Keratin intermediate filaments in the colon: guardians of epithelial homeostasis

Polari, Lauri; Alam, Catharina; Nyström, Joel H.; Heikkilä, Taina; Tayyab, Mina; Baghestani, Sarah; Toivola, Diana M.

doi:10.1016/j.biocel.2020.105878

Cited by 46 publications

(48 citation statements)

References 182 publications

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“…While this study did not address differentiation-related proteins, per se , we noted that keratin 8 and keratin 18 (components of intermediate filaments in gastrointestinal epithelial cells) (40) were increased in response to Aquamin ® . With keratin 8, expression was increased 1.25 ± 0.01-fold and 1.52 ± 0.09-fold in the normal and UC data sets respectively.…”

Section: Resultsmentioning

confidence: 82%

Cell-matrix adhesion contributes to permeability control in human colon organoids

Varani

Aslam

2021

Preprint

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Background and aims: Cell-cell adhesion structures (desmosomes and, especially, tight junctions) are known to play important roles in control of transepithelial permeability in the colon. The involvement of cell-matrix interactions in permeability control is less clear. The goals of the present study were to: i) determine if disruption of colon epithelial cell interactions with the extracellular matrix alters permeability control and ii) determine if increasing the elaboration of protein components of cell-matrix adhesion complexes improves permeability control and mitigates the effects of cell-matrix disruption. Methods: Human colon organoids were interrogated for transepithelial electrical resistance (TEER) under control conditions (0.25 mM calcium) and in the presence of Aquamin®, a multi-mineral product, at a level providing 1.5 mM calcium. The effects of Aquamin® on cell-matrix adhesion protein expression were determined in a proteomic screen and by Western blotting. In parallel, TEER was assessed in the presence of a function-blocking antibody directed at an epitope in the C-terminal region of laminin α3 chain. Results: Treatment of colon organoids with Aquamin® increased the expression of multiple basement membrane and hemidesmosomal proteins as well as keratin 8 and 18. TEER values were higher in the presence of Aquamin® than they were under control conditions. Anti-laminin antibody reduced TEER values under all conditions but was most effective in the absence of Aquamin®, where laminin expression was low and TEER values were lower to begin with. Conclusions: These findings provide evidence that cell-matrix interactions contribute to permeability control in the colon. They suggest that the elaboration of proteins important to cell-matrix interactions can be increased in human colon organoids by exposure to a multi-mineral natural product. Increasing the elaboration of such proteins may help to mitigate the consequences of disrupting cell-matrix interactions on permeability control.

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Section: Resultsmentioning

confidence: 82%

Cell-matrix adhesion contributes to permeability control in human colon organoids

Varani

Aslam

2021

Preprint

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“…The K7 expression in the endocrine pancreas is thus similar to the colon, i.e., species-dependent, as K7 is also expressed in mouse, but not in human colon epithelia, under basal conditions [19,38]. However, while most human colon carcinomas are K7negative, 5-34% of colon and rectal tumors upregulate and display patchy K7-positive cells, in addition to the reported neoexpression of K7 in various other cancers [19,38].…”

Section: Discussionmentioning

confidence: 84%

“…By contrast with other human tissues where K7 is present, such as in the transitional epithelium of the bladder, K7 is co-expressed with K19, rather than K18 [41]. Similarly, in mice, K7 and K19 are often co-expressed, e.g., in bile ducts, exocrine pancreatic ducts, renal collecting ducts, intestinal epithelial cells, and the bladder epithelium [18,19,36,41,42]. Hence, the mouse islets of Langerhans are, to our knowledge, an exception, as they express K7 but not K19 under basal conditions.…”

Section: Discussionmentioning

confidence: 95%

“…In polarized epithelial cells, such as colonocytes and exocrine pancreatic acinar cells, keratin filaments are concentrated at the apical domain, with thinner filament formation along the lateral domains and in the cytoplasm [18,19]. Hepatocytes on the other hand, form several small apical domains at their bile canaliculi [20,21] and the hepatocyte keratin network extends more homogenously from the nucleus outwards, across the cytoplasm [12].…”

Section: Keratin Expression In Islets Is Enriched Near the β-Cell Vertices And Lateral Edgesmentioning

confidence: 99%

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Keratin 7 Is a Constituent of the Keratin Network in Mouse Pancreatic Islets and Is Upregulated in Experimental Diabetes

Alam

Baghestani

Pajari

et al. 2021

IJMS

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Keratin (K) 7 is an intermediate filament protein expressed in ducts and glands of simple epithelial organs and in urothelial tissues. In the pancreas, K7 is expressed in exocrine ducts, and apico-laterally in acinar cells. Here, we report K7 expression with K8 and K18 in the endocrine islets of Langerhans in mice. K7 filament formation in islet and MIN6 β-cells is dependent on the presence and levels of K18. K18-knockout (K18‒/‒) mice have undetectable islet K7 and K8 proteins, while K7 and K18 are downregulated in K8‒/‒ islets. K7, akin to F-actin, is concentrated at the apical vertex of β-cells in wild-type mice and along the lateral membrane, in addition to forming a fine cytoplasmic network. In K8‒/‒ β-cells, apical K7 remains, but lateral keratin bundles are displaced and cytoplasmic filaments are scarce. Islet K7, rather than K8, is increased in K18 over-expressing mice and the K18-R90C mutation disrupts K7 filaments in mouse β-cells and in MIN6 cells. Notably, islet K7 filament networks significantly increase and expand in the perinuclear regions when examined in the streptozotocin diabetes model. Hence, K7 represents a significant component of the murine islet keratin network and becomes markedly upregulated during experimental diabetes.

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“…There are few antibodies available that recognize epithelial antigens like Ep-CAM (now classi ied as CD326 ; clones: Ber-EP4; MOC31 ; VU-1D9); Epithelial Speci ic Antigen (ESA; Clone: HEA125); Epithelial Membrane Antigen (EMA/MUC1/ CD227) [2,[6][7][8]. Epithelial cells also express most exclusively cytokeratins under different isoforms regarding the tissue they originate from [9,10]. Several monoclonal antibodies recognize either several cytokeratins (pancytokeratin, e.g.…”

Section: Introductionmentioning

confidence: 99%

Flow cytometry potential applications in characterizing solid tumors main phenotype, heterogeneity and circulating cells

Waeckel¹,

G²,

Anne-Emmanuelle³

et al. 2021

Arch Pathol Clin Res

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Flow cytometry (FCM) is a unique technique that allows rapid quantitative measurement of multiple parameters on a large number of cells at the individual level. FCM is based on immunolabelling with fluorochrome-conjugated antibodies, leading to high sensitivity and precision while time effective sample preparation. FCM can be performed on tissue following enzymatic or mechanical dissociation. The expression of epithelial antigens and cytokeratin isoforms help in distinguishing tumor cells from adjacent epithelial cells and from tumor infiltrating leukocytes. Tumor phenotypes can be characterized on expression intensity, aberrancies and presence of tumor-associated antigens as well as their cell proliferation rate and eventual heteroploidy. FCM can measure quantitative expression of hormone or growth factor receptors, immunoregulatory proteins to guide adjuvant therapy. Expression of adhesion molecules tells on tumor’s capacity for tissue invasion and metastasis seeding. Tumor heterogeneity can be explored quantitatively and rare, potentially emerging, clones with poor prognosis can be detected. FCM is easily applicable on fine needle aspiration and in any tumor related biological fluids. FCM can also be used to detect circulating tumor cells (CTC) to assess metastatic potential at diagnosis or during treatment. Detecting CTC could allow early detection of tumors before they are clinically expressed although some difficulties still need to be solved. It thus appears that FCM should be in the pathologist tool box to improve cancer diagnosis, classification and prognosis evaluation as well as in orientating personalized adjuvant therapy and immunotherapy. More developments are still required to better known tumor phenotypes and their potential invasiveness.

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Keratin intermediate filaments in the colon: guardians of epithelial homeostasis

Cited by 46 publications

References 182 publications

Cell-matrix adhesion contributes to permeability control in human colon organoids

Cell-matrix adhesion contributes to permeability control in human colon organoids

Keratin 7 Is a Constituent of the Keratin Network in Mouse Pancreatic Islets and Is Upregulated in Experimental Diabetes

Flow cytometry potential applications in characterizing solid tumors main phenotype, heterogeneity and circulating cells

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