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  • 1.
    Dahlin, Joakim S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala Univ, Dept Med Biochem & Microbiol, SE-75123 Uppsala, Sweden..
    Ding, Zhoujie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hallgren, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Distinguishing Mast Cell Progenitors from Mature Mast Cells in Mice2015In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 24, no 14, p. 1703-1711Article in journal (Refereed)
    Abstract [en]

    Mast cells originate from the bone marrow and develop into c-kit(+) FcRI(+) cells. Both mast cell progenitors (MCp) and mature mast cells express these cell surface markers, and ways validated to distinguish between the two maturation forms with flow cytometry have been lacking. Here, we show that primary peritoneal MCp from naive mice expressed high levels of integrin 7 and had a low side scatter (SSC) light profile; whereas mature mast cells expressed lower levels of integrin 7 and had a high SSC light profile. The maturation statuses of the cells were confirmed using three main strategies: (1) MCp, but not mature mast cells, were shown to be depleted by sublethal whole-body -irradiation. (2) The MCp were small and immature in terms of granule formation, whereas the mature mast cells were larger and had fully developed metachromatic granules. (3) The MCp had fewer transcripts of mast cell-specific proteases and the enzyme responsible for sulfation of heparin than mature mast cells. Moreover, isolated peritoneal MCp gave rise to mast cells when cultured in vitro. To summarize, we have defined MCp and mature mast cells in naive mice by flow cytometry. Using this strategy, mast cell maturation can be studied in vivo.

  • 2.
    Hertegård, Stellan
    et al.
    Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden;Karolinska Univ Hosp Huddinge, Dept Otorhinolaryngol, S-14186 Stockholm, Sweden.
    Nagubothu, Srinivasa Rao
    Karolinska Inst, Dept Lab Med, Stockholm, Sweden.
    Malmström, Emma
    Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden;Karolinska Univ Hosp Huddinge, Dept Otorhinolaryngol, S-14186 Stockholm, Sweden.
    Ström, Cecilia E.
    Karolinska Inst, Dept Lab Med, Stockholm, Sweden.
    Tolf, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Davies, Lindsay C.
    Karolinska Inst, Dept Lab Med, Stockholm, Sweden.
    Le Blanc, Katarina
    Karolinska Inst, Dept Lab Med, Stockholm, Sweden.
    Hyaluronan Hydrogels for the Local Delivery of Mesenchymal Stromal Cells to the Injured Vocal Fold2019In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 28, no 17, p. 1177-1190Article in journal (Refereed)
    Abstract [en]

    Mesenchymal stromal cells (MSCs) promote wound healing by expediting the inflammatory phase. Local injection of MSCs into injured vocal folds (VFs) is effective in animal models, suggesting suitability for clinical translation. Despite their therapeutic potential, MSCs do not persist within the VF. This study evaluates whether hyaluronan (HA) hydrogels offer a safe delivery vehicle for local injection of MSCs into VFs, and increase longevity of the cells within the injured tissue. MSCs +/- HA hydrogel were exposed to interleukin (IL)1 beta, IL8, and chemokine (C-C motif) ligand 4, and evaluated for mRNA expression of matrix remodeling genes and secretion of immunomodulatory/prohealing factors. Chemotaxis/invasion in response to inflammation was evaluated. A lapin model of VF injury evaluated in vivo effects of MSCs +/- HA hydrogel on enhancing VF healing. Histological evaluation of inflammation, type I collagen expression, HA hydrogel resorption, and MSC persistence was evaluated at 3 and 25 days after injury. MSCs within HA hydrogel were responsive to their extracellular environment, upregulating immunomodulatory factors when exposed to inflammation. Despite delayed migration out of the gel in vitro, the MSCs did not persist longer within the injured tissue in vivo. MSCs +/- HA hydrogel exerted equivalent dampening of inflammation in vivo. The gel was resorbed within 25 days and no edema was evident. HA hydrogels can be safely used in the delivery of MSCs to injured VFs, minimizing leakage of administered cells. MSCs within the HA hydrogel did not persist longer than those in suspension, but did exert comparable therapeutic effects.

  • 3.
    Hoeber, Jan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    König, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    Trolle, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    Lekholm, Emilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Zhou, Chunfang
    Nanologica AB , Södertälje, Sweden.
    Pankratova, Stanislava
    Univ Copenhagen, Inst Neurosci & Pharmacol, Copenhagen, Denmark.
    Åkesson, Elisabet
    Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    Kozlova, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    A Combinatorial Approach to Induce Sensory Axon Regeneration into the Dorsal Root Avulsed Spinal Cord2017In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 26, no 14, p. 1065-1077Article in journal (Refereed)
    Abstract [en]

    Spinal root injuries result in newly formed glial scar formation, which prevents regeneration of sensory axons causing permanent sensory loss. Previous studies showed that delivery of trophic factors or implantation of human neural progenitor cells supports sensory axon regeneration and partly restores sensory functions. In this study, we elucidate mechanisms underlying stem cell-mediated ingrowth of sensory axons after dorsal root avulsion (DRA). We show that human spinal cord neural stem/progenitor cells (hscNSPC), and also, mesoporous silica particles loaded with growth factor mimetics (MesoMIM), supported sensory axon regeneration. However, when hscNSPC and MesoMIM were combined, sensory axon regeneration failed. Morphological and tracing analysis showed that sensory axons grow through the newly established glial scar along "bridges" formed by migrating stem cells. Coimplantation of MesoMIM prevented stem cell migration, "bridges" were not formed, and sensory axons failed to enter the spinal cord. MesoMIM applied alone supported sensory axons ingrowth, but without affecting glial scar formation. In vitro, the presence of MesoMIM significantly impaired migration of hscNSPC without affecting their level of differentiation. Our data show that (1) the ability of stem cells to migrate into the spinal cord and organize cellular "bridges" in the newly formed interface is crucial for successful sensory axon regeneration, (2) trophic factor mimetics delivered by mesoporous silica may be a convenient alternative way to induce sensory axon regeneration, and (3) a combinatorial approach of individually beneficial components is not necessarily additive, but can be counterproductive for axonal growth.

  • 4.
    Jensen, Pernille Linnert
    et al.
    Laboratory of Reproductive Biology, University Hospital of Copenhagen, Denmark.
    Beck, Hans Christian
    entre for Clinical Proteomics, Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Denmark.
    Petersen, Jørgen
    Department of Biochemistry and Molecular Biology, University of Southern Denmark.
    Hreinsson, Julius
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Wånggren, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Laursen, Steen B
    Fertility clinic IVF-SYD, Denmark.
    Sørensen, Pernille Dissing
    ORIGIO a/s, Denmark.
    Christensen, Søren T
    Department of Biology, Section of Cell and Developmental Biology, University of Copenhagen, Denmark.
    Andersen, Claus Yding
    Laboratory of Reproductive Biology, University Hospital of Copenhagen, Denmark.
    Proteomic Analysis of Human Blastocoel Fluid and Blastocyst Cells2013In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 22, no 7, p. 1126-1135Article in journal (Refereed)
    Abstract [en]

    Human embryonic stem cells (hESCs) are derived from the inner cell mass (ICM) of the blastocyst and can differentiate into any cell type in the human body. These cells hold a great potential for regenerative medicine, but in order to obtain enough cells needed for medical treatment, culture is required on a large scale. In the undifferentiated state, hESCs appear to possess an unlimited potential for proliferation but optimal, defined and safe culture conditions remains a challenge. The aim of the present study was to identify proteins in the natural environment of undifferentiated hESCs, namely the blastocoel fluid, which is in contact with all the cells in the blastocyst, including hESCs. Fifty-three surplus human blastocysts were donated after informed consent and blastocoel fluid was isolated by micromanipulation. Using highly sensitive nano high pressure liquid chromatography tandem mass spectrometry, 286 proteins were identified in the blastocoel fluid and 1307 proteins in the corresponding cells of the blastocyst. Forty-two were previously uncharacterized proteins - eight of these originated from the blastocoel fluid. Furthermore, several heat shock proteins (Hsp27, Hsp60, Hsc70 and Hsp90) were identified in blastocoel fluid together with zona pellucida proteins (ZP2-4), Vitamin D binding protein and Retinol binding protein. Proteins that regulate ciliary assembly and function were also identified, including Bardet-biedl syndrome protein 7. This study has identified numerous proteins which cells from the ICM of the human blastocyst are exposed to via the blastocoel fluid. These results can be an inspiration for the development of improved culture conditions for hESCs.

  • 5.
    Junkunlo, Kingkamon
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Söderhäll, Kenneth
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Noonin, Chadanat
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Söderhäll, Irene
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    PDGF/VEGF-related receptor affects transglutaminase activity to control cell migration during crustacean hematopoiesis2017In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 26, no 20, p. 1449-1459Article in journal (Refereed)
    Abstract [en]

    The platelet-derived growth factor (PDGF) receptor, a tyrosine kinase (TK) receptor whose ligand is PDGF, is crucial in the transduction of extracellular signals into cells and mediates numerous processes, such as cell proliferation, differentiation, survival, and migration. We demonstrate the important roles of a receptor TK related to the PDGF/VEGF family protein (PVR) in controlling hematopoietic progenitor cell migration by affecting extracellular transglutaminase (TGase) activity. Pl_PVR1, GenBank accession No. KY444650, is highly expressed in hemocytes and the hematopoietic tissue (HPT). Sunitinib malate was used to block the PVF/PVR downstream pathway in HPT cell culture. The addition of Sunitinib also caused the HPT cells to increase in size and begin spreading. An increase in extracellular TGase activity on the HPT cell membrane was observed in a dose-dependent manner after treatment with Sunitinib malate. The presence of crude Ast1 provided a combinatorial beneficial effect that enhanced the number of spreading cells after inhibition of the Pl_PVR downstream signaling cascade. In addition, an increased immunoreactivity for beta-tubulin and elongation of beta-tubulin filaments were found in Pl_PVR signaling-inhibited cells. The potential roles of PVF/PVR signaling in controlling progenitor cell activity during hematopoiesis in crayfish were investigated and discussed.

  • 6.
    König, Niclas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Åkesson, Elisabet
    Telorack, Michèle
    Vasylovska, Svitlana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Ngamjariyawat, Anongnad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Sundström, Erik
    Oster, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Trolle, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Berens, Christian
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Seiger, Åke
    Kozlova, Elena N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Forced Runx1 expression in human neural stem/progenitor cells transplanted to the rat dorsal root ganglion cavity results in extensive axonal growth specifically from spinal cord-derived neurospheres2011In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 20, no 11, p. 1847-1857Article in journal (Refereed)
    Abstract [en]

    Cell replacement therapy holds great promise for treating a wide range of human disorders. However, ensuring the predictable differentiation of transplanted stem cells, eliminating their risk of tumor formation, and generating fully functional cells after transplantation remain major challenges in regenerative medicine. Here, we explore the potential of human neural stem/progenitor cells isolated from the embryonic forebrain (hfNSPCs) or the spinal cord (hscNSPCs) to differentiate to projection neurons when transplanted into the dorsal root ganglion cavity of adult recipient rats. To stimulate axonal growth, we transfected hfNSPC- and hscNSPC-derived neurospheres, prior to their transplantation, with a Tet-Off Runx1-overexpressing plasmid to maintain Runx1 expression in vivo after transplantation. Although pronounced cell differentiation was found in the Runx1-expressing transplants from both cell sources, we observed extensive, long-distance growth of axons exclusively from hscNSPC-derived transplants. These axons ultimately reached the dorsal root transitional zone, the boundary separating peripheral and central nervous systems. Our data show that hscNSPCs have the potential to differentiate to projection neurons with long-distance axonal outgrowth and that Runx1 overexpression is a useful approach to induce such outgrowth in specific sources of NSPCs.

  • 7. Lanner, Fredrik
    et al.
    Lee, Kian Leong
    Ortega, German C.
    Sohl, Marcus
    Li, Xiujuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Jin, Shaobo
    Hansson, Emil M.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Poellinger, Lorenz
    Lendahl, Urban
    Farnebo, Filip
    Hypoxia-Induced Arterial Differentiation Requires Adrenomedullin and Notch Signaling2013In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 22, no 9, p. 1360-1369Article in journal (Refereed)
    Abstract [en]

    Hypoxia (low oxygen) and Notch signaling are 2 important regulators of vascular development, but how they interact in controlling the choice between arterial and venous fates for endothelial cells during vasculogenesis is less well understood. In this report, we show that hypoxia and Notch signaling intersect in promotion of arterial differentiation. Hypoxia upregulated expression of the Notch ligand Dll4 and increased Notch signaling in a process requiring the vasoactive hormone adrenomedullin. Notch signaling also upregulated Dll4 expression, leading to a positive feedback loop sustaining Dll4 expression and Notch signaling. In addition, hypoxia-mediated upregulation of the arterial marker genes Depp, connexin40 (Gja5), Cxcr4, and Hey1 required Notch signaling. In conclusion, the data reveal an intricate interaction between hypoxia and Notch signaling in the control of endothelial cell differentiation, including a hypoxia/adrenomedullin/Dll4 axis that initiates Notch signaling and a requirement for Notch signaling to effectuate hypoxia-mediated induction of the arterial differentiation program.

  • 8.
    Liew, Lawrence J.
    et al.
    Univ Western Australia, Sch Med, Ear Sci Ctr, Perth, WA, Australia;Ear Sci Inst Australia, Perth, WA, Australia.
    Chen, Linda Q.
    Ear Sci Inst Australia, Perth, WA, Australia;Murdoch Univ, Sch Vet & Life Sci, Perth, WA, Australia.
    Wang, Allen Y.
    Univ Western Australia, Sch Med, Ear Sci Ctr, Perth, WA, Australia;Ear Sci Inst Australia, Perth, WA, Australia;Sir Charles Gairdner Hosp, Skull Base Surg, Dept Otolaryngol Head & Neck, Perth, WA, Australia.
    von Unge, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. Akershus Univ Hosp, Oslo, Norway;Univ Oslo, Oslo, Norway.
    Atlas, Marcus D.
    Univ Western Australia, Sch Med, Ear Sci Ctr, Perth, WA, Australia;Ear Sci Inst Australia, Perth, WA, Australia.
    Dilley, Rodney J.
    Univ Western Australia, Sch Med, Ear Sci Ctr, Perth, WA, Australia;Ear Sci Inst Australia, Perth, WA, Australia;Univ Western Australia, Sch Med, Ctr Cell Therapy & Regenerat Med, Perth, WA, Australia.
    Tympanic Membrane Derived Stem Cell-Like Cultures for Tissue Regeneration2018In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 27, no 10, p. 649-657Article in journal (Refereed)
    Abstract [en]

    Epidermal cells with stem cell-like characteristics have been identified in the tympanic membrane (TM) and localized specifically to the umbo and annulus regions. While they have been proposed to play a role in the regeneration of both acute and chronic TM perforations, evidence for the mechanism and regulation of their contribution is not yet described. Indeed, the behavior of these putative stem cells is largely unknown, in part due to a lack of refined methods for efficient cell isolation. In this study, we compared different explant techniques using normal and perforated rat TM tissues and investigated their ex vivo characteristics. TM after perforation in vivo showed increased staining for epidermal stem cell markers integrin 1 and cytokeratin (CK) 19, and for proliferation Ki-67, indicating activation of the proliferative centers. A mixed population of fibroblasts and epithelial cells were isolated from explant cultures. Excised TM umbo implanted on a culture well insert was the most effective technique. Explants made from perforated TM produced cells before those from unperforated TM. More importantly, the implanted TM umbo organoid was capable of producing cells in a continuous manner, allowing subsequent harvest using trypsin. Primary rat TM epithelial cell cultures positive for pancytokeratin had colony forming activity and could be enriched for CK 19-positive cells that were capable of culture expansion by proliferation and cell migration when subject to a wound assay. Taken together, trauma to the TM activated the proliferative centers and prompted early cell production from TM umbo organoid cultures, which produced TM stem cell-like cultures that proved suitable for tissue engineering of the TM.

  • 9.
    Ljung, Karin
    et al.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden; Karolinska Univ Hosp, Heart & Vasc Div, Stockholm, Sweden.
    Grönlund, Anna
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Felldin, Ulrika
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Rodin, Sergey
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
    Corbascio, Matthias
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden; Karolinska Univ Hosp, Heart & Vasc Div, Stockholm, Sweden.
    Österholm, Cecilia
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Grinnemo, Karl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery. Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Human Fetal Cardiac Mesenchymal Stromal Cells Differentiate In Vivo into Endothelial Cells and Contribute to Vasculogenesis in Immunocompetent Mice2019In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 28, no 5, p. 310-318Article in journal (Refereed)
    Abstract [en]

    Mesenchymal stromal cells (MSCs) have shown great potential as a treatment for systemic inflammatory diseases, but their local regenerative properties are highly tissue- and site specific. Previous studies have demonstrated that adult human MSCs respond to inflammatory cytokines through the release of paracrine factors that stimulate angiogenesis, but they do not themselves differentiate into vascular structures in vivo. In this study, we used human fetal cardiac MSCs (hfcMSCs) harvested during the first trimester of heart development and injected them into the subcutaneous tissue of normal immunocompetent mice treated with short-term costimulation blockade for tolerance induction. When hfcMSCs were transplanted subcutaneously together with Matrigel matrix, they contributed to vasculogenesis through differentiation into endothelial cells and generation of the basal membrane protein Laminin 4. These characteristics of hfcMSCs are similar to the mesodermal progenitors giving rise to the developing heart and they may be useful for treatment of ischemic injuries.

  • 10.
    Moll, Guido
    et al.
    Karolinska Inst, Dept Lab Med, Therapeut Immunol TIM, Stockholm, Sweden.;Charite, Berlin Brandenburg Sch Regenerat Therapies BSRT, D-13353 Berlin, Germany.;Charite, Dept Nephrol & Intens Care Med, D-13353 Berlin, Germany..
    Ignatowicz, Lech
    Lund Univ, Dept Clin Sci, Lund, Sweden..
    Catar, Rusan
    Charite, Dept Nephrol & Intens Care Med, D-13353 Berlin, Germany..
    Luecht, Christian
    Charite, Dept Nephrol & Intens Care Med, D-13353 Berlin, Germany..
    Sadeghi, Behnam
    Karolinska Inst, Dept Lab Med, Therapeut Immunol TIM, Stockholm, Sweden.;Karolinska Univ Hosp Huddinge, Ctr Allogene Stem Cell Transplantat CAST, Stockholm, Sweden..
    Hamad, Osama
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Jungebluth, Philipp
    Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Adv Ctr Translat Regenerat Med ACTREM, Stockholm, Sweden.;Heidelberg Univ, Dept Thorac Surg, Thoraxklin, Heidelberg, Germany..
    Dragun, Duska
    Charite, Berlin Brandenburg Sch Regenerat Therapies BSRT, D-13353 Berlin, Germany.;Charite, Dept Nephrol & Intens Care Med, D-13353 Berlin, Germany..
    Schmidtchen, Artur
    Lund Univ, Dept Clin Sci, Lund, Sweden..
    Ringden, Olle
    Karolinska Inst, Dept Lab Med, Therapeut Immunol TIM, Stockholm, Sweden.;Karolinska Univ Hosp Huddinge, Ctr Allogene Stem Cell Transplantat CAST, Stockholm, Sweden..
    Different Procoagulant Activity of Therapeutic Mesenchymal Stromal Cells Derived from Bone Marrow and Placental Decidua2015In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 24, no 19, p. 2269-2279Article in journal (Refereed)
    Abstract [en]

    While therapeutic mesenchymal stromal/stem cells (MSCs) have usually been obtained from bone marrow, perinatal tissues have emerged as promising new sources of cells for stromal cell therapy. In this study, we present a first safety follow-up on our clinical experience with placenta-derived decidual stromal cells (DSCs), used as supportive immunomodulatory and regenerative therapy for patients with severe complications after allogeneic hematopoietic stem cell transplantation (HSCT). We found that DSCs are smaller, almost half the volume of MSCs, which may favor microvascular passage. DSCs also show different hemocompatibility, with increased triggering of the clotting cascade after exposure to human blood and plasma in vitro. After infusion of DSCs in HSCT patients, we observed a weak activation of the fibrinolytic system, but the other blood activation markers remained stable, excluding major adverse events. Expression profiling identified differential levels of key factors implicated in regulation of hemostasis, such as a lack of prostacyclin synthase and increased tissue factor expression in DSCs, suggesting that these cells have intrinsic blood-activating properties. The stronger triggering of the clotting cascade by DSCs could be antagonized by optimizing the cell graft reconstitution before infusion, for example, by use of low-dose heparin anticoagulant in the cell infusion buffer. We conclude that DSCs are smaller and have stronger hemostatic properties than MSCs, thus triggering stronger activation of the clotting system, which can be antagonized by optimizing the cell graft preparation before infusion. Our results highlight the importance of hemocompatibility safety testing for every novel cell therapy product before clinical use, when applied using systemic delivery.

  • 11.
    Noonin, Chadanat
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Lin, Xionghui
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Jiravanichpaisal, Pikul
    Aquatic Molecular Genetics and Biotechnology Laboratory, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Bangkok.
    Söderhäll, Kenneth
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Söderhäll, Irene
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Invertebrate hematopoiesis: an anterior proliferation centre as a link between the hematopoietic tissue and the brain2012In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 21, no 17, p. 3173-3186Article in journal (Refereed)
    Abstract [en]

    During evolution, the innate and adaptive immune systems developed to protect organisms from nonself substances. The innate immune system is phylogenetically more ancient and is present in most multicellular organisms, whereas adaptive responses are restricted to vertebrates. Arthropods, lack the blood cells of the lymphoid lineage, and oxygen-carrying erythrocytes, making them suitable model animals to study the regulation of the blood cells of the innate immune system. Many crustaceans have a long life span and need to continuously synthesize blood cells, in contrast to many insects. The hematopoietic tissue (HPT) of Pacifastacus leniusculus provides a simple model to study hematopoiesis because the tissue can be isolated and the proliferation of stem cells and their differentiation can be studied both in vivo and in vitro. Here we demonstrate new findings of a physical link between the HPT and the brain. Actively proliferating cells were localized to an anterior proliferation centre (APC) in the anterior part of the tissue near the area linking the HPT to the brain, whereas more differentiated cells were detected in the posterior part. The central areas of HPT expand in response to lipopolysaccharide-induced blood loss. Cells isolated from the APC divide rapidly and form cell clusters in vitro; conversely, the cells from the remaining HPT form monolayers, and they can be induced to differentiate in vitro. Our findings offer an opportunity to learn more about invertebrate hematopoiesis and its connection to the central nervous system and thereby to obtain new information about the evolution of different blood and nerve cell lineages.

  • 12.
    Ong, Huan Ting
    et al.
    Ear Sci Inst Australia, Nedlands, WA, Australia.;Murdoch Univ, Sch Vet & Life Sci, Murdoch, WA, Australia..
    Redmond, Sharon L.
    Ear Sci Inst Australia, Nedlands, WA, Australia.;Univ Western Australia, Ear Sci Ctr, Perth, WA, Australia..
    Marano, Robert J.
    Ear Sci Inst Australia, Nedlands, WA, Australia.;Univ Western Australia, Ear Sci Ctr, Perth, WA, Australia..
    Atlas, Marcus D.
    Ear Sci Inst Australia, Nedlands, WA, Australia.;Univ Western Australia, Ear Sci Ctr, Perth, WA, Australia..
    von Unge, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. Akershus Univ Hosp, Div Surg, Oslo, Norway.;Univ Oslo, Oslo, Norway..
    Aabel, Peder
    Akershus Univ Hosp, Div Surg, Oslo, Norway.;Univ Oslo, Oslo, Norway..
    Dilley, Rodney J.
    Ear Sci Inst Australia, Nedlands, WA, Australia.;Univ Western Australia, Ear Sci Ctr, Perth, WA, Australia.;Univ Western Australia, Ctr Cell Therapy & Regenerat Med, Perth, WA, Australia..
    Paracrine Activity from Adipose-Derived Stem Cells on In Vitro Wound Healing in Human Tympanic Membrane Keratinocytes2017In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 26, no 6, p. 405-418Article in journal (Refereed)
    Abstract [en]

    Stem cell therapies for tympanic membrane repair have shown initial experimental success using mesenchymal stem cells in rat models to promote healing; however, the mechanisms providing this benefit are not known. We investigated in vitro the paracrine effects of human adipose-derived stem cells (ADSCs) on wound healing mechanisms for human tympanic membrane-derived keratinocytes (hTM) and immortalized human keratinocytes (HaCaT). ADSC conditioned media (CMADSC) were assessed for paracrine activity on keratinocyte proliferation and migration, with hypoxic conditions for ADSC culture used to generate contrasting effects on cytokine gene expression. Keratinocytes cultured in CMADSC showed a significant increase in cell number compared to serum-free cultures and further significant increases in hypoxic CMADSC. Assessment of ADSC gene expression on a cytokine array showed a range of wound healing cytokines expressed and under stringent hypoxic and serum-free conditions was upregulated (VEGF A, MMP9, Tissue Factor, PAI-1) or downregulated (CXCL5, CCL7, TNF-). Several of these may contribute to the activity of conditioned media on the keratinocytes with potential applications in TM perforation repair. VEGFA protein was confirmed by immunoassay to be increased in conditioned media. Together with gene regulation associated with hypoxia in ADSCs, this study has provided several strong leads for a stem cell-derived approach to TM wound healing.

  • 13.
    Sobol, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Raykova, Doroteya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Cavelier, Lucia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Khalfallah, Ayda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Schuster, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Methods of Reprogramming to Induced Pluripotent Stem Cell Associated with Chromosomal Integrity and Delineation of a Chromosome 5q Candidate Region for Growth Advantage2015In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 24, no 17, p. 2032-2040Article in journal (Refereed)
    Abstract [en]

    Induced pluripotent stem cells (iPSCs) have brought great promises for disease modeling and cell-based therapies. One concern related to the use of reprogrammed somatic cells is the loss of genomic integrity and chromosome stability, a hallmark for cancer and many other human disorders. We investigated 16 human iPSC lines reprogrammed by nonintegrative Sendai virus (SeV) and another 16 iPSC lines generated by integrative lentivirus for genetic changes. At early passages we detected cytogenetic rearrangements in 44% (7/16) of iPSC lines generated by lentiviral integration whereas the corresponding figure was 6% (1/16) using SeV-based delivery. The rearrangements were numerical and/or structural with chromosomes 5 and 12 as the most frequently involved chromosomes. Three iPSC lines with chromosome 5 aberrations were derived from one and the same donor. We present in this study the aberrant karyotypes including a duplication of chromosome 5q13q33 that restricts a candidate region for growth advantage. Our results suggest that the use of integrative lentivirus confers a higher risk for cytogenetic abnormalities at early passages when compared to SeV-based reprogramming. In combination, our findings expand the knowledge on acquired cytogenetic aberrations in iPSC after reprogramming and during culture.

1 - 13 of 13
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