (CAD). GSE21374...
Our research explores the role of M1 macrophage polarization in endothelium-to-myofibroblast transition (EndMT) and chronic allograft dysfunction (CAD). GSE21374 transcriptome sequencing data were obtained. Transplanted nephrectomy specimens from CAD patients were collected and studied to explore the infiltration of M1 and M2 macrophages using immunofluorescence, PCR, and Western blotting (WB). A co-culture model of M1 macrophages, polarized from mouse bone marrow-derived macrophages (BMDM) or Raw264.7, and aortic endothelial cells was established, and EndMT was tested using PCR and WB. RNA-sequencing was performed on the macrophages from the mouse BMDM. The TNF-α secreted from the polarized M1 macrophages was verified using ELISA. Based on the GEO public database, it was observed that macrophages were significantly infiltrated in CAD allograft tissues, with CD68(+) iNOS(+) M1 macrophages significantly infiltrating the glomeruli of allograft tissues, and CD68(+)CD206(+) M2 macrophages notably infiltrating the allograft interstitial area. The mRNA expression of the M1 macrophage marker inducible nitric oxide synthase (iNOS) was significantly increased ( < 0.05) and M1 macrophages were found to significantly promote the EndMT process . RNA-Sequencing analysis revealed that TNF signaling could be involved in the EndMT induced by M1 macrophages, and studies confirmed that TNF-α in the supernatant was significantly higher. The renal allograft tissues of CAD patients were found to be significantly infiltrated by M1 macrophages and could promote the progression of CAD by secreting the cytokine TNF-α to induce EndMT in endothelial cells.
Topics: Mice; Animals; Tumor Necrosis Factor-alpha; Kidney Transplantation; Endothelial Cells; Myofibroblasts; Macrophages; Allografts; Endothelium; RNA
PubMed: 37288756
DOI: 10.1080/0886022X.2023.2220418 -
Biomedicine & Pharmacotherapy =... Jun 2022CXCL12 and its receptors, which are highly expressed in the skin, are associated with various cutaneous diseases, including androgenic alopecia. However, their...
CXCL12 and its receptors, which are highly expressed in the skin, are associated with various cutaneous diseases, including androgenic alopecia. However, their expression and role during the hair cycle are unknown. This study aims to investigate the expression of CXCL12 and its receptor, CXCR4, in the vicinity of hair follicles and their effect on hair growth. CXCL12 was highly expressed in dermal fibroblasts (DFs) and its level was elevated throughout the catagen and telogen phases of the hair cycle. CXCR4 is expressed in the dermal papilla (DP) and outer root sheath (ORS). In hair organ culture, hair loss was induced by recombinant CXCL12 therapy, which delayed the telogen-to-anagen transition and decreased hair length. In contrast, the suppression of CXCL12 using a neutralizing antibody and siRNA triggered the telogen-to-anagen transition and increased hair length in hair organ culture. Neutralization of CXCR7, one of the two receptors for CXCL12, only slightly affected hair growth. However, inhibition of CXCR4, the other receptor for CXCL12, increased hair growth to a considerable extent. In addition, in hair organ culture, the conditioned medium from DFs with CXCL12 siRNA considerably increased the hair length and induced proliferation of DP and ORS cells. CXCL12, through CXCR4 activation, increased STAT3 and STAT5 phosphorylation in DP and ORS cells. In contrast, blocking CXCL12 and CXCR4 decreased the phosphorylation of STAT3 and STAT5. In summary, these findings suggest that CXCL12 inhibits hair growth via the CXCR4/STAT signaling pathway and that CXCL12/CXCR4 pathway inhibitors are a promising treatment option for hair growth.
Topics: Alopecia; Chemokine CXCL12; Hair; Hair Follicle; Humans; RNA, Small Interfering; Receptors, CXCR4; STAT5 Transcription Factor; Signal Transduction
PubMed: 35462338
DOI: 10.1016/j.biopha.2022.112996 -
Developmental Cell Jun 2023Mesenchymal-epithelial transitions are fundamental drivers of development and disease, but how these behaviors generate epithelial structure is not well understood....
Mesenchymal-epithelial transitions are fundamental drivers of development and disease, but how these behaviors generate epithelial structure is not well understood. Here, we show that mesenchymal-epithelial transitions promote epithelial organization in the mouse node and notochordal plate through the assembly and radial intercalation of three-dimensional rosettes. Axial mesoderm rosettes acquire junctional and apical polarity, develop a central lumen, and dynamically expand, coalesce, and radially intercalate into the surface epithelium, converting mesenchymal-epithelial transitions into higher-order tissue structure. In mouse Par3 mutants, axial mesoderm rosettes establish central tight junction polarity but fail to form an expanded apical domain and lumen. These defects are associated with altered rosette dynamics, delayed radial intercalation, and formation of a small, fragmented surface epithelial structure. These results demonstrate that three-dimensional rosette behaviors translate mesenchymal-epithelial transitions into collective radial intercalation and epithelial formation, providing a strategy for building epithelial sheets from individual self-organizing units in the mammalian embryo.
Topics: Animals; Mice; Mesoderm; Epithelium; Cell Differentiation; Embryo, Mammalian; Morphogenesis; Mammals
PubMed: 37080203
DOI: 10.1016/j.devcel.2023.03.018 -
Journal of Veterinary Diagnostic... Mar 2023Hamartomas are benign tumor-like lesions composed of disorganized growth of mature mesenchymal or epithelial tissues indigenous to the organ involved. Sporadically...
Hamartomas are benign tumor-like lesions composed of disorganized growth of mature mesenchymal or epithelial tissues indigenous to the organ involved. Sporadically observed in ruminants, vascular, fibrous, nasal, and pulmonary hamartomas have been reported in calves; pulmonary and cutaneous forms have been reported in sheep. A full-term elk calf found dead had a large intrathoracic mass replacing the left caudal lung lobe and compressing other thoracic organs. Histologically, cross- and tangential sections of bronchi were separated by collagenous mesenchyme and irregularly shaped canaliculi and saccules resembling terminal bronchioles. Rarely present were regions in which saccules, lined by simple cuboidal epithelium, transitioned into attenuated epithelium lining fully developed alveoli. These findings are consistent with a pulmonary hamartoma. To our knowledge, pulmonary hamartoma has not been reported previously in a non-domestic ruminant.
Topics: Animals; Epithelium; Hamartoma; Lung Neoplasms; Nose; Pulmonary Alveoli; Sheep; Sheep Diseases; Deer; Animals, Wild; Fatal Outcome
PubMed: 36476245
DOI: 10.1177/10406387221141091 -
Cancer Research Jan 2020Dissemination is an essential early step in metastasis but its molecular basis remains incompletely understood. To define the essential targetable effectors of this...
Dissemination is an essential early step in metastasis but its molecular basis remains incompletely understood. To define the essential targetable effectors of this process, we developed a 3D mammary epithelial culture model, in which dissemination is induced by overexpression of the transcription factor Twist1. Transcriptomic analysis and ChIP-PCR together demonstrated that protein kinase D1 (Prkd1) is a direct transcriptional target of Twist1 and is not expressed in the normal mammary epithelium. Pharmacologic and genetic inhibition of Prkd1 in the Twist1-induced dissemination model demonstrated that Prkd1 was required for cells to initiate extracellular matrix (ECM)-directed protrusions, release from the epithelium, and migrate through the ECM. Antibody-based protein profiling revealed that Prkd1 induced broad phosphorylation changes, including an inactivating phosphorylation of β-catenin and two microtubule depolymerizing phosphorylations of Tau, potentially explaining the release of cell-cell contacts and persistent activation of Prkd1. In patients with breast cancer, and expression correlated with metastatic recurrence, particularly in basal breast cancer. Prkd1 knockdown was sufficient to block dissemination of both murine and human mammary tumor organoids. Finally, knockdown blocked primary tumor invasion and distant metastasis in a mouse model of basal breast cancer. Collectively, these data identify Prkd1 as a novel and targetable signaling node downstream of Twist1 that is required for epithelial invasion and dissemination. SIGNIFICANCE: Twist1 is a known regulator of metastatic cell behaviors but not directly targetable. This study provides a molecular explanation for how Twist1-induced dissemination works and demonstrates that it can be targeted. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/2/204/F1.large.jpg.
Topics: Animals; Breast; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Datasets as Topic; Epithelial Cells; Epithelial-Mesenchymal Transition; Epithelium; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Mammary Neoplasms, Experimental; Mice; Microtubules; Neoplasm Invasiveness; Nuclear Proteins; Primary Cell Culture; Protein Kinase C; RNA-Seq; Signal Transduction; Twist-Related Protein 1
PubMed: 31676574
DOI: 10.1158/0008-5472.CAN-18-3241 -
Biomolecules Oct 2022A peritoneal adhesion (PA) is a fibrotic tissue connecting the abdominal or visceral organs to the peritoneum. The formation of PAs can induce a variety of clinical... (Review)
Review
A peritoneal adhesion (PA) is a fibrotic tissue connecting the abdominal or visceral organs to the peritoneum. The formation of PAs can induce a variety of clinical diseases. However, there is currently no effective strategy for the prevention and treatment of PAs. Damage to peritoneal mesothelial cells (PMCs) is believed to cause PAs by promoting inflammation, fibrin deposition, and fibrosis formation. In the early stages of PA formation, PMCs undergo mesothelial-mesenchymal transition and have the ability to produce an extracellular matrix. The PMCs may transdifferentiate into myofibroblasts and accelerate the formation of PAs. Therefore, the aim of this review was to understand the mechanism of action of PMCs in PAs, and to offer a theoretical foundation for the treatment and prevention of PAs.
Topics: Peritoneum; Epithelium; Extracellular Matrix; Myofibroblasts; Fibrin
PubMed: 36291710
DOI: 10.3390/biom12101498 -
Physiological Research Nov 2020Sensorineural hearing loss and vertigo, resulting from lesions in the sensory epithelium of the inner ear, have a high incidence worldwide. The sensory epithelium of the... (Review)
Review
Sensorineural hearing loss and vertigo, resulting from lesions in the sensory epithelium of the inner ear, have a high incidence worldwide. The sensory epithelium of the inner ear may exhibit extreme degeneration and is transformed to flat epithelium (FE) in humans and mice with profound sensorineural hearing loss and/or vertigo. Various factors, including ototoxic drugs, noise exposure, aging, and genetic defects, can induce FE. Both hair cells and supporting cells are severely damaged in FE, and the normal cytoarchitecture of the sensory epithelium is replaced by a monolayer of very thin, flat cells of irregular contour. The pathophysiologic mechanism of FE is unclear but involves robust cell division. The cellular origin of flat cells in FE is heterogeneous; they may be transformed from supporting cells that have lost some features of supporting cells (dedifferentiation) or may have migrated from the flanking region. The epithelial-mesenchymal transition may play an important role in this process. The treatment of FE is challenging given the severe degeneration and loss of both hair cells and supporting cells. Cochlear implant or vestibular prosthesis implantation, gene therapy, and stem cell therapy show promise for the treatment of FE, although many challenges remain to be overcome.
Topics: Animals; Ear, Inner; Epithelial-Mesenchymal Transition; Epithelium; Hair Cells, Auditory, Inner; Hearing Loss, Sensorineural; Humans; Noise
PubMed: 32901490
DOI: 10.33549/physiolres.934447 -
Angiogenesis May 2021Hematopoiesis in vertebrate embryos occurs in temporally and spatially overlapping waves in close proximity to blood vascular endothelial cells. Initially, yolk sac... (Review)
Review
Hematopoiesis in vertebrate embryos occurs in temporally and spatially overlapping waves in close proximity to blood vascular endothelial cells. Initially, yolk sac hematopoiesis produces primitive erythrocytes, megakaryocytes, and macrophages. Thereafter, sequential waves of definitive hematopoiesis arise from yolk sac and intraembryonic hemogenic endothelia through an endothelial-to-hematopoietic transition (EHT). During EHT, the endothelial and hematopoietic transcriptional programs are tightly co-regulated to orchestrate a shift in cell identity. In the yolk sac, EHT generates erythro-myeloid progenitors, which upon migration to the liver differentiate into fetal blood cells, including erythrocytes and tissue-resident macrophages. In the dorsal aorta, EHT produces hematopoietic stem cells, which engraft the fetal liver and then the bone marrow to sustain adult hematopoiesis. Recent studies have defined the relationship between the developing vascular and hematopoietic systems in animal models, including molecular mechanisms that drive the hemato-endothelial transcription program for EHT. Moreover, human pluripotent stem cells have enabled modeling of fetal human hematopoiesis and have begun to generate cell types of clinical interest for regenerative medicine.
Topics: Cell Differentiation; Cell Lineage; Endothelial Cells; Endothelium; Hematopoiesis; Hematopoietic Stem Cells; Humans
PubMed: 33783643
DOI: 10.1007/s10456-021-09783-9 -
Cells Jun 2022Endothelial-to-mesenchymal transition (EndoMT) is the process of endothelial cells progressively losing endothelial-specific markers and gaining mesenchymal phenotypes.... (Review)
Review
Endothelial-to-mesenchymal transition (EndoMT) is the process of endothelial cells progressively losing endothelial-specific markers and gaining mesenchymal phenotypes. In the normal physiological condition, EndoMT plays a fundamental role in forming the cardiac valves of the developing heart. However, EndoMT contributes to the development of various cardiovascular diseases (CVD), such as atherosclerosis, valve diseases, fibrosis, and pulmonary arterial hypertension (PAH). Therefore, a deeper understanding of the cellular and molecular mechanisms underlying EndoMT in CVD should provide urgently needed insights into reversing this condition. This review summarizes a 30-year span of relevant literature, delineating the EndoMT process in particular, key signaling pathways, and the underlying regulatory networks involved in CVD.
Topics: Cardiovascular Diseases; Endothelial Cells; Endothelium; Epithelial-Mesenchymal Transition; Humans; Hypertension, Pulmonary
PubMed: 35681530
DOI: 10.3390/cells11111834