gp130 Activation by Soluble Interleukin-6 Receptor/Interleukin-6 Enhances Osteoblastic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells

Erices, Alejandro; Conget, Paulette; Rojas, Cecilia; Minguell, José J.

doi:10.1006/excr.2002.5627

Cited by 81 publications

(58 citation statements)

References 37 publications

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“…IL-6 promotes terminal osteogenic differentiation by committed osteoprogenitors, but not by MSCs. 77 Thus, IL-6 secreted by MSCs, in response to Pam3Cys, might promote differentiation of preosteocytes into ALP-expressing, calcium-depositing osteocytes in the cell culture, leading to sporadic differentiation of the osteoprogenitors. Pam3Cys increased MSC proliferation and inhibited differentiation in induced MSC cultures.…”

Section: Discussionmentioning

confidence: 99%

Toll-like receptors and their ligands control mesenchymal stem cell functions

Pevsner‐Fischer

Morad

Cohen-Sfady

et al. 2006

Blood

446

403

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IntroductionMesenchymal stem cells (MSCs) comprise an adult population that resides in many organs and exhibits multiple functions and phenotypes upon in vitro culture; MSCs can be induced to differentiate into mesodermal cell lineages, 1,2 support and regulate hematopoiesis, [3][4][5][6][7] regulate the stem-cell niche, [8][9][10][11][12] and may participate in the repair of tissue damage inflicted by normal wear and tear, injury, or disease. [13][14][15][16] MSCs comprise 0.01% to 0.001% of the bone marrow (BM)-nucleated cells and are obtained by expansion of the BM, plastic-adherent cell fraction. 1,[17][18][19][20][21] Under certain physiologic or experimental conditions, MSCs can be induced to differentiate in vitro into cells of the mesodermal lineage, specifically to osteocytes, adipocytes, chondrocytes, myocytes, tenocytes, myocardiocytes, and hematopoietic supportive stroma. 1,17,19,22 MSCs are an attractive cell-based therapy tool for developmental defects; degenerating diseases; and bone, cartilage, muscle, and other mesodermal tissue injuries. [23][24][25][26][27][28][29][30] Toll-like receptors (TLRs) are a class of molecules first discovered to play a role in body development 31 and later found to play a role in body maintenance. [32][33][34][35][36] The TLR family has been shown to be of importance in the innate immune system for the recognition of pathogen-associated molecular patterns (PAMPs) by immune cells, initiating a primary response toward invading pathogens and recruitment of the adaptive immune response. 32,[37][38][39][40][41][42][43][44][45][46][47][48][49] TLRs can be activated not only by pathogen components, but also by mammalian endogenous molecules such as heat-shock proteins and extracellular matrix breakdown products. [50][51][52] In the steady state, during the generation of immune cells, as well as under pathologic conditions, there are intimate interactions between lymphocyte populations and the organ stroma mesenchyme. These interactions regulate cell growth and differentiation and control cell functions. It is possible therefore that lymphocytes and the stromal mesenchyme share regulatory mechanisms. To test this possibility we aimed, in the present study, to examine the expression and possible regulatory functions of TLRs in mesenchymal cells.We explored the expression of TLRs by MSCs, the response of MSCs to known TLR activators, and the ability of a TLR-2 ligand to regulate MSC proliferation and differentiation. We show here that cultured MSCs express TLR molecules 1 to 8, but not TLR-9. Activation of MSCs by TLR ligands induced interleukin-6 (IL-6) secretion and nuclear factor B (NF-B) nuclear translocation. Pam3Cys, a prototypic ligand for TLR-2, induced proliferation of MSCs and regulated their differentiation. Relatively little is known about the signals that regulate MSC proliferation, differentiation, and development. 53,54 Our findings suggest that TLR signaling may play a role in restraining MSC differentiation and thus promote MSC renewal. Materials and methods ...

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Section: Discussionmentioning

confidence: 99%

Toll-like receptors and their ligands control mesenchymal stem cell functions

Pevsner‐Fischer

Morad

Cohen-Sfady

et al. 2006

Blood

446

403

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“…Although studies showed that IL-6 is expressed in several mesenchymal tumors, little data are available concerning the association of IL-6 and its receptor proteins. Erices and colleagues 46 showed that IL-6R deficiency may represent for bone marrowderived mesenchymal stem cells to escape the osteoblastic differentiation by the cell itself as well as other stromal cells. Human osteoblasts express cell surface IL-6R, which is unable to transmit IL-6-induced signals until it is shed into its soluble form.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6/Soluble Interleukin-6 Receptor Signaling Attenuates Proliferation and Invasion, and Induces Morphological Changes of a Newly Established Pleomorphic Malignant Fibrous Histiocytoma Cell Line

Nakanishi

Yoshioka

Joyama

et al. 2004

The American Journal of Pathology

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Pleomorphic malignant fibrous histiocytoma (MFH)is occasionally associated with inflammatory paraneoplastic syndrome (PNS). Recently, we reported that interleukin (IL)-6, one of the candidate cytokines, which induces such systemic inflammatory reaction, may be a tumor-associated factor involved in the pathogenesis and its clinical manifestations of MFH. In the local microenvironment, tumor-induced inflammatory reaction may play a role favoring tumor progression. To clarify the biological relevance of IL-6 in MFH, we established a human MFH cell line, named MIPS-2, derived from a resected specimen of a patient presenting with PNS. In this patient, the serum IL-6 level ran parallel to the disease course: elevated serum IL-6 concentration normalized immediately after radical surgery, and re-elevation occurred on tumor recurrence. MIPS-2 presented pleomorphic appearance, severe nuclear abnormalities with prominent nucleoli, and tumorigenesis in nude mice. MIPS-2 expressed IL-6, IL-6 receptor (IL-6R

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“…[10][11][12] The adherent stromal cell layer in long-term bone marrow cultures (LTBMCs) is necessary for balanced proliferation and differentiation of hematopoietic progenitors. 13 IL-6 is produced at low levels in LTBMCs, and appears to participate in regulating their hematopoietic supportive activity.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-6 deficiency affects bone marrow stromal precursors, resulting in defective hematopoietic support

Rodrı́guez

Bernad

Aracil

2004

Blood

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Interleukin-6 (IL-6) is a critical factor in the regulation of stromal function and hematopoiesis. In vivo bromodeoxyuridine incorporation analysis indicates that the percentage of Lin ؊ Sca-1 ؉ hematopoietic progenitors undergoing DNA synthesis is diminished in IL-6-deficient (IL-6 ؊/؊ ) bone marrow (BM) compared with wild-type BM. Reduced proliferation of IL-6 ؊/؊ BM progenitors is also observed in IL-6 ؊/؊ long-term BM cultures, which show defective hematopoietic support as measured by production of total cells, granulocyte macrophage-colony-forming units (CFU-GMs), and erythroid burstforming units (BFU-Es). Seeding experiments of wild-type and IL-6 ؊/؊ BM cells on irradiated wild-type or IL-6-deficient stroma indicate that the hematopoietic defect can be attributed to the stromal and not to the hematopoietic component. In IL-6 ؊/؊ BM, stromal mesenchymal precursors, fibroblast CFUs (CFU-Fs), and stroma-initiating cells (SICs) are reduced to almost 50% of the wild-type BM value. Moreover, IL-6 ؊/؊ stromata show increased CD34 and CD49e expression and reduced expression of the membrane antigens vascular cell adhesion molecule-1 (VCAM-1), Sca-1, CD49f, and Thy1. These data strongly suggest that IL-6 is an in vivo growth factor for mesenchymal precursors, which are in part implicated in the reduced longevity of the long-term repopulating stem cell compartment of IL-6 ؊/؊ mice. IntroductionInterleukin-6 (IL-6) is a multifunctional cytokine with a major role in inflammatory responses and is the primary inducer of acutephase proteins. 1 IL-6 also regulates the proliferation and differentiation of hematopoietic cells from several lineages at different maturation stages. 1 In synergy with IL-3, IL-6 stimulates proliferation of granulocyte-macrophage, megakaryocyte, and erythroid progenitors. [2][3][4][5] This cooperation has also been shown in several in vivo model systems designed to evaluate the effect of IL-6 on the stem cell compartment. 3,4,6 The specific contribution of IL-6 to homeostasis in the lymphohematopoietic system has been evaluated in the IL-6 Ϫ/Ϫ mouse model, which showed a clear reduction in the number of the earliest clonogenic precursors and in the function of long-term repopulating stem cells (LTRSCs). 7 IL-6 Ϫ/Ϫ mice show a decrease in absolute numbers of spleen colonyforming units (CFU-Ss) at day 12 and of pre-CFU-S hematopoietic progenitors, as well as a deficit in the LTRSC compartment. 7 In addition to the effects in early hematopoiesis, IL-6 Ϫ/Ϫ mice show defects in T-and B-cell function 8 and in acute-phase responses. 9 These results strongly suggest an important in vivo role for IL-6 in the survival and self-renewal of hematopoietic stem cells (HSCs) and early progenitors.IL-6 is produced by a variety of cells including T and B cells, macrophages, fibroblasts, bone marrow stromal cells, and mesenchymal cells. [10][11][12] The adherent stromal cell layer in long-term bone marrow cultures (LTBMCs) is necessary for balanced proliferation and differentiation of hematopoietic progenitors. 13 ...

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gp130 Activation by Soluble Interleukin-6 Receptor/Interleukin-6 Enhances Osteoblastic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells

Cited by 81 publications

References 37 publications

Toll-like receptors and their ligands control mesenchymal stem cell functions

Toll-like receptors and their ligands control mesenchymal stem cell functions

Interleukin-6/Soluble Interleukin-6 Receptor Signaling Attenuates Proliferation and Invasion, and Induces Morphological Changes of a Newly Established Pleomorphic Malignant Fibrous Histiocytoma Cell Line

Interleukin-6 deficiency affects bone marrow stromal precursors, resulting in defective hematopoietic support

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