Profile
Description of Research
Research in the intestinal disease unit located at Åbo Akademi University is focused on the roles and regulation of molecular pathways in the health and disease of gastrointestinal epithelia of the colon and the endocrine pancreas, with focus on keratin intermediate filaments. Keratins are cytoskeletal dynamic structures important in protection from cellular stress. Keratin mutations predispose humans to diseases and the keratin (K)8 knockout mouse obtains an early IBD/ulcerative colitis-phenotype. Our aims are to understand how keratins help protect simple type epithelia on a molecular level, in particular in gastrointestinal organs with focus on intestine and the endocrine pancreas. Using keratin knockout mice, mice expressing keratin mutations, experimental models of colitis, colorectal cancer, diabetes, and cell systems including colon organoid 3D cultures, we study the role of keratins in e.g., mechanical stress, proliferation and differentiation, protein targeting, cancer, regeneration, and diabetes. We also aim to develop imaging modalities to detect IBD and colon cancer in mice in vivo. Webpage for the Epithelial biology laboratory at Åbo Akademi University: www.toivola-lab.org
Representative Publications
Ilomäki MA, Polari L, Stenvall C-GA, Tayyab M, Kähärä K, Ridge KM, Toivola DM. Defining a timeline of colon pathologies after keratin 8 loss: rapid crypt elongation and diarrhea are followed by epithelial erosion and cell exfoliation. Am. J. Physiol., Gastroenterol. Liver Physiol. 2024, 326:G67-G77.
Bhowmik AA, Heikkilä TRH, Polari L, Virta J, Liljenbäck H, Moisio O, Li XG, Viitanen R, Jalkanen S, Koffert J, Toivola DM, Roivainen A. Detection of Intestinal Inflammation by Vascular Adhesion Protein-1-Targeted [68Ga]Ga-DOTA-Siglec-9 Positron Emission Tomography in Murine Models of Inflammatory Bowel Disease. Mol Imaging Biol. 2024 Apr;26(2):322-333.
Stenvall C-G, Nyström JH, Butler-Hallissey C, Adam SA, Foisner R, Ridge KM, Gold-man RD, Toivola DM. Keratins couple with the nuclear lamina and regulate proliferation in colonic epithelial cells. Mol. Biol. Cell. 2022, 33 (13): ar121.
Polari L, Tenhami M, Anttila S, Helenius T, Kujari H, Kallajoki M, Voutilainen M, Toivola DM. Colonocyte keratin 7 expression is expressed de novo in inflammatory bowel diseases and associated with pathological changes and drug-resistance. Scientific Reports 2022, 12:22213.
Alam CM, Baghestani S, Pajari A, Omary MB, Toivola DM. Keratin 7 is a constituent of the keratin network in mouse pancreatic islets and is upregulated in experimental diabetes. Int. J. Mol. Sci 2021, 22:7784.
Stenvall C-GA, Tayyab M, Grönroos TJ, Ilomäki MA, Viiri K, Ridge KM, Polari L, Toivola DM. Targeted deletion of keratin 8 in intestinal epithelial cells disrupts tissue integrity and predisposes to tumorigenesis in the colon. Cell Mol Life Sci 2021 Dec 24;79(1):10.
Polari L, Alam CM, Nyström JH, Heikkilä T, Tayyab M, Baghestani S, Toivola DM. Keratin intermediate filaments in the colon: guardians of epithelial homeostasis. Int J Biochem Cell Biol. 2020 Dec;129:105878.
Lähdeniemi IAK, Misiorek JO, Antila CJM, Landor SK, Stenvall CA, Fortelius LE, Bergström LK, Sahlgren C, Toivola DM. Keratins regulate colonic epithelial cell differentiation through the Notch1 signalling pathway. Cell Death Differ. 2017 Jun;24(6):984-996.
Helenius TO, Antman CA, Asghar MN, Nyström JH, Toivola DM. Keratins Are Altered in Intestinal Disease-Related Stress Responses. Cells. 2016 Sep 10;5(3).
Misiorek JO, Lähdeniemi IAK, Nyström JH, Paramonov VM, Gullmets JA, Saarento H, Rivero-Müller A, Husøy T, Taimen P, Toivola DM. Keratin 8-deletion induced colitis predisposes to murine colorectal cancer enforced by the inflammasome and IL-22 pathway. Carcinogenesis. 2016 Aug;37(8):777-786.
Asghar MN, Priyamvada S, Nyström JH, Anbazhagan AN, Dudeja PK, Toivola DM. Keratin 8 knockdown leads to loss of the chloride transporter DRA in the colon. Am J Physiol Gastrointest Liver Physiol. 2016 Jun 1;310(11):G1147-54. doi: 10.1152/ajpgi.00354.2015.
Desai D, Prabhakar N, Mamaeva V, Karaman DS, Lähdeniemi IAK, Sahlgren C, Rosenholm J, Toivola DM. Targeted Modulation of Cell Differentiation in Distinct Regions of the Gastrointestinal Tract via Oral Administration of Differently PEI-PEG Functionalized Mesoporous Silica Nanoparticles. Int. J. Nanomedicine, in press, November 2015.
Helenius TO, Misiorek JO, Nyström JH, Fortelius LE, Habtezion A, Liao J, Asghar MN, Zhang H, Azhar S, Omary MB, Toivola DM. Keratin 8 absence downregulates colonocyte HMGCS2 and modulates colonic ketogenesis and energy metabolism. Mol Biol Cell, 26:2298-2310, 2015
Asghar MN, Silvander JS, Helenius TO, Lähdeniemi IA, Alam C, Fortelius LE, Holmsten RO, Toivola DM. The amount of keratin matters in stress protection of the colonic epithelium. PLoS One 10(5):e0127436, 2015
Asghar MN, Emani R, Alam C, Helenius TO, Grönroos TJ, Sareila O, Din MU, Holmdahl R, Hänninen A, Toivola DM. In vivo imaging of reactive oxygen and nitrogen species in murine colitis. Inflamm. Bowel Dis 20:1435-1447, 2014
Alam CM, Silvander JS, Daniel EN, Tao GZ, Kvarnström SM, Alam P, Omary MB, Hänninen A,Toivola DM. Keratin 8 modulates β-cell stress responses and normoglycaemia. J. Cell Sci. 126:5635-5644, 2013.
Habtezion A, Toivola DM, Asghar MN, Kronmal GS, Brooks JD, Butcher EC, Omary MB. Absence of keratin 8 confers a paradoxical microflora-dependent resistance to apoptosis in the colon. Proc Natl Acad Sci USA, 108:1445-1450, 2011.
Toivola DM, Habtezion A, Strnad P, Omary MB. Intermediate filaments take the heat as stress proteins. Trends Cell Biol, 20:79-91, 2010.
Ku NO, Toivola DM, Strnad P, Omary MB. Cytoskeletal keratin glycosylation protects epithelial tissue from injury.Nat Cell Biol. 12:876-885, 2010.