Systemic Dysfunction of Osteoblast Differentiation in Adipose-Derived Stem Cells from Patients with Multiple Myeloma

Cells - Tập 8 Số 5 - Trang 441
Sylvie Lang1, Christelle Mazurier2,3, Martine Auclair1, Nathalie Ferrand4, Séverine Jolly2,3, Tiffany Marie2,3, Ladan Kobari3, Indira Toillon1, François Delhommeau3, Bruno Fève5, Annette K. Larsen4, Michèle Sabbah4, Laurent Garderet6
1INSERM, UMR_S 938, Centre de Recherche Saint-Antoine-Team Genetic and Acquired Lipodystrophies, Institut Hospitalo-Universitaire de Cardiométabolisme et Nutrition (ICAN), Sorbonne Université, F-75012 Paris, France
2EFS Ile de France, Unité d’Ingénierie et de Thérapie Cellulaire, F-94017 Créteil, France
3INSERM, UMR_S 938, Centre de Recherche Saint-Antoine-Team Proliferation and Differentiation of Stem Cells, Institut Universitaire de Cancérologie, Sorbonne Université, F-75012 Paris, France
4INSERM, CNRS, UMR_S 938, Centre de Recherche Saint-Antoine- Team Cancer Biology and Therapeutics, Institut Universitaire de Cancérologie, Sorbonne Université, F-75012 Paris, France
5INSERM, UMR_S 938, Centre de Recherche Saint-Antoine-Team Genetic and Acquired Lipodystrophies, Institut Hospitalo-Universitaire de Cardiométabolisme et Nutrition (ICAN), Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, service d’Endocrinologie, Sorbonne Université, F-75012 Paris, France
6INSERM, UMR_S 938, Centre de Recherche Saint-Antoine-Team Proliferation and Differentiation of Stem Cells, Assistance Publique-Hôpitaux de Paris, Hôpital Saint Antoine, Département d’Hématologie et de Thérapie Cellulaire, Sorbonne Université, F-75012 Paris, France

Tóm tắt

Multiple myeloma is characterized by bone lesions linked to increased osteoclast and decreased osteoblast activities. In particular, the osteoblast differentiation of bone marrow-derived stem cells (MSC) is impaired. Among the potential therapeutic tools for counteracting bone lesions, adipose-derived stem cells (ASC) could represent an appealing source for regenerative medicine due to their similar characteristics with MSC. Our study is among the first giving detailed insights into the osteoblastogenic capacities of ASC isolated by fat aspiration from myeloma patients (MM-ASC) compared to healthy subjects (HD-ASC). We showed that MM-ASC and HD-ASC exhibited comparable morphology, proliferative capacity, and immunophenotype. Unexpectedly, although normal in adipocyte differentiation, MM-ASC present a defective osteoblast differentiation, as indicated by less calcium deposition, decreased alkaline phosphatase activity, and downregulation of RUNX2 and osteocalcin. Furthermore, these ASC-derived osteoblasts displayed enhanced senescence, as shown by an increased β-galactosidase activity and cell cycle inhibitors expression (p16INK4A, p21WAF1/CIP1.), associated with a markedly increased expression of DKK1, a major inhibitor of osteoblastogenesis in multiple myeloma. Interestingly, inhibition of DKK1 attenuated senescence and rescued osteoblast differentiation, highlighting its key role. Our findings show, for the first time, that multiple myeloma is a systemic disease and suggest that ASC from patients would be unsuitable for tissue engineering designed to treat myeloma-associated bone disease.

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Tài liệu tham khảo

Kumar, 2017, Multiple myeloma, Nat. Rev. Dis. Primers., 3, 17046, 10.1038/nrdp.2017.46

Mansour, 2017, Emerging Roles of Osteoclasts in the Modulation of Bone Microenvironment and Immune Suppression in Multiple Myeloma, Front. Immunol., 8, 954, 10.3389/fimmu.2017.00954

Callander, 2001, Myeloma bone disease, Semin. Hematol., 38, 276, 10.1016/S0037-1963(01)90020-4

Giuliani, 2006, Multiple myeloma bone disease: Pathophysiology of osteoblast inhibition, Blood, 108, 3992, 10.1182/blood-2006-05-026112

Terpos, 2018, Pathogenesis of bone disease in multiple myeloma: From bench to bedside, Blood Cancer J., 8, 7, 10.1038/s41408-017-0037-4

Fisher, 1999, Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro, Proc. Natl. Acad. Sci. USA, 96, 133, 10.1073/pnas.96.1.133

Lee, 2017, Bisphosphonate guidelines for treatment and prevention of myeloma bone disease, Intern. Med. J., 47, 938, 10.1111/imj.13502

Corre, 2007, Bone marrow mesenchymal stem cells are abnormal in multiple myeloma, Leukemia, 21, 1079, 10.1038/sj.leu.2404621

Arnulf, 2007, Phenotypic and functional characterization of bone marrow mesenchymal stem cells derived from patients with multiple myeloma, Leukemia, 21, 158, 10.1038/sj.leu.2404466

Garderet, 2007, Mesenchymal stem cell abnormalities in patients with multiple myeloma, Leuk. Lymphoma, 48, 2032, 10.1080/10428190701593644

Bafico, 2001, Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow, Nat. Cell Biol., 3, 683, 10.1038/35083081

Xu, 2018, Mesenchymal stem cells in multiple myeloma: A therapeutical tool or target?, Leukemia, 32, 1500, 10.1038/s41375-018-0061-9

Gimble, 2007, Adipose-derived stem cells for regenerative medicine, Circ. Res., 100, 1249, 10.1161/01.RES.0000265074.83288.09

Dominici, 2006, Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement, Cytotherapy, 8, 315, 10.1080/14653240600855905

Mizuno, 2012, Concise review: Adipose-derived stem cells as a novel tool for future regenerative medicine, Stem Cells, 30, 804, 10.1002/stem.1076

Bourin, 2013, Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells: A joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT), Cytotherapy, 15, 641, 10.1016/j.jcyt.2013.02.006

Secunda, 2015, Isolation, expansion and characterisation of mesenchymal stem cells from human bone marrow, adipose tissue, umbilical cord blood and matrix: A comparative study, Cytotechnology, 67, 793, 10.1007/s10616-014-9718-z

Zhu, M., Heydarkhan-Hagvall, S., Hedrick, M., Benhaim, P., and Zuk, P. (2013). Manual isolation of adipose-derived stem cells from human lipoaspirates. J. Vis. Exp., e50585.

Gorwood, 2019, Impact of HIV/SIV infection and viral proteins on adipose tissue fibrosis and adipogenesis, AIDS, 33, 953, 10.1097/QAD.0000000000002168

Lagathu, 2007, Some HIV antiretrovirals increase oxidative stress and alter chemokine, cytokine or adiponectin production in human adipocytes and macrophages, Antivir. Ther., 12, 489, 10.1177/135965350701200407

Cotter, 2011, HIV type 1 alters mesenchymal stem cell differentiation potential and cell phenotype ex vivo, AIDS Res. Hum. Retroviruses, 27, 187, 10.1089/aid.2010.0114

Dimri, 1995, A biomarker that identifies senescent human cells in culture and in aging skin in vivo, Proc. Natl. Acad. Sci. USA, 92, 9363, 10.1073/pnas.92.20.9363

Caron, 2008, Contribution of mitochondrial dysfunction and oxidative stress to cellular premature senescence induced by antiretroviral thymidine analogues, Antivir. Ther., 13, 27, 10.1177/135965350801300103

Silbermann, 2013, Myeloma bone disease: Pathophysiology and management, J. Bone Oncol., 2, 59, 10.1016/j.jbo.2013.04.001

Li, 2007, Elevated tumor necrosis factor-alpha suppresses TAZ expression and impairs osteogenic potential of Flk-1+ mesenchymal stem cells in patients with multiple myeloma, Stem Cells Dev., 16, 921, 10.1089/scd.2007.0074

Tian, 2003, The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma, N. Engl. J. Med., 349, 2483, 10.1056/NEJMoa030847

Gao, 2017, CD36 Is a Marker of Human Adipocyte Progenitors with Pronounced Adipogenic and Triglyceride Accumulation Potential, Stem Cells, 35, 1799, 10.1002/stem.2635

Baglio, 2015, Human bone marrow- and adipose-mesenchymal stem cells secrete exosomes enriched in distinctive miRNA and tRNA species, Stem Cell Res. Ther., 6, 127, 10.1186/s13287-015-0116-z

Gao, 2011, MicroRNA expression during osteogenic differentiation of human multipotent mesenchymal stromal cells from bone marrow, J. Cell Biochem., 112, 1844, 10.1002/jcb.23106

Aval, 2018, The effect of ketorolac and triamcinolone acetonide on adipogenic and hepatogenic differentiation through miRNAs 16/15/195: Possible clinical application in regenerative medicine, Biomed. Pharmacother., 97, 675, 10.1016/j.biopha.2017.10.126

Fakhry, 2013, Molecular mechanisms of mesenchymal stem cell differentiation towards osteoblasts, World J. Stem Cells, 5, 136, 10.4252/wjsc.v5.i4.136

Zhang, 2015, Exosomes in cancer: Small particle, big player, J. Hematol. Oncol., 8, 83, 10.1186/s13045-015-0181-x

Kumar, 2018, Acute myeloid leukemia transforms the bone marrow niche into a leukemia-permissive microenvironment through exosome secretion, Leukemia, 32, 575, 10.1038/leu.2017.259

Pinzone, 2009, The role of Dickkopf-1 in bone development, homeostasis, and disease, Blood, 113, 517, 10.1182/blood-2008-03-145169

Gustafson, 2010, Thiazolidinediones increase the wingless-type MMTV integration site family (WNT) inhibitor Dickkopf-1 in adipocytes: A link with osteogenesis, Diabetologia, 53, 536, 10.1007/s00125-009-1615-1

Veld, 2016, Abdominal adipose tissue in MGUS and multiple myeloma, Skeletal. Radiol., 45, 1277, 10.1007/s00256-016-2425-4

Chong, M., Yin, T., Chen, R., Xiang, H., Yuan, L., Ding, Y., Pan, C.C., Tang, Z., Alexander, P.B., and Li, Q.J. (2018). CD36 initiates the secretory phenotype during the establishment of cellular senescence. EMBO Rep., 19.

Oshima, 2005, Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2, Blood, 106, 3160, 10.1182/blood-2004-12-4940

Kwack, 2012, Dickkopf 1 promotes regression of hair follicles, J. Invest. Dermatol., 132, 1554, 10.1038/jid.2012.24

Lyros, 2014, Dickkopf-1, the Wnt antagonist, is induced by acidic pH and mediates epithelial cellular senescence in human reflux esophagitis, Am. J. Physiol. Gastrointest. Liver Physiol., 306, G557, 10.1152/ajpgi.00153.2013

Rani, 2018, Effect of Dickkopf1 on the senescence of melanocytes: In vitro study, Arch. Dermatol. Res., 310, 343, 10.1007/s00403-018-1820-1

Bajada, 2009, Decreased osteogenesis, increased cell senescence and elevated Dickkopf-1 secretion in human fracture non union stromal cells, Bone, 45, 726, 10.1016/j.bone.2009.06.015