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  • 1.
    Junker, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Lönnqvist, Susanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Rakar, Jonathan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Karlsson, Lisa K.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Grenegård, Magnus
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Kratz, Gunnar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Differentiation of human dermal fibroblasts towards endothelial cells2013In: Differentiation, ISSN 0301-4681, E-ISSN 1432-0436, Vol. 85, no 3, p. 67-77Article in journal (Refereed)
    Abstract [en]

    The ultimate goal of vascular tissue engineering is the production of functional grafts for clinical use. Difficulties acquiring autologous endothelial cells have motivated the search for alternative cell sources. Differentiation of dermal fibroblasts towards several mesenchymal lineages as well as endothelial cells has been proposed. The aim of the present study was to investigate the endothelial differentiation capacity of human dermal fibroblasts on a gene expression, protein expression and functional physiological level. Endothelial differentiation of fibroblasts was induced by culturing cells in 30% human serum, but not in fetal calf serum. Expression of proteins and genes relevant for endothelial function and differentiation was increased after induction. Furthermore, fibroblasts exposed to 30% human serum displayed increased uptake of low-density lipoprotein and formation of capillary-like networks. The results of this study may have an impact on cell sourcing for vascular tissue engineering, and the development of methods for vascularization of autologous tissue engineered constructs.

  • 2.
    Junker, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Rakar, Jonathan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Johnson, Hans
    Department of Surgery, Section of Plastic Surgery and Burn Centre, Haukeland University Hospital, Bergen, Norway.
    Kratz, Gunnar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Gene Expression Analysis of Adipogenic, Chondrogenic and Osteogenic Induced Human Dermal FibroblastsManuscript (preprint) (Other academic)
    Abstract [en]

    The use of adult stem cells in tissue engineering applications is a promising alternativewhen the possibility of acquiring autologous cells for transplantation is limited. Even so, theadult stem cell populations identified up to this point are far from optimal in aspects ofharvest and culture expansion. With the recent suggestion of stem cell plasticity inherent inhuman dermal fibroblasts, a new plausible candidate for use as cell source in tissuereconstruction has emerged. Fibroblast cultures can be induced to differentiate towardsadipocyte, chondrocyte and osteoblast-like cells in vitro, by the use of induction media. Thepresent works utilizes Affymetrix full expression micro array to identify if genes commonlyexpressed in stem cells differentiating towards the above-mentioned lineages also areexpressed in induced fibroblasts. Several genes important for differentiation andmaintenance of an adipose, cartilage or bone phenotype were found up-regulated in theinduced cultures. The results presented here provide further evidence for the plasticity ofhuman dermal fibroblasts, and their possible use in tissue engineering and reconstructivesurgery.

  • 3.
    Lönnqvist, Susanna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Rakar, Jonathan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Briheim, Kristina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Kratz, Gunnar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Biodegradable Gelatin Microcarriers Facilitate Re-Epithelialization of Human Cutaneous Wounds - An In Vitro Study in Human Skin2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 6, p. e0128093-Article in journal (Refereed)
    Abstract [en]

    The possibility to use a suspended tridimensional matrix as scaffolding for re-epithelialization of in vitro cutaneous wounds was investigated with the aid of a human in vitro wound healing model based on viable full thickness skin. Macroporous gelatin microcarriers, CultiSpher-S, were applied to in vitro wounds and cultured for 21 days. Tissue sections showed incorporation of wound edge keratinocytes into the microcarriers and thicker neoepidermis in wounds treated with microcarriers. Thickness of the neoepidermis was measured digitally, using immunohistochemical staining of keratins as epithelial demarcation. Air-lifting of wounds enhanced stratification in control wounds as well as wounds with CultiSpher-S. Immunohistochemical staining revealed expression of keratin 5, keratin 10, and laminin 5 in the neoepidermal component. We conclude that the CultiSpher-S microcarriers can function as tissue guiding scaffold for re-epithelialization of cutaneous wounds.

  • 4.
    Nyman, Erika
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Henricson, Joakim
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Rakar, Jonathan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Olausson, Patrik
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences.
    Ghafouri, Bijar
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Anderson, Chris
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Dermatology and Venerology.
    Kratz, Gunnar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Exogenous hyaluronic acid induces accelerated re-epithelialization and altered protein expression in adult human skin wounds in vivoManuscript (preprint) (Other academic)
    Abstract [en]

    Background

    Hyaluronic acid, a large glycosaminoglycan involved in proliferation, migration, and tissue repair, is suggested to play an important role in ideal scarless fetal wound healing. This study aimed to investigate the effect of exogenous hyaluronic acid intradermal during deep dermal wound healing. Study parameters were erythema, re-epithelialization, and protein expression examined by using a previously described, minimally invasive in vivo human wound model in combination with tissue viability imaging, histology, and proteomics.

    Methods

    Standardized deep dermal wounds were created in the ventral forearm in ten healthy volunteers using blood collection lancets. The wound sites were injected with hyaluronic acid or saline solution, prior to wounding, or were left untreated. To quantify changes in red blood cell concentration as a measurement of inflammation, the study sites were photographed daily for two weeks using a tissue viability imaging system. At 24 hours and after 14 days, biopsy specimens were taken for histology and proteomics analysis.

    Results

    The inflammatory response was not affected by the injection of hyaluronic acid, as measured by tissue viability imaging. Hyaluronic acid significantly induced (p < 0.05) accelerated reepithelialization at 24 hours, and wounds treated with hyaluronic acid showed an altered protein expression.

    Conclusion

    The results from the present study are in concordance with  previous in vitro findings and suggest that exogenous hyaluronic acid has a  positive effect on the healing process of cutaneous wounds. We conclude that hyaluronic acid injected intradermally induces accelerated re-epithelialization and alters protein expression in vivo in human deep dermal skin wounds.

  • 5.
    Rakar, Jonathan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Fibroblast Differentiation and Models of Human Skin2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis combines three publications and one manuscript, covering two principal topics: functional differentiation of human fibroblasts and laboratory models of human skin. The two topics favourably unite in the realm of tissue engineering. This thesis is therefore split into three main parts: 1. a discussion of phenotypic plasticity as it pertains to fibroblasts and the stem cell continuum; 2. a short review of engineered tissue, with particular focus on soluble factors and materials; and, 3. a motivated review of the biology, diversity and culture of skin, including skin construction.

    The intended goal of our research endeavor was to achieve the  formulation of a bioactive therapy for skin regeneration. The main hypothesis was that fibroblast-to-keratinocyte differentiation would facilitate wound healing, and that the protocol for such a method could be adapted to clinical translation. The foundation for the hypothesis lay in the differentiation capabilities of primary dermal fibroblasts (Paper I). However, the goal has not yet been achieved. Instead, intermediate work on the construction of skin for the purpose of creating a model test-bed has resulted in two other publications. The use of excised human skin, a formidable reference sample for tissue engineered skin, has been used to investigate a gelatinbased material in re-epithelialization (Paper II). A first attempt at standardizing a constructed skin model also resulted in a publication: an evaluation of melanocyte influences on keratinocyte-mediated contraction (Paper III).

    The introduction of melanocytes into a skin model raised questions about other appendages of the integumentary system. Our previous experience with preadipocyte isolation and identification, and our attempts at constructing three-dimensional adipose tissue, motivated further investigations into fibroblast-to-adipocyte differentiation. We investigated the possibility of activating thermogenesis in fibroblasts, a property otherwise reserved for cells of the adipogenic and myogenic lineages. Our attempts were successful, and are presently in manuscript form (Paper IV). Some further experiments and optimizations are necessary before establishing a reproducible protocol for thermogenic induction.

    The knowledge obtained through these scientific inquiries have moved us closer to achieving our goals, but methodological advances are still necessary. In the meantime, we have new test-beds for investigating different interactions in skin, and that enables many new questions to be asked and answered.

    List of papers
    1. Interpreted gene expression of human dermal fibroblasts after adipo-, chondro- and osteogenic phenotype shifts
    Open this publication in new window or tab >>Interpreted gene expression of human dermal fibroblasts after adipo-, chondro- and osteogenic phenotype shifts
    Show others...
    2012 (English)In: Differentiation, ISSN 0301-4681, E-ISSN 1432-0436, Vol. 84, no 4, p. 305-313Article in journal (Refereed) Published
    Abstract [en]

    Autologous cell-based therapies promise important developments for reconstructive surgery. In vitro expansion as well as differentiation strategies could provide a substantial benefit to cellular therapies. Human dermal fibroblasts, considered ubiquitous connective tissue cells, can be coaxed towards different cellular fates, are readily available and may altogether be a suitable cell source for tissue engineering strategies. Global gene expression analysis was performed to investigate the changes of the fibroblast phenotype after four-week inductions toward adipocytic, osteoblastic and chondrocytic lineages. Differential gene regulation, interpreted through Gene Set Enrichment Analysis, highlight important similarities and differences of induced fibroblasts compared to control cultures of human fibroblasts, adipocytes, osteoblasts and articular chondrocytes. Fibroblasts show an inherent degree of phenotype plasticity that can be controlled to obtain cells supportive of multiple tissue types.

    Place, publisher, year, edition, pages
    Wiley-Blackwell / Elsevier, 2012
    Keywords
    Fibroblasts, Phenotype, Plasticity, Media induction, Differentiation
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-86119 (URN)10.1016/j.diff.2012.08.003 (DOI)000310572700003 ()
    Available from: 2012-12-07 Created: 2012-12-07 Last updated: 2017-12-07
    2. Biodegradable Gelatin Microcarriers Facilitate Re-Epithelialization of Human Cutaneous Wounds - An In Vitro Study in Human Skin
    Open this publication in new window or tab >>Biodegradable Gelatin Microcarriers Facilitate Re-Epithelialization of Human Cutaneous Wounds - An In Vitro Study in Human Skin
    2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 6, p. e0128093-Article in journal (Refereed) Published
    Abstract [en]

    The possibility to use a suspended tridimensional matrix as scaffolding for re-epithelialization of in vitro cutaneous wounds was investigated with the aid of a human in vitro wound healing model based on viable full thickness skin. Macroporous gelatin microcarriers, CultiSpher-S, were applied to in vitro wounds and cultured for 21 days. Tissue sections showed incorporation of wound edge keratinocytes into the microcarriers and thicker neoepidermis in wounds treated with microcarriers. Thickness of the neoepidermis was measured digitally, using immunohistochemical staining of keratins as epithelial demarcation. Air-lifting of wounds enhanced stratification in control wounds as well as wounds with CultiSpher-S. Immunohistochemical staining revealed expression of keratin 5, keratin 10, and laminin 5 in the neoepidermal component. We conclude that the CultiSpher-S microcarriers can function as tissue guiding scaffold for re-epithelialization of cutaneous wounds.

    Place, publisher, year, edition, pages
    Public Library of Science, 2015
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-120232 (URN)10.1371/journal.pone.0128093 (DOI)000355979500074 ()26061630 (PubMedID)
    Available from: 2015-07-21 Created: 2015-07-20 Last updated: 2017-12-04
    3. Human melanocytes mitigate keratinocyte-dependent contraction in an in vitro collagen contraction assay
    Open this publication in new window or tab >>Human melanocytes mitigate keratinocyte-dependent contraction in an in vitro collagen contraction assay
    2015 (English)In: Burns, ISSN 0305-4179, E-ISSN 1879-1409, Vol. 41, no 5, p. 1035-1042Article in journal (Refereed) Published
    Abstract [en]

    Scarring is an extensive problem in burn care, and treatment can be especially complicated in cases of hypertrophic scarring. Contraction is an important factor in scarring but the contribution of different cell types remains unclear. We have investigated the contractile behavior of keratinocytes, melanocytes and fibroblasts by using an in vitro collagen gel assay aimed at identifying a modulating role of melanocytes in keratinocyte-mediated contraction. Cells were seeded on a collagen type I gel substrate and the change in gel dimensions were measured over time. Hematoxylin and Eosin-staining and immunohistochemistry against pan-cytokeratin and microphthalmia-associated transcription factor showed that melanocytes integrated between keratinocytes and remained there throughout the experiments. Keratinocyte- and fibroblast-seeded gels contracted significantly over time, whereas melanocyte-seeded gels did not. Co-culture assays showed that melanocytes mitigate the keratinocyte-dependent contraction (significantly slower and 18-32% less). Fibroblasts augmented the contraction in most assays (approximately 6% more). Non-contact co-cultures showed some influence on the keratinocyte-dependent contraction. Results show that mechanisms attributable to melanocytes, but not fibroblasts, can mitigate keratinocyte contractile behavior. Contact-dependent mechanisms are stronger modulators than non-contact dependent mechanisms, but both modes carry significance to the contraction modulation of keratinocytes. Further investigations are required to determine the mechanisms involved and to determine the utility of melanocytes beyond hypopigmentation in improved clinical regimes of burn wounds and wound healing.

    Place, publisher, year, edition, pages
    ELSEVIER SCI LTD, 2015
    Keywords
    Melanocytes; Keratinocytes; Contraction; Wound healing; Fibroblasts; Scars
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-120329 (URN)10.1016/j.burns.2014.10.034 (DOI)000357350100015 ()25466959 (PubMedID)
    Available from: 2015-07-31 Created: 2015-07-31 Last updated: 2017-12-04
  • 6.
    Rakar, Jonathan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Krammer, Markus P.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Kratz, Gunnar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Human melanocytes mitigate keratinocyte-dependent contraction in an in vitro collagen contraction assay2015In: Burns, ISSN 0305-4179, E-ISSN 1879-1409, Vol. 41, no 5, p. 1035-1042Article in journal (Refereed)
    Abstract [en]

    Scarring is an extensive problem in burn care, and treatment can be especially complicated in cases of hypertrophic scarring. Contraction is an important factor in scarring but the contribution of different cell types remains unclear. We have investigated the contractile behavior of keratinocytes, melanocytes and fibroblasts by using an in vitro collagen gel assay aimed at identifying a modulating role of melanocytes in keratinocyte-mediated contraction. Cells were seeded on a collagen type I gel substrate and the change in gel dimensions were measured over time. Hematoxylin and Eosin-staining and immunohistochemistry against pan-cytokeratin and microphthalmia-associated transcription factor showed that melanocytes integrated between keratinocytes and remained there throughout the experiments. Keratinocyte- and fibroblast-seeded gels contracted significantly over time, whereas melanocyte-seeded gels did not. Co-culture assays showed that melanocytes mitigate the keratinocyte-dependent contraction (significantly slower and 18-32% less). Fibroblasts augmented the contraction in most assays (approximately 6% more). Non-contact co-cultures showed some influence on the keratinocyte-dependent contraction. Results show that mechanisms attributable to melanocytes, but not fibroblasts, can mitigate keratinocyte contractile behavior. Contact-dependent mechanisms are stronger modulators than non-contact dependent mechanisms, but both modes carry significance to the contraction modulation of keratinocytes. Further investigations are required to determine the mechanisms involved and to determine the utility of melanocytes beyond hypopigmentation in improved clinical regimes of burn wounds and wound healing.

  • 7.
    Rakar, Jonathan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Lönnqvist, Susanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Sommar, Pehr
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Junker, Johan
    Harvard University, MA 02115 USA .
    Kratz, Gunnar
    Linköping University, Department of Clinical and Experimental Medicine, Plastic Surgery, Hand Surgery and Burns. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Interpreted gene expression of human dermal fibroblasts after adipo-, chondro- and osteogenic phenotype shifts2012In: Differentiation, ISSN 0301-4681, E-ISSN 1432-0436, Vol. 84, no 4, p. 305-313Article in journal (Refereed)
    Abstract [en]

    Autologous cell-based therapies promise important developments for reconstructive surgery. In vitro expansion as well as differentiation strategies could provide a substantial benefit to cellular therapies. Human dermal fibroblasts, considered ubiquitous connective tissue cells, can be coaxed towards different cellular fates, are readily available and may altogether be a suitable cell source for tissue engineering strategies. Global gene expression analysis was performed to investigate the changes of the fibroblast phenotype after four-week inductions toward adipocytic, osteoblastic and chondrocytic lineages. Differential gene regulation, interpreted through Gene Set Enrichment Analysis, highlight important similarities and differences of induced fibroblasts compared to control cultures of human fibroblasts, adipocytes, osteoblasts and articular chondrocytes. Fibroblasts show an inherent degree of phenotype plasticity that can be controlled to obtain cells supportive of multiple tissue types.

  • 8.
    Rakar, Jonathan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Plastic Surgery, Hand Surgery and Burns . Linköping University, Faculty of Health Sciences.
    Sommar, Pehr
    Linköping University, Department of Clinical and Experimental Medicine, Plastic Surgery, Hand Surgery and Burns . Linköping University, Faculty of Health Sciences.
    Lönnqvist, Susanna
    Linköping University, Department of Clinical and Experimental Medicine, Plastic Surgery, Hand Surgery and Burns . Linköping University, Faculty of Health Sciences.
    Johnson, Hans
    Department of Surgery, Section of Plastic Surgery and Burn Centre, Haukeland University Hospital, Bergen, Norway.
    Junker, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Plastic Surgery, Hand Surgery and Burns . Linköping University, Faculty of Health Sciences.
    Kratz, Gunnar
    Linköping University, Department of Clinical and Experimental Medicine, Plastic Surgery, Hand Surgery and Burns . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Plastic Surgery, Hand surgery UHL.
    Evaluating Multi-Lineage Induction of Human Dermal FibroblastsUsing Gene Expression AnalysisManuscript (preprint) (Other academic)
    Abstract [en]

    During the past decades, several adult stem cell populations from a range of tissues have been characterized. Since principally all human cells contain the same genetic material, the specific gene expression profile determines the cell phenotype. The notion of terminally differentiated somatic cells being necessarily restricted to one phenotype has been challenged, and instead an inherent range of plasticity for any given cell type has been suggested. We have in previous work shown that normal human dermal fibroblasts have an inherent plasticity and can be induced to differentiate towards adipogenic, chondrogenic, endotheliogenic and osteogenic lineages when subjected to defined induction media. The aim of the present study was to further study the differentiation of human dermal fibroblasts on a gene expression level. This was achieved by employing genome wide expression analysis using microarray technology. Selected gene expression was also evaluated over time using real-time PCR. Several master regulatory genes important for lineage commitment, as well as phenotypically relevant genes, were found regulated in the respective induced cultures. The results obtained in this study strengthen previously published results showing an inherent ability for controllable phenotype alteration of human dermal fibroblasts in vitro. We conclude that adipogenic, chondrogenic, endotheliogenic and osteogenic induction results in novel phenotypes that show a genetic readiness for lineage-specific biological functionality.

  • 9.
    Yaghmaeian Salmani, Behzad
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Monedero Cobeta, Ignacio
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Rakar, Jonathan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Bauer, Susanne
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Rodriguez Curt, Jesús
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Starkenberg, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Evolutionarily conserved anterior expansion of the central nervous system promoted by a common PcG-Hox program2018In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 145, no 7, article id dev160747Article in journal (Refereed)
    Abstract [en]

    A conserved feature of the central nervous system (CNS) is the prominent expansion of anterior regions (brain) compared with posterior (nerve cord). The cellular and regulatory processes driving anterior CNS expansion are not well understood in any bilaterian species. Here, we address this expansion in Drosophila and mouse. We find that, compared with the nerve cord, the brain displays extended progenitor proliferation, more elaborate daughter cell proliferation and more rapid cell cycle speed in both Drosophila and mouse. These features contribute to anterior CNS expansion in both species. With respect to genetic control, enhanced brain proliferation is severely reduced by ectopic Hox gene expression, by either Hox misexpression or by loss of Polycomb group (PcG) function. Strikingly, in PcG mutants, early CNS proliferation appears to be unaffected, whereas subsequent brain proliferation is severely reduced. Hence, a conserved PcG-Hox program promotes the anterior expansion of the CNS. The profound differences in proliferation and in the underlying genetic mechanisms between brain and nerve cord lend support to the emerging concept of separate evolutionary origins of these two CNS regions.

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