TY - JOUR A1 - Wong, David A1 - Winter, Oliver A1 - Hartig, Christina A1 - Siebels, Svenja A1 - Szyska, Martin A1 - Tiburzy, Benjamin A1 - Meng, Lingzhang A1 - Kulkarni, Upasana A1 - Fähnrich, Anke A1 - Bommert, Kurt A1 - Bargou, Ralf A1 - Berek, Claudia A1 - Van, Trung Chu A1 - Bogen, Bjarne A1 - Jundt, Franziska A1 - Manz, Rudolf Armin T1 - Eosinophils and Megakaryocytes Support the Early Growth of Murine MOPC315 Myeloma Cells in Their Bone Marrow Niches JF - PLOS ONE N2 - Multiple myeloma is a bone marrow plasma cell tumor which is supported by the external growth factors APRIL and IL-6, among others. Recently, we identified eosinophils and megakaryocytes to be functional components of the micro-environmental niches of benign bone marrow plasma cells and to be important local sources of these cytokines. Here, we investigated whether eosinophils and megakaryocytes also support the growth of tumor plasma cells in the MOPC315. BM model for multiple myeloma. As it was shown for benign plasma cells and multiple myeloma cells, IL-6 and APRIL also supported MOPC315. BM cell growth in vitro, IL-5 had no effect. Depletion of eosinophils in vivo by IL-5 blockade led to a reduction of the early myeloma load. Consistent with this, myeloma growth in early stages was retarded in eosinophil-deficient Delta dblGATA-1 mice. Late myeloma stages were unaffected, possibly due to megakaryocytes compensating for the loss of eosinophils, since megakaryocytes were found to be in contact with myeloma cells in vivo and supported myeloma growth in vitro. We conclude that eosinophils and megakaryocytes in the niches for benign bone marrow plasma cells support the growth of malignant plasma cells. Further investigations are required to test whether perturbation of these niches represents a potential strategy for the treatment of multiple myeloma. KW - plasma cells KW - human multiple-myeloma KW - immune response KW - receptor expression KW - B-cells KW - stromal cells KW - dexamethasone KW - april KW - survival KW - Interleukin-5 Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-115269 VL - 9 IS - 10 ER - TY - JOUR A1 - Rackwitz, Lars A1 - Eden, Lars A1 - Reppenhagen, Stephan A1 - Reichert, Johannes C. A1 - Jakob, Franz A1 - Walles, Heike A1 - Pullig, Oliver A1 - Tuan, Rocky S. A1 - Rudert, Maximilian A1 - Nöth, Ulrich T1 - Stem cell- and growth factor-based regenerative therapies for avascular necrosis of the femoral head JF - Stem Cell Research & Therapy N2 - Avascular necrosis (AVN) of the femoral head is a debilitating disease of multifactorial genesis, predominately affects young patients, and often leads to the development of secondary osteoarthritis. The evolving field of regenerative medicine offers promising treatment strategies using cells, biomaterial scaffolds, and bioactive factors, which might improve clinical outcome. Early stages of AVN with preserved structural integrity of the subchondral plate are accessible to retrograde surgical procedures, such as core decompression to reduce the intraosseous pressure and to induce bone remodeling. The additive application of concentrated bone marrow aspirates, ex vivo expanded mesenchymal stem cells, and osteogenic or angiogenic growth factors (or both) holds great potential to improve bone regeneration. In contrast, advanced stages of AVN with collapsed subchondral bone require an osteochondral reconstruction to preserve the physiological joint function. Analogously to strategies for osteochondral reconstruction in the knee, anterograde surgical techniques, such as osteochondral transplantation (mosaicplasty), matrix-based autologous chondrocyte implantation, or the use of acellular scaffolds alone, might preserve joint function and reduce the need for hip replacement. This review summarizes recent experimental accomplishments and initial clinical findings in the field of regenerative medicine which apply cells, growth factors, and matrices to address the clinical problem of AVN. KW - osteochondral allografts KW - autologous chondrocyte implantation KW - osteogenesis imperfecta KW - segmental collapse KW - mesenchymal cells KW - progenitor cells KW - stromal cells KW - sheep model KW - colony-stimulating factor KW - core depression Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135413 VL - 3 IS - 7 ER - TY - JOUR A1 - Giordano, Rosaria A1 - Canesi, Margherita A1 - Isalberti, Maurizio A1 - Isaias, Ioannis Ugo A1 - Montemurro, Tiziana A1 - Viganò, Mariele A1 - Montelatici, Elisa A1 - Boldrin, Valentina A1 - Benti, Riccardo A1 - Cortelezzi, Agostino A1 - Fracchiolla, Nicola A1 - Lazzari, Lorenza A1 - Pezzoli, Gianni T1 - Autologous mesenchymal stem cell therapy for progressive supranuclear palsy: translation into a phase I controlled, randomized clinical study JF - Journal of Translational Medicine N2 - Background: Progressive Supranuclear Palsy (PSP) is a sporadic and progressive neurodegenerative disease which belongs to the family of tauopathies and involves both cortical and subcortical structures. No effective therapy is to date available. Methods/design: Autologous bone marrow (BM) mesenchymal stem cells (MSC) from patients affected by different type of parkinsonisms have shown their ability to improve the dopaminergic function in preclinical and clinical models. It is also possible to isolate and expand MSC from the BM of PSP patients with the same proliferation rate and immuphenotypic profile as MSC from healthy donors. BM MSC can be efficiently delivered to the affected brain regions of PSP patients where they can exert their beneficial effects through different mechanisms including the secretion of neurotrophic factors. Here we propose a randomized, placebo-controlled, double-blind phase I clinical trial in patients affected by PSP with MSC delivered via intra-arterial injection. Discussion: To our knowledge, this is the first clinical trial to be applied in a no-option parkinsonism that aims to test the safety and to exploit the properties of autologous mesenchymal stem cells in reducing disease progression. The study has been designed to test the safety of this " first-in-man" approach and to preliminarily explore its efficacy by excluding the placebo effect. Trial registration: NCT01824121 KW - Parkinson's disease KW - cellular therapy KW - deep brain-stimulation KW - bone-marrow KW - transplantation KW - receptor tyrosine kinase KW - Richardson-Olszewski-Syndrome KW - multiple system atrophy KW - advanced therapy medicinal products KW - mesenchymal stem and stromal cells KW - progressive supranuclear palsy KW - treatment options KW - adrenal medulla KW - stromal cells Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117594 VL - 12 IS - 14 ER - TY - JOUR A1 - Ebert, Regina A1 - Benisch, Peggy A1 - Krug, Melanie A1 - Zeck, Sabine A1 - Meißner-Weigl, Jutta A1 - Steinert, Andre A1 - Rauner, Martina A1 - Hofbauer, Lorenz A1 - Jakob, Franz T1 - Acute phase serum amyloid A induces proinflammatory cytokines and mineralization via toll-like receptor 4 in mesenchymal stem cells JF - Stem Cell Research N2 - The role of serum amyloid A (SAA) proteins, which are ligands for toll-like receptors, was analyzed in human bone marrow-derived mesenchymal stem cells (hMSCs) and their osteogenic offspring with a focus on senescence, differentiation andmineralization. In vitro aged hMSC developed a senescence-associated secretory phenotype (SASP), resulting in enhanced SAA1/2, TLR2/4 and proinflammatory cytokine (IL6, IL8, IL1\(\beta\), CXCL1, CXCL2) expression before entering replicative senescence. Recombinant human SAA1 (rhSAA1) induced SASP-related genes and proteins in MSC, which could be abolished by cotreatment with the TLR4-inhibitor CLI-095. The same pattern of SASP-resembling genes was stimulated upon induction of osteogenic differentiation, which is accompanied by autocrine SAA1/2 expression. In this context additional rhSAA1 enhanced the SASP-like phenotype, accelerated the proinflammatory phase of osteogenic differentiation and enhanced mineralization. Autocrine/paracrine and rhSAA1 via TLR4 stimulate a proinflammatory phenotype that is both part of the early phase of osteogenic differentiation and the development of senescence. This signaling cascade is tightly involved in bone formation and mineralization, but may also propagate pathological extraosseous calcification conditions such as calcifying inflammation and atherosclerosis. KW - human atherosclerotic lesions KW - senescence KW - expression KW - toll-like receptor KW - mineralization KW - osteogenic differentiation KW - serum amyloid A KW - inflammation KW - mesenchymal stem cells KW - WNT5A KW - model KW - lines KW - stromal cells KW - RT-PCR Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148491 VL - 15 ER -