Irma Thesleff

University of Helsinki, Helsinki, Uusimaa, Finland

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Publications (283)1164.76 Total impact

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    ABSTRACT: Continuous growth of rodent incisors relies on epithelial stem cells (SCs) located in the SC niche called labial cervical loop (LaCL). Here we found a population of apoptotic cells residing in a specific location of the LaCL in mouse incisor. Activated Caspase3 and Caspase 9, expressed in this location colocalized in part with Lgr5 in putative stem cells. The addition of Caspase inhibitors to incisors ex vivo resulted in concentration dependent thickening of LaCL. To examine the role of Wnt signaling in regulation of apoptosis we exposed the LaCL of postnatal day 2 (P2) mouse incisor ex vivo to BIO, a known activator of Wnt/beta-catenin signaling. This resulted in marked thinning of LaCL as well as enhanced apoptosis. We found that Wnt/beta-catenin signaling was intensely induced by BIO in the mesenchyme surrounding the LaCL, but, unexpectedly, no beta-catenin activity was detected in the LaCL epithelium either before or after BIO treatment. We discovered that the expression of Fgf10, an essential growth factor for incisor epithelial SCs was dramatically down regulated in the mesenchyme around BIO-treated LaCL, and that exogenous Fgf10 could rescue the thinning of the LaCL caused by BIO. We conclude that the homeostasis of the epithelial SC population in the mouse incisor depends on a proper rate of apoptosis and that this apoptosis is controlled by signals from the mesenchyme surrounding the LaCL. Fgf10 is a key mesenchymal signal limiting apoptosis of incisor epithelial SCs and its expression is negatively regulated by Wnt/beta-catenin. This article is protected by copyright. All rights reserved. © 2015 AlphaMed Press.
    Stem Cells 02/2015; DOI:10.1002/stem.1972 · 7.70 Impact Factor
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    ABSTRACT: The aim of the study was to characterize the molecular relationship between ameloblastoma and keratocystic odontogenic tumor (KCOT) by means of a genome-wide expression analysis. Total RNA from 27 fresh tumor samples of 15 solid/multicystic intraosseous ameloblastomas and 12 sporadic KCOTs was hybridized on Affymetrix whole genome arrays. Hierarchical clustering separated ameloblastomas and KCOTs into 2 distinct groups. The gene set enrichment analysis based on 303 dental genes showed a similar separation of ameloblastomas and KCOTs. Early dental epithelial markers PITX2, MSX2, DLX2, RUNX1, and ISL1 were differentially overexpressed in ameloblastoma, indicating its dental identity. Also, PTHLH, a hormone involved in tooth eruption and invasive growth, was one of the most differentially upregulated genes in ameloblastoma. The most differentially overexpressed genes in KCOT were squamous epithelial differentiation markers SPRR1A, KRTDAP, and KRT4, as well as DSG1, a component of desmosomal cell-cell junctions. Additonally, the epithelial stem cell marker SOX2 was significantly upregulated in KCOT when compared with ameloblastoma. Taken together, the gene expression profile of ameloblastoma reflects differentiation from dental lamina toward the cap/bell stage of tooth development, as indicated by dental epithelium-specific transcription factors. In contrast, gene expression of KCOT indicates differentiation toward keratinocytes.
    Journal of Dental Research 11/2014; 94(1). DOI:10.1177/0022034514556815 · 4.14 Impact Factor
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    ABSTRACT: Mesenchymal stem cells occupy niches in stromal tissues where they provide sources of cells for specialized mesenchymal derivatives during growth and repair. The origins of mesenchymal stem cells have been the subject of considerable discussion, and current consensus holds that perivascular cells form mesenchymal stem cells in most tissues. The continuously growing mouse incisor tooth offers an excellent model to address the origin of mesenchymal stem cells. These stem cells dwell in a niche at the tooth apex where they produce a variety of differentiated derivatives. Cells constituting the tooth are mostly derived from two embryonic sources: neural crest ectomesenchyme and ectodermal epithelium. It has been thought for decades that the dental mesenchymal stem cells giving rise to pulp cells and odontoblasts derive from neural crest cells after their migration in the early head and formation of ectomesenchymal tissue. Here we show that a significant population of mesenchymal stem cells during development, self-renewal and repair of a tooth are derived from peripheral nerve-associated glia. Glial cells generate multipotent mesenchymal stem cells that produce pulp cells and odontoblasts. By combining a clonal colour-coding technique with tracing of peripheral glia, we provide new insights into the dynamics of tooth organogenesis and growth.
    Nature 07/2014; DOI:10.1038/nature13536 · 42.35 Impact Factor
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    ABSTRACT: * = equally contributing authors Objectives: Embryonic glial cells along peripheral nerves can be viewed as a stem cell niche from which various cell types, including myelinating and non-myelinating Schwann cells, endoneural fibroblasts and melanocytes, arise during development. Peripheral nerves are intimately associated with the tooth anlagen during prenatal development, and we hypothesized that glial-derived cells could participate in tooth organogenesis. When fully developed, the tooth is densely innervated. With a potential role in tooth formation during development, we also aimed to investigate if nerve-associated Schwann cells could play important roles in the continuous growth and injury-induced repair of mouse incisors. Methods: We used mouse strains that allow for selective and permanent genetic labeling of peripheral glial cells. Immunohistochemistry and in situ hybridization were performed using standard protocols on 14 μm sagittal cryosections of embryonic heads, and 30 μm sections of the adult teeth. Both in vivo and in vitro techniques were used to study the effects of tooth damage, including FACS (Fluorescence-Activated Cell Sorting) analysis to validate data. Results: Our data show that progeny from peripheral nervous system glia give rise to dental mesenchymal stem cells and odontoblasts during development. Clonal fate mapping after single recombination events showed organized streams of pulp cells connected to domains of odontoblasts inserted into the odontoblast layer. Glia-derived dental mesenchymal stem cells stay in the self-renewing mouse incisor throughout the lifetime, and are involved in regeneration of the matrix after damage to the teeth. Conclusion: Our results demonstrate the existence of an unanticipated mechanism during craniofacial development. This mechanism involves conversion of nerve-associated glial cells into organ-forming mesenchymal stem cells during embryonic and adult tooth formation, as well as during regeneration after injury.
    IADR General Session and Exhibition 2014; 06/2014
  • Irma Thesleff
    Experimental Cell Research 04/2014; DOI:10.1016/j.yexcr.2014.04.008 · 3.37 Impact Factor
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    ABSTRACT: Epithelial reorganization involves coordinated changes in cell shapes and movements. This restructuring occurs during formation of placodes, ectodermal thickenings that initiate the morphogenesis of epithelial organs including hair, mammary gland, and tooth. Signaling pathways in ectodermal placode formation are well known, but the cellular mechanisms have remained ill defined. We established imaging methodology for live visualization of embryonic skin explants during the first wave of hair placode formation. We found that the vast majority of placodal cells were nonproliferative throughout morphogenesis. We show that cell compaction and centripetal migration are the main cellular mechanisms associated with hair placode morphogenesis and that inhibition of actin remodeling suppresses placode formation. Stimulation of both ectodysplasin/NF-κB and Wnt/β-catenin signaling increased cell motility and the number of cells committed to placodal fate. Thus, cell fate choices and morphogenetic events are controlled by the same molecular pathways, providing the framework for coordination of these two processes.
    Developmental Cell 03/2014; 28(5):588-602. DOI:10.1016/j.devcel.2014.02.003 · 10.37 Impact Factor
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    ABSTRACT: Mammalian tooth development is characterized by formation of primary teeth that belong to different tooth classes and are later replaced by a single set of permanent teeth. The first primary teeth are initiated from the primary dental lamina, and the replacement teeth from the successional dental lamina at the lingual side of the primary teeth. An interdental lamina connects the primary tooth germs together. Most mammalian tooth development research is done on mouse, which does not have teeth in all tooth classes, does not replace its teeth, and does not develop an interdental lamina. We have used the ferret (Mustela putorius furo) as a model animal to elucidate the morphological changes and gene expression during the development of the interdental lamina and the initiation of primary teeth. In addition we have analyzed cell-cell signaling taking place in the interdental lamina as well as in the successional lamina during tooth replacement. By 3D reconstructions of serial histological sections we observed that the morphogenesis of the interdental lamina and the primary teeth are intimately linked. Expression of Pitx2 and Foxi3 in the interdental lamina indicates that it has odontogenic identity, and there is active signaling taking place in the interdental lamina. Bmp4 is coexpressed with the stem cell factor Sox2 at its lingual aspect suggesting that the interdental lamina may retain competence for tooth initiation. We show that when tooth replacement is initiated there is Wnt pathway activity in the budding successional lamina and adjacent mesenchyme but no active Fgf or Eda signaling. Genes associated with human tooth replacement phenotypes, including Runx2 and Il11rα, are mostly expressed in the mesenchyme around the successional lamina in the ferret. Our results highlight the importance of the dental lamina in the mammalian tooth development during the initiation of both primary and replacement teeth.
    Differentiation 01/2014; 87(1-2). DOI:10.1016/j.diff.2013.11.004 · 2.84 Impact Factor
  • Irma Thesleff, Marja L. Mikkola
    Seminars in Cell and Developmental Biology 01/2014; DOI:10.1016/j.semcdb.2014.02.002 · 5.97 Impact Factor
  • I Thesleff
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    ABSTRACT: Teeth are typical examples of organs in which genes determine the progress of development from initiation to the final shape, size and structure, whereas environmental factors play a minor role. Advances in gene technology over the last three decades have led to powerful novel methods to explore the mechanisms of embryonic development. Today we know a few hundred genes that regulate tooth development, and mutations in dozens of these genes have been shown to cause aberrations in tooth development in mice and/or humans. The functions of an increasing number of genes in tooth development have been discovered using genetically modified mouse models. We are now beginning to understand the 'programme' underlying the process of tooth formation. Key components of the programme are signals mediating communication between cells and complex gene regulatory networks in which the signal pathways are integrated. Understanding the mechanisms of tooth development at the level of genes, cells and molecules will lay the basis for new ways to prevent and treat dental defects and diseases. Over the last decade knowledge about dental stem cells has accumulated rapidly and novel stem cell technologies have been developed. Combining stem cell research with knowledge on the mechanisms of tooth development may open up novel possibilities for clinical tooth regeneration.
    Australian Dental Journal 11/2013; 59. DOI:10.1111/adj.12102 · 1.37 Impact Factor
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    ABSTRACT: Ameloblastomas are locally invasive odontogenic tumors that exhibit a high rate of recurrence and often associate with the third molars. They are suggested to originate from dental epithelium because the tumor cells resemble epithelial cells of developing teeth. Expression of the transcription factor SOX2 has been previously localized in epithelial stem and progenitor cells in developing teeth as well as in various tumors. Here, we show that SOX2 is expressed in the epithelial cells of follicular and plexiform ameloblastomas. SOX2 was localized in the dental lamina of developing human primary molars. It was also expressed in the fragmented dental lamina associated with the third molars and in the epithelium budding from its posterior aspect in mice. However, no SOX2 expression was detected in either Hertwig's epithelial root sheath directing the formation of roots or in the epithelial cell rests of Malassez covering the completed roots. SOX2 was associated with supernumerary tooth formation in odontoma-like tumors induced by Wnt signal activation in mice. We propose that SOX2 functions in maintaining the progenitor state of epithelium in ameloblastomas and that ameloblastomas may originate from SOX2-expressing dental lamina epithelium.
    European Journal Of Oral Sciences 10/2013; DOI:10.1111/eos.12095 · 1.73 Impact Factor
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    ABSTRACT: Background: Foxi3 is a member of the large forkhead box family of transcriptional regulators, which have a wide range of biological activities including manifold developmental processes. Heterozygous mutations in Foxi3 were identified in several hairless dog breeds characterized by sparse fur coat and missing teeth. A related phenotype called hypohidrotic ectodermal dysplasia (HED) is caused by mutations in the ectodysplasin (Eda) pathway genes. Results: Expression of Foxi3 was strictly confined to the epithelium in developing ectodermal appendages in mouse embryos, but no expression was detected in the epidermis. Foxi3 was expressed in teeth and hair follicles throughout embryogenesis, but in mammary glands only during the earliest stages of development. Foxi3 expression was decreased and increased in Eda loss- and gain-of function embryos, respectively, and was highly induced by Eda protein in embryonic skin explants. Also activin A treatment upregulated Foxi3 mRNA levels in vitro. Conclusions: Eda and activin A were identified as upstream regulators of Foxi3. Foxi3 is a likely transcriptional target of Eda in ectodermal appendage placodes suggesting that HED phenotype may in part be produced by compromised Foxi3 activity. Besides hair and teeth, Foxi3 may have a role in nail, eye, and mammary, sweat, and salivary gland development. Developmental Dynamics, 2013. © 2013 Wiley Periodicals,Inc.
    Developmental Dynamics 06/2013; 242(6). DOI:10.1002/dvdy.23952 · 2.67 Impact Factor
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    ABSTRACT: Tooth renewal is initiated from epithelium associated with existing teeth. The development of new teeth requires dental epithelial cells that have competence for tooth formation, but specific marker genes for these cells have not been identified. Here, we analyzed expression patterns of the transcription factor Sox2 in two different modes of successional tooth formation: tooth replacement and serial addition of primary teeth. We observed specific Sox2 expression in the dental lamina that gives rise to successional teeth in mammals with one round of tooth replacement as well as in reptiles with continuous tooth replacement. Sox2 was also expressed in the dental lamina during serial addition of mammalian molars, and genetic lineage tracing indicated that Sox2+ cells of the first molar give rise to the epithelial cell lineages of the second and third molars. Moreover, conditional deletion of Sox2 resulted in hyperplastic epithelium in the forming posterior molars. Our results indicate that the Sox2+ dental epithelium has competence for successional tooth formation and that Sox2 regulates the progenitor state of dental epithelial cells. The findings imply that the function of Sox2 has been conserved during evolution and that tooth replacement and serial addition of primary teeth represent variations of the same developmental process. The expression patterns of Sox2 support the hypothesis that dormant capacity for continuous tooth renewal exists in mammals.
    Development 03/2013; 140(7). DOI:10.1242/dev.089599 · 6.27 Impact Factor
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    ABSTRACT: Loss- and gain-of function approaches modulating canonical Wnt/β-catenin activity have established a role for the Wnt/β-catenin pathway during tooth development. Here we show that Wnt/β-catenin signaling is required in the dental mesenchyme for normal incisor development, as locally restricted genetic inactivation of β-catenin results in a splitting of the incisor placode, giving rise to two incisors. Molecularly this is first associated with down-regulation of Bmp4 and subsequent splitting of the Shh domain at a subsequent stage. The latter phenotype can be mimicked by ectopic application of the BMP antagonist Noggin. Conditional genetic inactivation of Bmp4 in the mesenchyme reveals that mesenchymal BMP4 activity is required for maintenance of Shh expression in the dental ectoderm. Taken together our results indicate that β-catenin together with Lef1 and Tcf1 are required to activate Bmp4 expression in order to maintain Shh expression in the dental ectoderm. This provides a mechanism whereby the number of incisors arising from one placode can be varied through local alterations of a mesenchymal signaling circuit involving β-catenin, Lef1, Tcf1 and Bmp4.
  • Jukka Jernvall, Irma Thesleff
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    ABSTRACT: Teeth are found in almost all vertebrates, and they therefore provide a general paradigm for the study of epithelial organ development and evolution. Here, we review the developmental mechanisms underlying changes in tooth complexity and tooth renewal during evolution, focusing on recent studies of fish, reptiles and mammals. Mammals differ from other living vertebrates in that they have the most complex teeth with restricted capacity for tooth renewal. As we discuss, however, limited tooth replacement in mammals has been compensated for in some taxa by the evolution of continuously growing teeth, the development of which appears to reuse the regulatory pathways of tooth replacement.
    Development 10/2012; 139(19):3487-97. DOI:10.1242/dev.085084 · 6.27 Impact Factor
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    ABSTRACT: Uncovering the origin and nature of phenotypic variation within species is the first step in understanding variation between species. Mouse models with altered activities of crucial signal pathways have highlighted many important genes and signal networks regulating the morphogenesis of complex structures, such as teeth. The detailed analyses of these models have indicated that the balanced actions of a few pathways regulating cell behavior modulate the shape and number of teeth. Currently, however, most mouse models studied have had gross alteration of morphology, whereas analyses of more subtle modification of morphology are required to link developmental studies to evolutionary change. Here, we have analyzed a signaling network involving ectodysplasin (Eda) and fibroblast growth factor 20 (Fgf20) that subtly affects tooth morphogenesis. We found that Fgf20 is a major downstream effector of Eda and affects Eda-regulated characteristics of tooth morphogenesis, including the number, size and shape of teeth. Fgf20 function is compensated for by other Fgfs, in particular Fgf9 and Fgf4, and is part of an Fgf signaling loop between epithelium and mesenchyme. We showed that removal of Fgf20 in an Eda gain-of-function mouse model results in an Eda loss-of-function phenotype in terms of reduced tooth complexity and third molar appearance. However, the extra anterior molar, a structure lost during rodent evolution 50 million years ago, was stabilized in these mice.
    Development 07/2012; 139(17):3189-99. DOI:10.1242/dev.079558 · 6.27 Impact Factor
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    ABSTRACT: The continuously growing mouse incisor serves as a valuable model to study stem cell regulation during organ renewal. Epithelial stem cells are localized in the proximal end of the incisor in the labial cervical loop. Here, we show that the transcription factor Sox2 is a specific marker for these stem cells. Sox2+ cells became restricted to the labial cervical loop during tooth morphogenesis, and they contributed to the renewal of enamel-producing ameloblasts as well as all other epithelial cell lineages of the tooth. The early progeny of Sox2-positive stem cells transiently expressed the Wnt inhibitor Sfrp5. Sox2 expression was regulated by the tooth initiation marker FGF8 and specific miRNAs, suggesting a fine-tuning to maintain homeostasis of the dental epithelium. The identification of Sox2 as a marker for the dental epithelial stem cells will facilitate further studies on their lineage segregation and differentiation during tooth renewal.
    Developmental Cell 07/2012; 23(2):317-28. DOI:10.1016/j.devcel.2012.05.012 · 10.37 Impact Factor
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    Irma Thesleff
    Head & Face Medicine 05/2012; 8(1). DOI:10.1186/1746-160X-8-S1-I8 · 0.87 Impact Factor
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    ABSTRACT: Mammary glands and hair follicles develop as ectodermal organs sharing common features during embryonic morphogenesis. The molecular signals controlling the initiation and patterning of skin appendages involve the bone morphogenetic proteins and Wnt family members, which are commonly thought to serve as inhibitory and activating cues, respectively. Here, we have examined the role of the Bmp and Wnt pathway modulator Sostdc1 in mammary gland, and hair and vibrissa follicle development using Sostdc1-null mice. Contrary to previous speculations, loss of Sostdc1 did not affect pelage hair cycling. Instead, we found that Sostdc1 limits the number of developing vibrissae and other muzzle hair follicles, and the size of primary hair placodes. Sostdc1 controls also the size and shape of mammary buds. Furthermore, Sostdc1 is essential for suppression of hair follicle fate in the normally hairless nipple epidermis, but its loss also promotes the appearance of supernumerary nipple-like protrusions. Our data suggest that functions of Sostdc1 can be largely attributed to its ability to attenuate Wnt/β-catenin signaling.
    Developmental Biology 04/2012; 364(2):149-61. DOI:10.1016/j.ydbio.2012.01.026 · 3.64 Impact Factor
  • Maria Jussila, Irma Thesleff
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    ABSTRACT: Teeth develop as ectodermal appendages from epithelial and mesenchymal tissues. Tooth organogenesis is regulated by an intricate network of cell-cell signaling during all steps of development. The dental hard tissues, dentin, enamel, and cementum, are formed by unique cell types whose differentiation is intimately linked with morphogenesis. During evolution the capacity for tooth replacement has been reduced in mammals, whereas teeth have acquired more complex shapes. Mammalian teeth contain stem cells but they may not provide a source for bioengineering of human teeth. Therefore it is likely that nondental cells will have to be reprogrammed for the purpose of clinical tooth regeneration. Obviously this will require understanding of the mechanisms of normal development. The signaling networks mediating the epithelial-mesenchymal interactions during morphogenesis are well characterized but the molecular signatures of the odontogenic tissues remain to be uncovered.
    Cold Spring Harbor perspectives in biology 03/2012; 4(4):a008425. DOI:10.1101/cshperspect.a008425 · 8.23 Impact Factor
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    ABSTRACT: Craniosynostosis and supernumerary teeth most often occur as isolated developmental anomalies, but they are also separately manifested in several malformation syndromes. Here, we describe a human syndrome featuring craniosynostosis, maxillary hypoplasia, delayed tooth eruption, and supernumerary teeth. We performed homozygosity mapping in three unrelated consanguineous Pakistani families and localized the syndrome to a region in chromosome 9. Mutational analysis of candidate genes in the region revealed that all affected children harbored homozygous missense mutations (c.662C>G [p.Pro221Arg], c.734C>G [p.Ser245Cys], or c.886C>T [p.Arg296Trp]) in IL11RA (encoding interleukin 11 receptor, alpha) on chromosome 9p13.3. In addition, a homozygous nonsense mutation, c.475C>T (p.Gln159X), and a homozygous duplication, c.916_924dup (p.Thr306_Ser308dup), were observed in two north European families. In cell-transfection experiments, the p.Arg296Trp mutation rendered the receptor unable to mediate the IL11 signal, indicating that the mutation causes loss of IL11RA function. We also observed disturbed cranial growth and suture activity in the Il11ra null mutant mice, in which reduced size and remodeling of limb bones has been previously described. We conclude that IL11 signaling is essential for the normal development of craniofacial bones and teeth and that its function is to restrict suture fusion and tooth number. The results open up the possibility of modulation of IL11 signaling for the treatment of craniosynostosis.
    The American Journal of Human Genetics 07/2011; 89(1):67-81. DOI:10.1016/j.ajhg.2011.05.024 · 11.20 Impact Factor

Publication Stats

18k Citations
1,164.76 Total Impact Points

Institutions

  • 1976–2014
    • University of Helsinki
      • • Institute of Biotechnology
      • • Institute of Dentistry
      • • Department of Oral Pathology
      • • Department of Pathology
      • • Department of Bacteriology and Immunology
      • • Department of Otolaryngology
      Helsinki, Uusimaa, Finland
  • 2008
    • Helsinki University Central Hospital
      • Department of Clinical Chemistry
      Helsinki, Southern Finland Province, Finland
  • 1992–1995
    • University of Oulu
      • • Biocenter Oulu
      • • Department of Biochemistry
      Oulu, Oulu, Finland
  • 1991
    • Harvard University
      Cambridge, Massachusetts, United States
    • University of Turku
      • Department of Medical Biochemistry and Genetics
      Turku, Western Finland, Finland
  • 1988
    • Friedrich Miescher Institute for Biomedical Research
      Bâle, Basel-City, Switzerland
  • 1980–1981
    • National Institutes of Health
      • Laboratory of Cell and Developmental Biology
      Maryland, United States